RECTUM CANCER MANAGEMENT

1. EVIDENCE BASED
MANAGEMENT OF RECTAL
MALIGNANCY
Dr. Kanhu Charan Patro
M.D,D.N.B (RADIATION ONCOLOGY)
[EX.SR - TATAMEMORIAL HOSPITAL]
Consultant- Radiation Oncology
MAHATMA GANDHI CANCER HOSPITAL
VISAKHAPATNAM
Email-drkcpatro@gmail.com
M-09160470564

2. Levels of evidence
 Level I=large double blind RCTs, or, metaanalysis of
smaller RCTs , with clinically relevant outcomes
I a=evidence from meta-analysis of RCT
I b=evidence from at least 1 RCT
 Level II=small RCTs, non-blinded RCTs
II a=evidence from one well designed non-RCT
II b=evidence from one well-designed quasi-
experimental study
 Level III=observational [cohort ] studies , case-
control studies , non-RCTs
 Level IV=opinion of expert committees, or
respected authorities
 Level V=expert opinion 2

3. ? ?
3

4. 4

5. Rectal Cancer
Introduction
 Together with colon, it is third commonest cancer in
USA
 In India, it is not common but incidence is rising
 More frequent in population which consumes high fat-
low fiber diet
 Affects both the sexes equally
5

6. 6

7. 7

8. Introduction ..contd..
 Surgery is the mainstay of treatment
 Narrow confines of the pelvis limits the adequacy
of resected margins
 Proximity of the anal sphincter- poor quality of life
 RT plays an important role for the above two
reasons
8

9. Preoperative staging
 Clinical
examination
 ERUS
 CT scan
 MRI
T2 sen Spe T3 sen
ERUS 94 86 90
CT 79
MR 94 69 82
For local invasion, endoluminal US was most
accurate
Poor sensitivity 67%
specificity 77%
Lymph node
detection
9

10. TNM Staging
 T1 localised disease
 T2
 T3
 T4 Locally
 N1 Advanced
 N2
 Metastatic disease
Stage IIA T3, N0, M0
Stage IIB T4, N0, M0
Stage IIIA T1, N1, M0
T2, N1, M0
Stage IIIB T3, N1, M0
T4, N1, M0
Stage IIIC N2, M0
Stage IV M1
10

11.  Likelihood of LN involvement
 pT1 – 5.6%
 pT2 – 10%
 pT3 – 36.7%
 pT4 – 77.7%
11

12. PET scan
Metabolic imaging
 Role in Detection of regional and metastatic
disease*
changed Rx in 17%
altered preop staging in 40%
 Assessment of tumor response to therapy
12

13. aims
 local control
 long-term survival
 preservation of
 anal sphincter
 bladder
 sexual function
 maintenance or improvement in QOL.
13

14. Mainstay treatment-
 Surgery
 AR
 LAR
 APR
 TOTAL MESORECTAL EXCISION
 MINIMUM OF 12 NODE DISSECTION
TEMPORARY/PERMANENT
COLOSTOMY
14

15. Non TME Surgery
Blunt intramesorectal dissection
Rectosacral fascia traction
Disruption of NVB
Dissection onto front of rectum
Nodal or occult micrometastatic disease
frequently left in situ
15

16. 16

17.  TME surgery-
 Principle- enbloc removal of
tumor within envelope of
endopelvic fascia
 Plane between visceral and
parietal pelvic fascia
 Entire mesorectm remains within
the fascia
 Lateral dissection separates
mesorectum from NVB
 12-15 perirectal and pelvic LNs
Complete removal of vascular suppy,
lymphatics, lymph nodes.
17

18. 1.Heald : Lancet 1986
Retrospective
Local recurrence 32-35% with conventional surgery
4-9% with TME
Increase in overall survival by 30%
2.Prospective
Dutch colorectal cancer group
LR 9% c/w 16%
18

19. Incidence and predominant location on
recurrences after TME
IJROBP 2006 Roels S
5 subsites were noted as predominant
risk of recurrences
1) Mesorectal
2) Posterior pelvic/ Presacral space
(22%)
3) Lateral pelvic wall (6%)
4) Inferior pelvic especially if tumor
<6cm from anal verge (11%)
5) Anterior pelvic (5%)
6) Anastamotic recurrences (10-21%)
19

20. 20

21. Prognosis/Local Failure
 T stage
 Nodal involvement
 CRM – Quirke et al Lancet 1986 : 86% with CRM +ve developed LRR
c/w 3% with CRM –ve
CRM of at least 2 to 5 mm results in a much lower rate of local failures
than with lesser margins
 Location of the tumor in the rectum (tumors located low in the rectum
have a higher incidence of local failure)
 Experience and ability of the surgeon
 Local-regional failure rates of less than 5% after TME without the use of
any adjuvant therapy 21

