JOURNAL CLUB GERMAN RECTAL CANCER TRIAL

1. Preoperative versus Postoperative
Chemoradiotherapy for Rectal
Cancer
Rolf Sauer, M.D., Heinz Becker, M.D., et al. for the German Rectal
Cancer Study Group
Volume 351:1731-1740 October 2004
GERMAN RECTAL CANCER TRIAL

2. HOW WE DISCUSS ANY CLINICAL
TRIAL
• BACKGROUND
• RATIONALE
• AIM
• OBJECTIVES:ENDPOINTS
• TRIAL METHODOLOGY
• RESULTS
• CONCLUSION
• DISCUSSION

3. BACKGROUND OF THE STUDY
In Rectal Cancer

4. LR following non TME Surgery averages approx. 25-30%

5. Total Mesorectal Excision (TME):
Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004

6. ADJUVANT THERAPY
Chemotherapy
Radiation
therapy
CTRTRT alone

9. Adjuvant Chemoradiation Therapy
Study Description Outcome
GITSG (1988)
Gastrointenstinal
study group
4 arm trial
S/S+RT/S+CT/S+CRT
227 patients B2 ,
10 yr OS 45 % vs 27%,LRR 10% vs 25%
Significant benefit with CRT
NCCTG 79-47-51
(NEJM 1991)
Stage II –III
RT alone or CRT
(5FUX2> 5FU +RT>
5FUX2) (50% APR)
5-yr LR 14% (CRT) vs 25%
5-yr DM 29% vs 46%
5-yr OS 55% vs 45%
NSABP R-01(1988) 3 arm RCT
500 patientsPT3/T4N+
S/S+CT/S+RT
S+CT: Improved DFS& OS
S+RT: Reduction in LRR 16% vs 25 % favouring RT
No survival benefit
NSABP -02 (1999) 2 arm RCT
Postop CT (5FU or
MOF)
postop CRT
PORT : no benefit on DFS or OS, reduced the at 5
yr-LRR (13% to 8%) (P = .02).
Post-op CT: benefit in DFS at 5 yr (55% vs 47%; P =
.009), 5-year OS (65% vs 62%; P = .17).

10. Postoperative Treatment In Rectal
Cancer
1990 NIH Consensus Statement:
• Combined postoperative chemotherapy and
radiation improves local control and survival in
patients with stage II and III rectal cancer and is
recommended

11. Preoperative treatment
Preoperative RT alone
Pre-operative chemoradiotherapy

12. Preoperative approach
 Pre-operative RT : rationale
o Tumour downstaging and improve resection,
o Better tolerance than postoperative RT
o Sphincter preservation

13. Short Course Preoperative Radiotherapy

14. Preoperative chemo-RT
Rationale
 improved compliance of preop RT
 Reduced toxicity of Preop chemo-RT than post op
 RT more effective pre op due to oxygenation
 Tumour downstaging and improve resection,
 Sphincter preservation
 Reduced local recurrence
 survival benefit

15. Preoperative chemoradiotherapy
Trial N (pt.) Randomisation Median
F/U
LR OS
French
study
cT3-4
cN+
733 Pre op CRT
45 Gy + 5FU & LV
f/b Sx
Preop RT f/b Sx
- 5yr
8.1%
Vs
16.5%
P - 0.048
5yr
NSS
EORTC
22921
4arm
study
1011 1.Pre op RT
Sx+/- CT
2. Pre op CRTSx
+/-CT
10.4 Yrs
(7.8-
13.1)
10yrs
22.4% vs
11.8% vs
14.5% vs
11.7%
P –0.0017
10yr
49%vs
50.7%vs
51.8%vs
48.4%
P – 0.91
Sauer R et al. German CAO/ARO/AIO-94 JCO 2012
Bosset J et.al. EORTC 22921 Lancet Oncol 2014

16. Aim of the study
• To compare preoperative chemoradiotherapy
with postoperative chemoradiotherapy for
the management of locally advanced rectal
cancer

17. OBJECTIVE ENDPOINTS
• Primary endpoints of the study are
 5-year overall-survival,
 Local control
 distant control
• secondary endpoints include
 rate of curative (R0) resections
 sphincter saving procedures
 toxicity of radio chemotherapy
 surgical complications
 quality of life.

