preoperative radiotherapy and chemotherapy in locally advanced cancer rectum, short course radiotherapy versus long course CTRT

1. Journal club
Rectal Cancer: Preoperative
Management
Presenter: Dr. Gaurav Kumar

2. Introduction

3. Local Recurrence Following Surgery Alone:
Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004

4. MDTSurgery
Radiation
Therapy
Systemic
Therapy
Imaging
Psychologist
&
Rehabilitation
Need for Multidisciplinary approach

5. Pre-op RT vs. surgery alone
Swedish Rectal Cancer Trial (NEJM 1997;336:980 ): 1168 patients randomised
to 25 Gy (5x5) PRT or no RT.
Surgery alone Preop. RT
Rate of local recurrence 27% 11% p<0.001
5-year overall survival 48% 58% p=0.004
Dutch Colorectal Cancer Group (Kapiteijn E. NEJM 2001;345:638): 1861
patients randomised TME vs PRT+TME
TME PRT+TME
Recurrence rate 2.4% 8.2%
OS ns ns

6. Pre-op vs. post-op Chemo RT
Randomized trial of the German Rectal Cancer study Group
(Sauer R et al. N Engl J Med 2004;351:1731-40):
– cT3 or cT4 or node-positive rectal cancer
– 50.4 Gy (1.8 Gy per day)
– 5-FU: 1000 mg/m2 per day (d1-5) during 1. and 5. week
Preop CRT Postop CRT
Patients N=415 N=384
5 y. OS 76% 74% p=0.8
5 y. local relapse 6% 13% p=0.006
G3,4 toxic effects 27% 40% p=0.001
• Increase in sphincter-preserving surgery with preop Th.

7. MRC CR07/NCIC-CTG C016 (Sebag-Montefiore et al. 2009):
1350pt. with resectable rectal cancer randomized
▫ 25 Gy/5# + Surgery (TME)
▫ Surgery (TME) + (45 Gy & 5 FU)
Preop RT Postop CRT
5 y. OS 80.8% 78.7%
5 y. local relapse 4.4% 10.6%
DFS 79.5% 74.5%
Pre-op RT vs. post-op Chemo RT cont.

8. Preop short course RT vs long course CTRT
Polish Study (Br J Surg. 2006):
316 pts with resectable T3-4 rectal cancer, no sphincter involvement, tumor
palpable on DRE (1999-2002).
– RT  short-course RT with 5 Gy/d x 5 days + Surgery (TME)
– CRT  50.4 Gy (1.8 Gy /# over 5.5 weeks) + bolus 5-FU 325 mg/m²/d + LV
x 5 days 1st and 5th wks of RT + Surgery (TME)
Preop SCRT Preop LCRT
5 y. OS 67.2% 66.2%
5 y. local relapse 9.0% 14.2%
DFS 58.4% 55.6%

9. Trial details:

10. Material & methods
 Registered under Clinical Trials.gov
 Eligibility: Primary/locally recurrent rectal cancers
cT4/palpably fixed cT3
Adenocarcinoma
Age </= 75 years
WHO PS </= 2
Fit for Surgery/Chemotherapy
Written consent
 Exclusion: M1 disease
Medical comorbidities- Not fit for Sx/CT
Peripheral neuropathy- As oxaliplatin is used

11. Material & methods cont.
 Workup: Clinical history & examination
Colonoscopy/Rectoscopy
Pelvic MRI/CT
Abdomen/Chest CT (or CXR)
Blood counts/Clinical chemistry
Study Groups
 Group A: 5x5 Gy RT (week 1)
1 week gap
Consolidation Chemotherapy with FOLFOX4 2 weekly x 3
4 - 5 weeks gap
Surgery
 Group B: Long course CTRT (RT- 50.4Gy/28# & CT- 5-FU+Leucovorin bolus
week 1st and 5th of RT + Oxaliplatin weekly/5 cycles)
6 weeks gap
Surgery
12
wks
12
wks

12. Chemotherapy details
Group A: Cosolidation Chemotherapy
1st chemotherapy week 3 (RT- week 1, No concurrent)
2nd chemotherapy week 5
3rd chemotherapy week 7
Regimen: FOLFOX4 q2wkly
Inj. Oxaliplatin @85 mg/m² D1
Inj. 5-FU400 mg/m² bolus D1,D2 & 600 mg/m² CI D1,2
Inj. Leucovorin 200 mg/m² D1,2 before 5-FU
Group B: Cocurrent chemotherapy
Week 1 & 5 of RT- Inj. 5-FU @ 325 mg/m² x 5 days (Bolus)
Inj. Leucovorin @ 20 mg/m² x 5days (Bolus)
Weekly with RT - Inj. Oxaliplatin @ 50 mg/m²

