The Stockholm III Trial on Different Preoperative Radiotherapy Regimens in Rectal Cancer

Rectal Cancer Clinical Trial

— Stockholm III  

Official title:

A Prospective Randomized Trial on Different Preoperative Radiotherapy Regimens in Rectal Cancer, Stockholm III.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00904813
• Other study ID #: 98/240
• Status: Completed
• Phase: N/A
• Start date: November 1998
• Est. completion date: March 31, 2018

Study information

• Verified date: April 2021
• Source: Karolinska Institutet
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Preoperative radiotherapy (RT) is recommended to many patients with localised rectal cancer, not previously treated with pelvic RT. However, the optimum fractionation, the timing of surgery and the best use of concomitant chemotherapy remains controversial. There are theoretical reasons to believe that radiotherapy given in larger fractions during a shorter period of time might result in more late side effects than giving a conventional, more protracted RT in patients with rectal cancer. In addition, the optimum timing of surgery after RT, with respect to postoperative morbidity, mortality and potential downsizing of the tumour is not known. To address these questions, a prospective randomized multicenter trial was initiated, the Stockholm III trial, in which patients with primarily resectable rectal cancer were randomized to short-course preoperative RT (5x5 Gy) followed by surgery within one week or after 4-8 weeks or long-course preoperative RT(25x2 Gy) followed by surgery after 4-8 weeks.

Description:

840 participants (men and women) with a biopsy verified adenocarcinoma of the rectum scheduled for an open abdominal procedure were enrolled at 18 Swedish Hospitals during 1998-2013. In the initial protocol patients were randomly assigned (1:1:1) between three different RT courses; 5x5 Gy with surgery within 1 week (SRT), 5x5 Gy with surgery after 4-8 weeks (SRT-delay) or 25x2 Gy during 5 weeks without concomitant chemotherapy and surgery after 4-8weeks (LRT-delay). After a protocol amendment on May 21, 1999, participating hospitals could choose to randomise patients to just the short-course radiotherapy arms (1:1) or to all three arms. Randomisation was done by telephone by the Regional Cancer Centre in Stockholm, Sweden, after assessing inclusion and exclusion criteria. Computer generated randomisation lists were constructed by use of permuted block technique (block size of six for the three- arm randomisation, block size of four for the two-arm randomisation) and stratified by participating center. Investigators and patients were not masked to treatment. Follow-up was recommended at 3-, 6- and 12 months after surgery, and yearly thereafter. Although follow-up according to national guidelines with a minimum follow-up at 1 and 3 years was allowed. Patient data was also collected from the Swedish ColoRectal Cancer Register (SCRCR) and medical records. Primary outcome: 1. Time to local recurrence. Secondary outcomes: 1. Recurrence-free survival 2. Frequency of postoperative complications 3. Frequency of tumour regression

Recruitment information / eligibility

• Status: Completed
• Enrollment: 840
• Est. completion date: March 31, 2018
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Biopsy confirmed clinically resectable rectal adenocarcinoma within 15 cm from the anal verge
• Planned for bowel resection with an abdominal procedure.
• Informed consent.

Exclusion Criteria:

• Distant metastases
• Locally advanced unresectable tumors
• Planned for local excision
• Previous radiotherapy to the abdominal or pelvic region
• Severe ischemic heart disease or symptoms of severe arteriosclerosis

Related Conditions & MeSH terms

• Rectal Cancer
• Rectal Neoplasms

Intervention

Radiation:
• Short-course RT
Preoperative radiotherapy (RT) given 5 times 5 Gray during five consecutive days, preferably Monday - Friday, with a four-field box technique, including the primary tumour and the primary and secondary lymph nodes in the pelvis.
• Long-course RT
Preoperative radiotherapy (RT) given 2 Gy in 25 fractions during 5 weeks, total dose 50 Gy with a four-field box technique, including the primary tumour and the primary and secondary lymph nodes in the pelvis.