18. Trial Methodology
• Enrolled patients February 1995 - September 2002.
Eligibility criteria
• Histopathologically confirmed, resectable adenocarcinoma with the inferior
margin within 16 cm from the anal verge.
 ERUS(endorectal USG) and CT scan of the abdomen and pelvis were performed
to rule out TNM stage I tumors and distant metastases.
Exclusion criteria:
• Age > 75 years of age.
• Previously had cancer other than nonmelanoma skin cancer.
• Previously received chemotherapy.
• Previously received Pelvic radiotherapy
• Contraindications to chemoradiotherapy.

19. Randomization
• After written informed consent had been obtained, eligible
patients were randomly assigned to receive either postop
CTRT or preop CTRT
• Randomization was performed by the study center in
Erlangen, Germany with stratification according to Surgeon.
• Beginning in October 1998, prerandomization according to
the double- consent design of Zelen was permitted at the
request of 16 of the 26 participating centers.

20. According to this design, informed consent is sought after the patient is told the
result of randomization that is whether pt. is in control group or intervention
group and, as suggested by the term “double,” the result of randomization is
disclosed to patients in both groups.
According to this design, data must be analysed according to the result of
randomization and any decisions made by patients to receive the alternative
treatment must be disregarded with respect to the analysis
ARM1:Post-op chemo-RT
ARM2:Pre-op chemo-RT

21. Arm 1:Post-op chemo-RT Arm 2:Pre-op chemo-RT

22. RADIATION THERAPY
Technique:
 Three or 4-field box technique.
 Include the entire tumor bed, the
perirectal, presacral and the internal iliac
nodal groups.
 superior border: L5/S1 junction.
 Inferior border: bottom of the obturator
foramen after LAR or includes the perineal
scar after APR resection.
 Anteriorly: dorsal wall of the bladder
 Posteriorly: the sacrum has to be included.
 The lateral margins : 1–2 cm lateral of the
linea terminalis.
Dose:
 ARM A:POST-OP RT:
50.4Gy/28#
@1.8Gy/#,5#/week. To
pelvis.+5.4Gy/3# boost to
tumour bed
 ARM B:PREOP RT :50.40
Gy/28# @1.8Gy/#,5#/week.
to pelvis

23. CHEMOTHERAPY
ADJUVANT CHEMOTHERAPY
• Four cycles of bolus 5FU (500mg/m2 /day, 5d/week, every
4wks) were started 4 weeks after surgery in preop ARM B or
4weeks after post-op Chemo-rt in ARM A
CONCURRENT CHEMOTHERAPY
• During the first and fifth weeks of radiotherapy, 5FU was
given as a 120-hour continuous infusion at a dose
of 1000 mg per square meter per day

24. SURGERY
• Total mesorectal excision(TME) was performed in all the
patients according to a standardized technique.
• To rule out potential bias with respect to the quality of
surgery and the commitment to sphincter preservation,
patients were stratified according to surgeon
• Assessment of the intended surgical procedure before
randomization (i.e., whether sphincter preservation was
deemed possible or not) was included to evaluate the efficacy
of preoperative chemoradiotherapy in permitting sphincter-
sparing surgery in patients with low-lying tumors.

25. FOLLOW-UP & ASSESSMENT OF TOXICITY
• DURING THERAPY:
 patients were monitored weekly for signs of acute toxic effects.
• AFTER THERAPY:
 Patients were followed at 3-month intervals for 2 years and then at 6-
month intervals for 3 years.
 long-term toxic effects were assessed at 1, 3 and 5-years.
• FOR CHEMOTHERAPY
 Acute and long-term toxic effects were graded according to a German
classification system (correspond to WHO criteria).
• FOR RADIOTHERAPY
 RTOG and EORTC criteria for acute and late toxicity used

26. Statistical analysis: sample size calculation
• The primary end point was overall survival.
• The study was designed to have 80 percent power to detect an absolute
difference of 10 % in 5-year OS rate, with a two-sided alpha level of 0.05.
• The sample size required to detect this difference was 340 patients
per group.
• Because an estimated 15 percent dropout rate was expected, the
enrolment period was extended to the end of September 2002, at
which point 823 patients had been enrolled
• Secondary end points were DFS, LR and DR, postoperative complications,
acute and long-term toxic effects, and sphincter preservation.
• All eligible and consenting patients were included in the analyses according
to the intention-to-treat principle.
• End points were measured beginning at the time of randomization.