13. Radiotherapy details
Group A: Short course RT 5 Gy x 5# (1 week) followed by consolidation CT
Group B: Long course RT 50.4 Gy/28# (6 weeks) with concurrent
Surgery details
Both Groups: Resection attempted regardless of clinical response
R1 – Cancer cells within 1 mm of Sx margin
R2 – Pathological proof of cancer cells at Sx margin (Not mere
perop finding)
Postop complications defined – within 30 days of Sx
Acute toxicity: NCI CTCAE v 3 scale
Late toxicity: RTOG/EORTC scale (1 month after Sx)

14. Follow up: 3 monthly x 2years
6 monthly thereafter
Follow up method: Physical examination
Serum CEA
Abdomen + Pelvic CT at 1 year & 2 year
CT thorax/CXR at 1 year & 2 year
* Routine MRI not mandatory for inclusion criteria
* Oxaliplatin initially included in both groups based on a retrospective study
published at that time but was left to physician discretion from 2012
(RCTs proved no benefit from oxaliplatin in preop RT setting)
*Overall preoperative treatment time: </= 7 weeks for both groups

15. Statistics
 Primary End point: R0 resection
 Secondary End points: Overall survival
DFS
Locoregional failure rates
Distant relapse rate
pathological CR
Acute & Late toxicities
Postoperative complications
Sample size calculation:
Assumption that R0 rate after conventional CTRT to be 75%
To detect 10 % benefit in R0 rates
(significance level 0.05 and power 80 %)
540 participants

16. Stats cont.
 Categorical variables compared : chi-square/Fischer exact/ Mann-whitney U-
test
 Survival : Kaplan Meier method
 DFS : local/distant/death – whichever occurred earlier
 Acute toxicity/ compliance measured as treatment progressed
 Randomisation : By telephone to a data centre independent from investigator
 Stratification : According to cT3/cT4/recurrent tumours
Institution based
*Statistician blinded to treatment group assigned
* Accural : 2008-2014

19. Results

20. Acute toxicity/Adherence to treatment
5x5 Gy RT + CT
n=256 (%)
Long course CTRT
n=259 (%)
P-value
Oxaliplatin use
Yes
No
Preop CT not given
183 (72)
72 (28)
01
166 (64)
93 (36)
0.062
Grade of toxicity
0
1
2
3
4
Toxic deaths
65 (25)
72 (28)
57 (22)
49 (19)
10 (4)
03 (1)
45 (17)
59 (23)
94 (36)
42 (16)
12 (5)
07 (3)
0.006
Radiotherapy dose reduction 0 20 (8) <0.001
Radiotherapy time prolongation >/= 1 wk 0 12(5) <0.001

21. 5x5 Gy RT + CT
n=256 (%)
Long course CTRT
n=259 (%)
P-value
Chemotherapy dose reduction
Yes (Toxicity)
Yes (Organizational/unknown cause)
Yes (Cancer progression)
No
CT not given
No data
51 (20)
05 (2)
01 (0.5)
197 (77.5)
1
1
66 (26)
05 (2)
0
188 (73)
0
0
0.15
Chemotherapy cycle delay, no
dose reduction
Yes (Toxicity)
Yes (Organizational/unknown cause)
No
CT not given
No data
43 (17)
13 (5)
198 (78)
1
1
NA
-
-
-
-
-
Radiotherapy +/- CT dose
reduction/delay
Yes
No
95 (37)
161 (63)
87 (34)
172 (66)
0.4

22. Acute toxicity cont.
 Median interval between start of RT & Surgery
Group A: 12.4 weeks
Group B: 12.4 weeks
 Median overall time of preoperative treatment
Group A: 6.6 weeks
Group B: 5.5 weeks (p=<0.001)
 Median interval between start of RT(5x5 Gy) and 1st consolidation
chemotherapy = 9 days