22. Stage 5 year, no adjuvant XRT
T1 10%
T2 15-35%
T3 20-45%
T4 >50%
N+ 40-65%
More than half of there recurrances are local
Survival inversely related to recurrance
With surgery alone, 5 yr survival
T1,T2 - 80%
T3, N+ < 25%
Hence, Need for adjuvant treatment for high
risk patients
Generally – need for adj Rx if risk of LR >20%
22

23. Rationale of Adjuvant Therapy
After surgery 20-50% patients develop
loco-regional recurrence (LRR)
Stage I : 5-15%
Stage II : 20-30%
Stage III : 20-50%
Hence Adjuvant treat. is aimed to reduce the LRR
and improve survival
23

24. Radiation Therapy as Adjuvant
Therapy
Preoperative RT (Neoadjuvant)
Postoperative RT (Adjuvant)
Combined with Chemotherapy
24

25. Addition of radiotherapy
 Adjuvant
 Disadvantage
1) increased small bowel toxicity
2) Potentially radioresistant hypoxic bed
3) May require a long time for healing for wound before
RT
4) If APR, large portal to include perineal scar
25

26. NSABP R01
1977-86
 N=555
 3 arms-
 Post op Chemo improved
DFS
 Post op RT reduced LR not
OS
Postoperative Radiation and Postoperative Systemic Chemotherapy in the
Management of Resectable Rectal Carcinoma
26

27. NSABP R 02
1987-92
 Post op CT +/- RT
 N=694
 PORT reduced LR (8% vs
13%) not OS or DFS
Compare Adjuvant MOF With and Without Radiation, to Adjuvant LV+5FU With and
Without Radiation, in Patients with Dukes' B and C Carcinoma of the Rectum
Post op RT did not improve OS
BUT improved Local control
27

28. GITSG GI-7175 1975-80
 N=227
Adjuvant postop RT and CT in
Rectal cancer: a review of the
GITSG : RO 1988
5yr Rec LR 10yr OS
Surgery alone 55% 25% 27%
Sx – CTRT (40-44 Gy + 5FU) 33% 10% 54%
28

29. NIH consensus 1990
 Adjuvant CTRT in stage II and III rectal
Ca
 Standard of care
 Which type of chemo?
29

30.  5 FU
 Leucovorin
 Levamisole
Metastatic disease where 5-FU and leucovorin
improved response rate
Most regimens have used FU
traditionally
NEW-
Oxaliplatin , Irinotecal, Oral 5FU
30

31. NNCTG/86-47-51 [bolus 5FU VS PI]
 N=660
 Improvement in RFS
(63% vs 53%
 4yr OS (70% vs 60%)
 Distant mets(31% vs
40%)
Improving Adjuvant Therapy for Rectal Cancer by Combining Protracted-
Infusion Fluorouracil with Radiation Therapy after Curative Surgery, O'Connell
; NEJM 1994
31

32.  Infusional 5-FU is superior to bolus 5-FU and
is considered to be a standard adjuvant
therapy
32

33. INT 114 1990-92
n= 1695
In pT3, pT4, pN+
 2# chemo – CTRT – 2# chemo
 4 arms 5FU vs 5FU+Levamisole vs FU+LV vs 5FU+LV+levamisole
 RT = 45Gy/25# to pelvis – 5.4Gy boost ; 3 or 4 fields
 RESULT = no diff in DFS or OS
 High rates of failure in T3,T4
Adjuvant Therapy in Rectal Cancer: Analysis of Stage, Sex,
and Local Control—Final Report of Intergroup 0114- J.E. Tepper
33

34.  Tumors located high in the rectum
 T1-2N or T3N0 disease,
 Tumors where the surgeon has been formally trained
to perform a TME and there is confirmation that this
has been performed,
 HPR- surgical margins by the method of Quirke et al
and where at least 12-14 nodes have been identified
in the pathology specimen to confirm N0 status
Intergroup 0114 : JE Tepper
Favourable Subset of patients
34

35. Favourable Subset of patients
 Prognostic factors in stage T3N0 rectal cancer: do all patients require
postoperative pelvic irradiation and chemotherapy
 Willett CG (MGH)
high risk factors- 1) perirectal invasion>2mm
2) LVI
3) Poorly dfferentiated
10 yr LC – 95 vs 87%
10 yr RFS – 71 vs 55%
 T3N0 rectal cancer: results following sharp mesorectal excision and no
adjuvant therapy
 Merchant NB (MSKCC)
LAR or APR with sharp TME results in LRF <10%
histopath factor of significance = LVE 35