27. Statistical test
 Chi-square tests were used to compare proportions.
 Survival anlysis were carried out by the K-M method.
 The Kaplan-Meier survival curve is defined as the probability of surviving in a given
length of time while considering time in many small intervals.
 The Cox proportional-hazards model was used to calculate hazard ratios and 95 %
CI.
 Hazard ratio is measure of how often a particular event happens in one group compared to another
group, over time
 Intention to treat analysis
 Once randomized always analysed
 A two-sided P value ≤ 0.05 was considered to indicate statistical significance.

28. RESULTS
First results were published after median
Follow up of 45.8 months.

29. Significantly more
patients in the preop
chemo-RT group than in
the postop chemo-RT
group had tumours
located 5 cm or less
from the anal verge
Most of baseline
characteristics of 799
patients were similar
in the two groups

30. 823 patients from 26 hospitals
Randomisation
402 pts POST-OP CHEMORT421 pts PREOP CHEMORT
16 pts not included in
analysis
 5 pts withdrew consent
 11 pts not meet inclusion
8 pts not included in analysis
 4 pts withdrew consent
 4 pts not meet inclusion
405 pts assigned & evaluated in
pre op treatment group
394 pts assigned & evaluated
in post op treatment group
9 pts requested a
change in treatment
group (signf)
19 patients requested a
change in treatment group
415 pts treated according to
the preoperative protocol
384 pts treated according to
the postoperative protocol

31. COMPLIANCE TO TREAMENT
• In the preoperative-treatment group, 92 percent received the prescribed
radiotherapy and 89 percent completed preoperative chemoradiotherapy as planned.
• In the postoperative-treatment group, 28 percent were excluded from receiving
postoperative chemoradiotherapy according to the protocol specifications, either
because of stage I disease (18 percent) or because of intraoperatively detected
distant metastases or postoperative complications or death (10 percent).

32. PROTOCOL VIOLATION
Protocol violations occurred more frequently in the
postoperative-treatment group and were mainly due to
patients’ refusal to receive radiotherapy or chemotherapy

33. Histopathological tumour staging
• After preoperative chemoradiotherapy, there was a significant shift toward
earlier TNM stages (P<0.001):
• 8 percent of the patients in this group had a complete response, only 25 percent
(as compared with 40 percent in the postoperative-treatment group) had
positive lymph nodes (TNM stage III)

34. The rates of complete resection and sphincter sparing
surgery did not differ between the group
TYPE OF SURGERY

35. among 194 patients with tumours that were determined by the surgeon before
randomization to require an abdominoperineal excision, a statistically significant increase
in sphincter preservation was achieved among patients who received preoperative
chemoradiotherapy

36. Postoperative morbidity did not
differ significantly between the
groups.
• In-hospital mortality was 0.7 percent in the preoperative
chemoradiotherapy group and 1.3 percent in the postoperative-
treatment group P=0.41).
• overall rate of postop complications:36 percent in the preoperative-
treatment group and 34 percent in the post operative treatment
group (P=0.68).
• rate of anastomotic leakage 11 percent in the preoperative and 12
percent in the postoperative-treatment group (P=0.77).
• rates of delayed sacral-wound healing 10 percent in the
preoperative vs. 8 percent in the postoperative P=0.10
• postop bleeding 3 percent vs. 2 percent p=0.50
• Postop ileus 2 percent vs. 1 percent, respectively; P=0.26

37. Toxicity of chemoradiotherapy
The overall rates of acute and long term side effects were lower with the preoperative
than with the postoperative (27% vs 40%)
especially with respect to acute and chronic diarrhea
and the development of strictures at the anastomotic site.

