IT IS THE LANDMARK TRIAL IN THE CARCINOMA RECTUM. IT COMPARES SHORT COURSE VERSUS LONG COURSE RADIOTHERAPY . ALSO COMPARED TIMING OF SURGERY.

1. Johan Erlandsson, Torbjörn Holm, David Pettersson, Åke Berglund, Björn Cedermark, Calin
Radu, Hemming Johansson , Mikael Machado, Fredrik Hjern, Olof Hallböök, Ingvar Syk,
Bengt Glimelius, Anna Martling
Optimal fractionation of preoperative radiotherapy and
timing
to surgery for rectal cancer (Stockholm III): a
multicentre,
randomised, non-blinded, phase 3, non-inferiority trial
Lancet Oncol 2017
Published : February 9, 2017
Dr Pallavi Jain
Junior resident
IMS , BHU

2. Introduction
• PORT reduces the risk of local recurrence after surgery for rectal cancer by more
than 50%, even with optimised total mesorectal excision surgery.
• Conventionally fractionated long-course radiotherapy (ie, 5# of 1·8–2 Gy per wk
during 5–6 wks), most often in combination with chemotherapy, has been the
predominant t/t in most countries.
• Short-course radiotherapy (ie, 5# of 5 Gy in 1 week [5×5 Gy]), and surgery within
the following wk has been commonly used in Sweden and in some other
countries in northern and western Europe.
• However, the optimal fractionation and timing of sx in relation to RT is still
controversial.

3. • Short-course radiotherapy with surgery delayed for 4–8 weeks (short-course
radiotherapy with delay) is an alternative t/t option that might lead to fewer p/o
complications and enhance tumour regression which could facilitate surgery.
• These three regimens, without concomitant chemotherapy, have never been
compared in a prospective randomised trial and the effects on tumour
response, local recurrence, radiation toxicity, and p/o complications are still
contentious.
• The Stockholm III trial aimed to compare these 3 different schedules of
radiotherapy (short-course RT, short-course RT with delay, and long-course
RT with delay) in pts with primary adenocarcinoma of the rectum.

4. Two preplanned interim analyses have shown that pts in the short-course
radiotherapy with delay group had a lower pathological tumour stage, a higher
proportion of pts achieving a complete pathological response, and a greater
degree of tumour regression than did patients in the short-course radiotherapy
group.

5. Locating the study
TYPE Phase III randomized
Institution Multicentric(Sweden) - 18
period Oct 5, 1998 -Jan 31, 2013
Total number of patient 840
Clinical trial registration NCT00904813
Median follow up period 5.7 years
Analysis type Intention to treat

6. Methods
•Pretreatment assessment
• Physical examination
• Rigid rectoscopy and colonoscopy
• CT or MRI of the pelvis
• Chest radiography
• CT and/or ultrasonography of the liver.
•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.

7. • Exclusion criteria :
• Distant metastases
• Locally advanced unresectable tumour
• Planned for local excision
• Previously RT to the abdominal or pelvic region
• Severe ischaemic heart disease or symptoms of severe arteriosclerosis
• The study was approved by the ethics committees at the Karolinska
Institute and at all participating hospitals.

8. Randomization and masking
• Patients were randomly assigned (1:1:1) to :
• short-course RT (5 × 5 Gy) with sx within 1 wk (SRT)
• short-course RT (5 × 5 Gy) with sx after 4–8 wks (SRT with delay)
• long-course RT (25×2 Gy) with sx after 4–8 wks (LRT with delay)

9. • After a protocol amendment on May 21, 1999, participating hospitals could
choose to randomise pts to just the SRT arms (1:1) or to all 3 arms.
• Hospitals participating in 3- armed comparison could randomize individual
pts into 2-armed comparison if the pt did not give informed consent for
LRT or if the radiotherapy department could not guarantee t/t within a
reasonable time frame.
• Randomisation was done by telephone by the Regional Cancer Centre in
Stockholm, Sweden.

10. Procedures
• Preoperative staging included assessment of local tumour extent and
distant metastases.
• During the first years, 1998–2003, staging methods varied between
hospitals, but after 2003, pelvic MRI and CT of the liver and chest became
standard at all hospitals, replacing the previous use of chest radiography
and ultrasound of the liver.