Locations

Country	Name	City	State
Sweden	Danderyds Hospital	Danderyd	Stockholm
Sweden	Eskilstuna Hospital	Eskilstuna
Sweden	Falun Hospital	Falun
Sweden	Gävle Sjukhus	Gävle
Sweden	Helsingborg Hospital	Helsingborg
Sweden	Linköping University Hospital	Linköping
Sweden	MAS University Hospital	Malmö
Sweden	Mora Hospital	Mora	Dalarna
Sweden	Vrinnevi Hospital	Norrköping
Sweden	Norrtälje Hospital	Norrtälje	Stockholm
Sweden	Södertälje Hospital	Södertälje	Stockholm
Sweden	Ersta Hospital	Stockholm
Sweden	Karolinska University Hospital	Stockholm
Sweden	South Hospital	Stockholm
Sweden	St Görans Hospital	Stockholm
Sweden	Norrlands Universitetssjukhus	Umeå
Sweden	Uppsala University Hospital	Uppsala
Sweden	Visby Hospital	Visby

Sponsors (3)

Lead Sponsor	Collaborator
Karolinska Institutet	Swedish Cancer Society, The Swedish Research Council

Country where clinical trial is conducted

Sweden, 

References & Publications (6)

Erlandsson J, Holm T, Pettersson D, Berglund Å, Cedermark B, Radu C, Johansson H, Machado M, Hjern F, Hallböök O, Syk I, Glimelius B, Martling A. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a — View Citation

Erlandsson J, Lörinc E, Ahlberg M, Pettersson D, Holm T, Glimelius B, Martling A. Tumour regression after radiotherapy for rectal cancer - Results from the randomised Stockholm III trial. Radiother Oncol. 2019 Jun;135:178-186. doi: 10.1016/j.radonc.2019.0 — View Citation

Erlandsson J, Pettersson D, Glimelius B, Holm T, Martling A. Postoperative complications in relation to overall treatment time in patients with rectal cancer receiving neoadjuvant radiotherapy. Br J Surg. 2019 Aug;106(9):1248-1256. doi: 10.1002/bjs.11200. — View Citation

Pettersson D, Cedermark B, Holm T, Radu C, Påhlman L, Glimelius B, Martling A. Interim analysis of the Stockholm III trial of preoperative radiotherapy regimens for rectal cancer. Br J Surg. 2010 Apr;97(4):580-7. doi: 10.1002/bjs.6914. — View Citation

Pettersson D, Glimelius B, Iversen H, Johansson H, Holm T, Martling A. Impaired postoperative leucocyte counts after preoperative radiotherapy for rectal cancer in the Stockholm III Trial. Br J Surg. 2013 Jun;100(7):969-75. doi: 10.1002/bjs.9117. Epub 2013 Apr 2. — View Citation

Pettersson D, Lörinc E, Holm T, Iversen H, Cedermark B, Glimelius B, Martling A. Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br J Surg. 2015 Jul;102(8):972-8; discussion 978. doi: 10.1002/bjs.9811. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Local Recurrence.	Local recurrence was defined as tumour growth below the level of the sacral promontory, related to the previous rectal cancer, and diagnosed radiographically with MRI, CT, or both, or clinically (preferably with histological confirmation). A diagnosis of local recurrence was confirmed and reported by the patient-responsible physician to the Swedish ColoRectal Cancer Registry (SCRCR), a nationwide validated national registry. Local recurrence was measured both as first and any event occurring during follow-up (censoring date March 30 2015), when all patients had been followed for at least 2 years.	From date of randomisation until date of local recurrence or date of death from any cause, whichever came first, assessed up to end of follow-up.
Secondary	Number of Participants With Postoperative Complications in Relation to Preoperative Radiotherapy Regimen and Overall Treatment Time.	Postoperative complications was defined as any cardiovascular event, infectious, neurological or surgical complications occurring within 30 days after surgery, or during the same hospital admission, validated from medial records. Overall postoperative complication was defined as having at least one postoperative complication. Participants were grouped based on type of preoperative radiotherapy (RT) regimen (eg short- or long course) and overall treatment time (OTT), defined as time between start of RT and surgery. Participants receiving short-course RT were categorised into four different groups; Group A: OTT 7 days, Group B: OTT 8-13 days, Group C: OTT 5-7 weeks, Group D: OTT 8-13 weeks. Participants receiving long-course RT were categorised into two different groups; Group E: OTT 9-11 weeks, Groups F: OTT 12-14 weeks.	From surgery until 30 days postoperatively.
Secondary	Tumour Regression Based on the Dworak Grading Scoring System	Tumour regression (TRG) was assessed using the Dworak grading scoring system, ranging from scores 0 to 4 with higher scores indicating better tumour regression. Definition of scores; 0 = no regression, 1 = dominant tumour mass with obvious fibrosis and/or vasculopathy, 2 = dominantly fibrotic changes with few tumour cells or groups (easy to find), 3 = very few (difficult to find microscopically) tumour cells in fibrotic tissue with or without mucous substance, 4 = no tumour cells, only fibrotic mass (total regression or complete response). All available microscopy slides were assessed by one pathologist, blinded to treatment.	At the time of surgery.