38. Overall survival:
HR for death
0.96 , 95 % CI
OS at five years was 76 percent in the preoperative-
treatment group and 74 percent in the postoperative-
treatment group (P=0.80)
OS among the 799 Patients Randomly Assigned to Preoperative or
Postoperative Chemoradiotherapy, According to an Intention-to-Treat Analysis.
Follow-up data were available for 781 patients.

39. DFS:
HR 0.87 , 95 %
CI
68 percent in the preoperative-treatment group and 65 percent in
the postoperative-treatment group (P=0.32)
verall Survival (Panel A) and Disease-free Survival (Panel B)
among the 799 Patients Randomly Assigned to Preoperative or
Postoperative
Chemoradiotherapy, According to an Intention-to-Treat Analysis.
Follow-up data were available for 781 patients.
DFS among the 799 Patients Randomly Assigned to Preoperative or
PostoperativeChemoradiotherapy, According to an Intention-to-Treat Analysis.
Follow-up data were available for 781 patients.

40. Local recurrences
The cumulative incidence of local recurrences at five years was 6 percent in the
group assigned to preoperative chemoradiotherapy and 13 percent in the group
assigned to postoperative chemoradiotherapy (P=0.006)

41. Distant recurrences
The cumulative incidence of distant recurrences at five years was 36 percent in the
preoperative-treatment group and 38 percent in the postoperative-treatment
(P=0.84)

42. Update analysis- 11 years follow up
J Clin Oncol 30, 2012

43. OS benefit: non significant
The overall survival at 10 years in the intention-to-treat population was 59.6% (95% CI,
54.9% to 64.7%) in the preoperative arm and 59.9% (95% CI, 55.2% to 65.1%) in the
postoperative arm (P=0.85)

44. Local Recurrence: significant

45. LR
Preop CRT
Post op CRT
Post op:no CRT

46. Multivariate Cox regression
analysis for local recurrence
revealed that
• incomplete local resection
(R1)
• not receiving CRT at all
were significantly associated
with a higher LR risk

47. Distant Recurrence: not significant

48. forest plot analysis showed increased HRs for local recurrences for almost all subgroups
for patients actually treated with postoperative as compared with preoperative CRT
with the strongest difference in patients who had surgery involving intersphincteric or
APR

49. CONCLUSION
• In conclusion, although no survival benefit was
achieved with preoperative as compared with
postoperative chemoradiotherapy,
• Trial suggest that preoperative chemoradiotherapy is
the preferred treatment for patients with locally
advanced rectal cancer, given that it is associated with
 superior overall compliance rate,
 an improved rate of local control,
 reduced toxicity,
 increased rate of sphincter preservation in patients
with low-lying tumors.

50. DISCUSSION

51. COMPLIMENT
• RCT comparing preop chemoradiotherapy with that of postoperative
chemort for rectal cancer were initiated in the United States by the RTOG
(trial 94-01) and the NSABP(protocol R-03).
• Unfortunately, both studies suffered from low enrolment and were
closed prematurely.
• preop chemoradiotherapy, given as planned (i.e., without any modification
or dose reduction) in most of the patients assigned to this group (89
percent), significantly reduced rates of local failure and acute and long-
term toxic effects.
• Among patients with tumors judged by the surgeon to require an
abdominoperineal excision, the rate of sphincter-preserving surgery was
more than doubled after preoperative chemoradiotherapy.
• Postponing surgery for a six-week course of neoadjuvant treatment plus a
six-week interval to allow tumor shrinkage and recovery from side effects
did not result in an increased rate of surgical complications or an
increased incidence of tumor progression.