11. Preoperative radiotherapy
• Dose:
• SRT (5 × 5 and 5 × 5ds groups) received a total dose of 25 Gy over 5
consecutive days
• LRT (25 × 2 ds group) total dose of 50 Gy with a daily fractional dose of
2 Gy in 25 fractions over 5 wks
• Four-field box technique
• Lower limit : 3–4 cm above the anal verge or at least 5 cm below the lowest
part of the visible tumour.
• Upper beam limit: At mid L5, or 1–1·5 cm above the promontory.
• Dorsal limit: behind the sacrum
• Anterior limit: sufficiently ventral to cover the obturator nodes, the entire
mesorectum with tumour extension and the internal iliac nodes.
• Lateral limits: 1–1·5cm outside the pelvic rim.

12. • In the early years of the study, no individual tumour target was
drawn, but this practice became more common with time at most
centres.
• The anal canal was included in the target volume only if an
abdominoperineal resection (APR) was planned.
• Appropriate shielding of non-target volumes was prescribed.
Individual 3-D dose planning of the tumour target volume and
multileaf collimators were used at some hospitals during the
latter part of the study.

13. Surgery
• Pts underwent :
• Anterior resection
• APR
• Hartmann’s procedure.
• The standard operation included TME, defined as removal of the
rectum with the entire mesorectum by sharp dissection along the
mesorectal fascia down to the pelvic floor.
• Patients randomized to the 5 × 5 group were scheduled for surgery 1
– 7 days after the completion of RT. In the delayed surgery groups
operation was planned for 28 – 56 days after the completion of RT.
• Bowel preparation, and antiseptic and antithrombotic prophylaxis
were administered according to local routines.

14. Pathology
• The pathology report included information :
• Tumour size
• Depth of invasion
• Extension in relation to the circumferential resection margin of the mesorectum
• Involvement of regional lymph nodes, vessel and nerve invasion
• Tumour differentiation.
• Tumours were classified according to the tumour node
metastasis staging system.
• Surgery was defined as curative if all macroscopic tumour was
removed, no distant metastases were found and the pathologist
reported tumour-free margins in the specimen.

15. Follow-up
• Follow-up, which included local recurrence, distant metastases, and
adverse events, using chest radiograph or CT scan of the chest and CT
scan of the abdomen or MRI was used if there was a suspicion of local
recurrence and endoscopy was used at the discretion of the treating
physician
• Duration: 3 months, 6 months, and 12 months after surgery, and yearly
thereafter, although follow-up according to the national guidelines with a
minimum follow-up at 1 year and 3 years was allowed.
• All follow-up was done in person or by telephone contact with the patient
and recorded in the registry.

16. OUTCOMES:
• Primary end points:
• Time to local recurrence
• Secondary end points:
• Overall survival
• Acute and late toxicity
• Postoperative morbidity
• Quality of life

17. Primary Outcome Measures:
1. Time to Local Recurrence-
Time Frame: 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.
Definition: 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).
Local recurrence was measured both as first and any event occurring
during follow-up (censoring date March 30 2015), when all pts had
been followed for at least 2 yrs.
Outcomes measures

18. Secondary Outcome Measures
1.Overall survival :
Time Frame: Date of randomisation until death from any cause or
emigration
2. Number of Participants With Postoperative Complications in
Relation to Preoperative Radiotherapy Regimen and Overall Treatment
Time.
Time Frame: From surgery until 30 days postoperatively.
Postoperative complications was defined as any cvs event, infectious,
neurological or surgical complications occurring within 30 days after
sx, or during the same hospital admission, validated from medial
records.
Overall postoperative complication was defined as having at least one
postoperative complication.

19. 3. Late complications and late RT toxicity:
Time frame: minimum of 30 days after sx
Defined as bowel obstruction, pelvic abscess, anal incontinence, anastomotic
or stomal complication, incisional hernia, sexual dysfunction, urinary problem,
pelvic insufficiency fracture, or other (fistula, PID, and severe perineal or
pelvic pain), and reported by the responsible surgeon.
4. Acute RT toxicity:
Analysis of acute radiation toxicity was not stated as a secondary outcome in
the original protocol; however, this was considered an important factor in
relation to p/o complications and was analysed as a matter of safety.
Defination: unplanned patient admission to hospital with symptoms of
radiation side-effects, corresponding to the RTOG scales 3–4, between RT
initiation and the date of sx.
Secondary Outcome Measures

20. Trial Profile
Between Oct 5, 1998 - Jan 31, 2013, 840 pts were recruited from 18 hospitals in Sweden.

21. WHY Two arm ???
Hospitals that chose to participate in only the two-arm
randomisation generally did so for logistical reasons, such as
insufficient radiotherapy capacity during parts of the year,
patients not consenting to be randomised to long-course
radiotherapy with delay, or hospital preference to take part only in
the two-arm randomisation.