23. Acute Toxicity profile
Group A
(5x5 Gy)
(%)
Group B
(50.4 Gy/28#)
(%)
P-value
Acute toxicity (Total) 75 83 0.006
Acute toxicity (Grade III-IV) 23 21
Diarrhoea low high 0.001
Neutropenia high low 0.032
Neutropenic fever 2 3 NS
Toxic deaths 2 5 0.09

24. Late toxicity
Group A
(5x5 Gy)
(%)
Group B
(50.4 Gy/28#)
(%)
P-value
Late complications
Death due to complication
Grade 3-4
Grade 1-2
No complication
No data
NA (R2, LR, Tumor not resected, P/o deaths)
1 (0.5)
15 (8)
19 (11)
143 (80)
5
78
2 (1)
10 (6)
25 (15)
135 (79)
7
75
0.54
Death
In patient with cancer
From treatment complication
From inter-current illness
Unknown cause
64 (25)
52
6
4
2
84 (33)
67
13
2
2

25. Oncological outcome
Group A
(5x5 Gy)
(%)
Group B
(50.4 Gy/28#)
(%)
Locoregional status
No tumor resection/R2 resection
Pelvic recurrence after R0/R1
Locoregional control
No data (LFU)
42 (16)
35 (13)
184 (70)
0
54 (22)
18 (7)
179 (71)
3
Distant metastasis
Yes [as firs event]
No
No data (LFU)
75 (29) [60(23)]
186 (71)
0
62 (25) [58 (23)]
189 (75)

26. Overall Survival

27. Cumulative Local
failure

28. Oncological outcome cont.
Group A
(5x5 Gy)
(%)
Group B
(50.4 Gy/28#)
(%)
P-value
Overall Survival (3 years) 73 65 0.046
DFS (3 years) 53 52 NS
Cumulative local failure (3 years) 22 21 0.82
Cumulative distant failure (3 years) 30 27 0.25
Radical rescue surgery
(Combined for local & distant failure)
6 5 NS

29. Surgery & Pathology

30. Group A
(5x5 Gy)
N=261 (%)
Group B
(50.4 Gy/28#)
N=254 (%)
P-value
Postoperative Complication
Postoperative deaths (30 days)
Anastomotic dehisence (Re-Surgery required)
Other complications (Re-Surgery required)
Treated conservatively
No complications
No data
NA (Tumor not resected)
0
13 (6)
18 (8)
31 (15)
152 (71)
6
41
4
8 (4)
14 (7)
23 (12)
148 (75)
7
49
0.18
Surgery & Pathology cont.

31. Surgery & Pathology cont.

32. Surgery & Pathology cont.

33. Discussion

34. Short course RT + CT Long course CTRT
R0 resection rate
DFS
Local failure rate
Distant metastasis rate
Postoperative
complication
Late complication
Overall survival
No difference between
the groups
Better in short course preop RT

35. Six key results of the study in favour of Short course
RT with consolidation chemotherapy
 Improved patient survival
 Lower toxicity
 Greater convenience
 Lower cost
 Patient preference
 Logistic advantage for high burden centre

36.  Similar distant& local failures in both groups
Survival with recurrences higher in Short course group (OS higher)
Hypothesis:
Long lasting Antitumor immune response activated due to large
fraction size of RT
▪ Low rate of acute preop toxicity in short course group
Reason:
Sequential RT & CT in short course, so overlapping toxicity low
More flexibility in short course with chemotherapy delivery

37. Limitations of the study
 5-FU bolus used instead of continuous infusion/capecitabine (standard of care)
* 2 RCTs have proven equal efficacy of bolus and continuous infusion 5-FU in P/O
RT
 Lack of MRI for staging purpose
* Economic reasons & long waiting list
 Short follow up
 Imbalance of oxaliplatin use in two groups
* difference of imbalance however is only 4%

38. Related articles

40. No difference in OS, RFS, Distant recurrences and late
toxicity between short course and long course

44. Equivalent tumor down staging in short
course if surgery delayed to 4-8 weeks

46. No difference in Local control/OS/ Short term
QOL between short and long course RT

49. Long term health related QOL similar in
short course vs long course RT groups

53. Thank You

54. The German Study: A Shifting Concept

55. German study cont.

56. German trial cont.
10 - Year Radiotherapy
+ Sx
Surgery P
Local recurrence 5% 11% < 0.0001
Overall Survival 48% 49% 0.86
Cancer specific deaths 17% 22% 0.04