52. Comment
 With the increasing use of preoperative treatment in patients with
rectal cancer, accurate staging is needed to avoid unnecessary
treatment of early-stage tumors.
 Our trial was designed to show an absolute difference of 10
percentage points in overall survival between standard
postoperative and preoperative chemoradiotherapy.
• However the results show no statistically significant difference in
the incidence of distant recurrence or in the rates of disease-free or
overall survival could be demonstrated.
• Given that the rate of local recurrence with preoperative
chemoradiotherapy and total mesorectal excision was only 6
percent, it is possible that further progress in the prevention of
distant recurrences might be accomplished with more effective
chemotherapy

53. Criticism: lack of data
• The study reported by Sauer et al. is
commendable in that it confirms the theoretical
advantages of adding preoperative chemotherapy
to preoperative radiotherapy for the treatment of
rectal cancer.
• However table 1 shows lack of proper data
maintenance
• The reason for this lack of data is unclear,
especially since the enrolment criteria specifically
include this measurement.

54. • in 75 patients distance
of the tumor from the
anal verge was unknown
(may have included anal
canal & sigmoid colon
cancer)
• in about one fourth of
the patients,stage was
unknown;
• in about 7 percent, the
nodal status was
unknown.
Criticism: lack of data

55. According to Table 2 92 percent and 89 percent of the patients assigned to
preoperative chemoradiotherapy received full doses of radiotherapy and
chemotherapy, respectively, as compared with 54 percent and 50 percent of the
patients assigned to postoperative chemoradiotherapy.
Criticism: protocol violation & compliance

56. Criticism: protocol violation & compliance
• Results show that preoperative chemoradiotherapy, as
compared with postoperative chemoradiotherapy,
significantly improves local control
• However, the improved rate of local control achieved with
the preoperative approach could have resulted from the
higher percentage of patients in that group who received
full doses of radiotherapy and chemotherapy
• thus may not constitute clear evidence that the
preoperative strategy reduces local failure.
• This observation could be extended to other end points
examined, considering that the authors found no
statistically significant difference in the incidence of distant
recurrences or in the rates of disease-free and overall
survival between the two groups

57. Criticism: sphincter preservation
• Sauer et al. conclude that preoperative chemoradiotherapy increases the rate
of sphincter preservation.
• However, the trial was not designed to address this issue.
• The benefit with respect to sphincter preservation was found only in the
subgroup of patients in whom abdominoperineal resection was deemed
necessary.
• There was no stratification according to this factor.
• The analysis of sphincter preservation was performed not according to the
intention-to-treat principle but according to the actual treatment given.
• More patients in the postoperative-treatment group than in the preoperative-
treatment group requested a change in their assigned treatment (19 patients
vs. 9 patients, P=0.05).
• This difference may explain, at least in part, the imbalance in the numbers of
patients who underwent abdominoperineal resection (116 in the preoperative-
treatment group and 78 in the postoperative-treatment group).

59. • The authors do not mention two randomized
trials(EORTC & MRC ) designed to investigate
whether shrinkage of tumors after preoperative
radiotherapy, with or without chemotherapy,
increases the rate of anterior resection in both,
the difference in the rate of sphincter
preservation was statistically nonsignificant
• The surgeon's willingness to modify the operation
in cases with tumor shrinkage is of pivotal
importance in this respect.

60. Criticism: over treatment in stage 1 & 4
 in the postoperative-chemoradiotherapy group 18% pt were found to have stage
I disease, and about 10 percent were found intraoperatively to have distant
metastases
Because of the randomized assignment to treatment, it is reasonable to assume
that there were similar percentages of patients with stage I and stage IV disease —
patients who were not likely to derive any benefit from chemoradiotherapy — in the
preoperative group were also treated
 These pt. can be spared by unnecessary toxic effects if post op Chemo RT chosen

61. Traditionally, patients with stage I disease and patients with distant metastases
have been considered ineligible for postoperative radiotherapy.
The Swedish Rectal Cancer Trial, however, demonstrated that preoperative
radiotherapy significantly improved local control even in patients with stage I rectal
cancer.
Preoperative radiotherapy may also be beneficial for patients with early-stage
tumors within the lower part of the rectum when sphincter-preserving surgery is
attempted.
Likewise, for those with stage IV disease, survival times have been dramatically
increased in recent years through the use of more effective systemic
chemotherapy.
Thus, sustained local control has become important in this group of patients too.
Over treatment in stage 1 & 4:may be required

62. THANK YOU