22. Deviations from protocol
74 (9%) patients had a protocol violation.
Deviations from protocol were:
• no radiotherapy (seven patients [<1%]),
• different fractionation schedule than random assignment (17 patients [2%]),
• incorrect interval between radiotherapy and surgery (61 patients [7%]),
• no abdominal surgery (three patients <1%),
• combination of the above :
• 3 pts (<1% all in long-course radiotherapy with delay)
• 2 pts with deviant radiotherapy (other than randomised to) no surgery
• 1 pt with no radiotherapy and no surgery
• No patient had distant metastases detected at the time of
randomisation; however, 15 patients (2%) had metastases detected
at the time of surgery and remained in the analyses.

23. PATIENT CHARACTERISTICS
Higher number of patients with a greater tumour height in the LRT with delay
group compared with other groups, which could account for the higher number
of pts who had an anterior resection in that group.

24. • Median follow- up time for all patients was 5∙2 years (range 2∙0–14∙6).
Adjuvant
chemotherapy
15%
SHORT COURSE
RT
13%
SHORT COURSE
RT WITH DELAY
13%
LONG COURSE
RT WITH DELAY
19%
Frequency of adjuvant chemotherapy was not significantly
different between the groups.

25. Outcomes Short course RT Short course rt with delay Long course rt with delay
Median interval between
start of radiotherapy and
surgery
8 days 47 days 76 days
Median time from local
recurrance
28.3 months 22.1 months 33.3 months
5 yr OS 73% 76% 78%
5 yr Recurrance free
survival
65% 64% 65%

26. No significant difference between treatment groups was noted for cumulative incidence of local recurrence,
the cumulative incidence of distant metastases, overall survival, or cumulative incidence of intercurrent
death.

27. Two Arm Randomisation
• When patients randomly assigned to short-course SRT or SRT with delay
were analysed separately according to whether they were part of the 3-
arm or 2-arm randomisations, no differences in local recurrence, distant
metastases, overall survival, or recurrence-free survival were noted.
Outcomes Short course RT Short course rt with delay
Median interval between start of
radiotherapy and surgery
8 days 45 days
Median time from local recurrence 33.3 months 19.3 months
5 yr OS 76% 77%
5 yr Recurrence free survival 65% 68%

28. • 30-day mortality for all patients was less than 1% (six patients);
deaths occurred in :
• 2 pts after SRT(cause : MI)
• 3 after SRT with delay(cause 2: MI, 1 pt: respiratory failure)
• 1 after LRT with delay( cause: unknown)
• None of the causes of death was judged to be a consequence of
allocated treatment.
• 30 patients (4%) were admitted to hospital due to acute radiation
toxicity. The two most common reasons for admission were
diarrhoea (11 [37%] of 30 pts) and abdominal pain (7 [23%] of 30
pts).
• No patient died due to radiation toxicity during the interval from
start of radiotherapy to surgery.

29. • MC P/O complication was surgical-site infection.
• P/O and surgical complications did not differ b/w t/t groups in the 3-
arm randomisation but significantly fewer surgical and overall
complications were reported after SRT with delay in 2- arm
randomisation.
• Frequency of reoperation was not significantly different between t/t
grps in either 3-arm randomisation or the pooled comparison.
SRT SRT with delay

30. • The most common late complication was bowel
obstruction and pelvic abscesses.
• No significant differences between grps were noted in
the 3-arm randomisation or in the short-course
radiotherapy comparison in terms of late complications.
Late complications

31. DISCUSSION
• In this multicentre, randomised, non-inferiority trial, no
significant differences between 3 different preoperative
radiotherapy regimens for rectal cancer were observed
regarding time to local or distant recurrence, recurrence-free
survival, or overall survival.
• By delaying surgery for 4–8 wks after the end of SRT, a
significantly lower frequency of P/O complications was reported;
however, radiation toxicity required admission to hospital in
about 7% of these patients.
• The strength of this study is the randomised, controlled design.

32. LACUNAS OF STUDY
1. Due to insufficient resources for RT at certain hospitals, and
concerns about the LRT-delay schedule, the possibility of a two-
armed randomisation was introduced as a protocol amendment
after about a year -> alteration resulted in an imbalance of patients,
with fewer patients enrolled in the LRT with delay grp.
• To address this imbalance, and any potential selection bias, analyses were
done in the three-arm randomisation population in accordance with the initial
protocol, as well as in the population of patients included in either of the short-
course RT groups from both randomisations.

33. 2.
Study took long time to complete. During the prolonged study period,
the local recurrence rate on a population basis decreased from 15% to
about 5%.This improved local control was anticipated after about a year
of patient inclusion and a revision of the power calculations and
outcomes was done as a protocol amendment; however, the primary
endpoint and sample size was not adjusted.

34. 3.
In the beginning of the study, pts with early-stage tumours (T1–T2) could be
included, provided abdominal surgery was planned, but since the implementation
of MRI in 2003 there was a shift in t/t indications for RT based on the concept
“good”, “bad”, and “ugly” tumours.
Acc to this concept:
“good” tumours are treated with surgery alone,
“bad” tumours with radiotherapy and surgery,
“ugly” tumours with chemoradiotherapy and surgery.
Thus, during most of the study period, only pts with “bad” or “intermediate risk”
tumours were included in the trial.
Although 25–30% of the pts had pathological stage I disease, with a low risk of
local relapse, the stage distribution was not fundamentally different from other
radiotherapy or chemoradiotherapy trials in rectal cancer.

35. 4.
Since the trial was initiated, several studies have shown that
whenever LRT with delay is considered it should be given with
concomitant chemotherapy to improve local control.
No concomitant chemotherapy was given in this trial.

36. • Our trial shows similar oncological and safety outcomes btw SRT
and SRT with delay. Short-course radiotherapy with delayed surgery
has also previously been reported to be well tolerated and to induce
complete pathological responses.
• In the groups with a delay to surgery, about 6% of patients
developed estimated grade 3–4 radiation-induced toxicity. Because
of the very short interval btw RT and Sx in the short-course
radiotherapy group, the radiation toxicity is probably obscured by
early P/O complications, therefore the relative frequency of toxicity
should be interpreted with caution.
• After a follow-up of 5 years, delaying surgery for 4-8 weeks after
radiotherapy treatment with 5 × 5 Gy was oncologically safe.
Long-term HRQoL was similar among the treatment arms.

37. • Distant metastasis is now the major cause of rectal cancer
relapse.
• Studies indicate that a delayed start of adj CTH due to P/O
complications might have a negative impact on survival. A
concern with delaying Sx after RT is that it will have a similar
effect as delayed adjuvant treatment.
• In this trial, a small number of pts were treated with adj CTH,
thus why it is not possible to exclude a negative influence on
survival. However, the benefit of adj CTH in patients with rectal
cancer treated with radiotherapy or chemoradiotherapy
preoperatively is highly controversial.
• On the other hand, a possible benefit of SRT with delay is that
upfront chemotherapy can be given to patients with a high risk
of distant metastases during the waiting time after the end of
RT.

38. • This concept has been studied in the recently closed RAPIDO trial
and in a recently published Polish trial. Results from the RAPIDO
trial are not yet available but the Polish trial reported improved
tolerability and improved survival after SRT f/b consolidation
chemotherapy compared to conventional chemoradiotherapy.
• The present aim in rectal cancer treatment must be to maintain a low
rate of local recurrence, minimise the risk of early and late treatment
toxicity and postoperative complications, and to address the problem
of distant disease. This might be achieved with short-course
radiotherapy with delay and chemo-therapy in the period between
radiotherapy and surgery.

39. CONCLUSION
• SRT with surgery delayed for 4–8 weeks might have certain advantages
over immediate surgery in rectal cancer treatment.
• Oncological outcomes seem similar to SRT with sx within a week; acute
radiation toxicity is observed but the p/o complications are significantly
fewer.
• SRT with delay also gives an opportunity to optimise pts, such as to cease
smoking, initiate an individualised training programme, adjust blood
pressure, provide nutritional support or other medical interventions, and
plan surgery well in advance.
• LRT with delay seems to be no different than short-course radiotherapy
with delay, but prolongs the treatment time substantially.