36. Resectable rectal cancer
algorithm
36
SURGERY
T1,T2-N0 >T1,T2-N0
OBSERVATION CT+RT
CT+RT[2 CYCLE CHEMORADIATION+CONCURRENT CHEMO2 CYCLE CHEMO]

37. Management of
Loco-regional Advanced
disease
37

38. Pre-op
CTRT
Post-op
CTRT
?
38

39. Pre op treatment
Rationale / advantage
 1. downstaging
 2. decreased tumor seeding
 3. decreased acute toxicity
 4. more oxic cells – improved radiosensitivity
 5. enhanced sphincter preservation
Downside
 Overtreatment of T1, T2 disease
39

40. Uppasala(Sweden)
40

41. Uppasala(Sweden)
 N= 471
 preoperative irradiation at
comparable, or even lower dosage
levels, is more efficient in reducing
the local recurrence rate than
postoperative irradiation
 higher dosages are necessary to kill
micrometastases in surgically
disturbed tissue than in nondisturbed
tissue
 RT technique
Pre- or postoperative radiotherapy in rectal and
rectosigmoid carcinoma: report from a randomized
multicenter trial.- Påhlman L: Ann Surg 1990
Pre-op Post-op
LR
12% 21%
41

42. Meta-analysis – benefit of preop
RT
Camma et al , JAMA 2000
14 RCTs
Overall survival benefit +
Colorectal Cancer Collaboratice Group, Lancet 2001
14 RCTs
Reduced LR , not OS
42

43. Swedish Rectal Cancer Trial
 N=1168
 Surgery alone (notTME)
 25Gy/5# - Surgery
 21% benefit in OS (95%CI 8-34%)
IMPROVED SURVIVAL WITH PREOPERATIVE RADIOTHERAPY IN
RESECTABLE RECTAL CANCER - -NEJM 1997
LR-27 OS-58
11 48
10% absolute OS
advtg
43

44. BUT
 Excessive acute and late toxicity ( 5Gy per fraction)
 Slower recovery of bowel function
 More bowel incontinence
 Higher incidence of sexual dysfunction
 Poorer quality of life
 Short interval for downstaging
Interval before surgery-
 Downstaging max after 10 days (Graf et al, RO 1997)
 Increase chance of downstaging if interval > 2 weeks ( LYON
90.01 , JCO 1999)
 No downstaging at 7 days (Dutch CKVO , JCO 2001)
NO CONSENSUS YET
44

45. Need for preop RT with TME?
 Dutch CKVO 95-04
 N=1861 pts
 25 Gy – Sx vs Sx alone
 2 yr local recurrence 2% vs 8%
 No benefit in OS/Sph preserv
45

46. Swedish council of technology
assessment in health care 2003
 systematic review of radiation therapy trials
 25 351 patients
 Preoperative RT at BED>30 Gy decreases the relative risk of a
local failure by 50-70%
 Postop RT decreases the risk by 30-40% at doses that generally
are higher
 strong evidence that preop RT is more effective than
postoperative.
 moderate evidence that preoperative radiotherapy significantly
decreases the local failure rate (from 8% to 2% after 2 years)
also with TME.
 strong evidence that preoperative radiotherapy improves
survival (~ 10%)
46

47. Chemotherapy in preop setting
47

48. Chemotherapy
 With RT – enhance radiosensitivity
 Adjuvant – eradicate micro mets
48

49. EORTC 22921
Patients with T3
or resectable T4 M0
rectal cancer
(N = 1011) Preoperative RT-CT
45 Gy total with
Leucovorin (20 mg/m2/day) plus
Fluorouracil (350 mg/m2/day) in
5-day courses on Weeks 1, 5
(n = 506)
Preoperative RT
45 Gy total
(n = 505)
Surgery*
3-10 wks after
preoperative
treatments
Week 5
*Anterior resection or
abdominoperineal resection.
Week 1
-Chemotherapy with Preoperative Radiotherapy in Rectal Cancer –Bosset NEJM
2006
49

50. Results-
Preop CTRT was well tolerated c/w postop CTRT
(<50% complaince)
Chemoradiotherapy resulted in downsizing and down-
staging of tumors
Decrease in local recurrence with chemotherapy
8.6% vs 17%
No difference in OS with chemotherapy
Increase rate of pCR with preop CTRT 14% vs 5% with
RT alone
-Chemotherapy with Preoperative Radiotherapy in Rectal Cancer –Bosset NEJM
2006
50

51.  So,
if RT is given, then 5FU based chemotherapy
given concurrently with RT prior to or
following surgery gives significant advantage
in local control
51

52. FFCD 9203
 N=762
 RT +/- CT Sx CT
 5-year incidence of LR was lower with CTRT 8% v
16%
 pCR more frequent with CTRT 12% VS 4%
 No difference in sphincter preservation 52% VS 53%
 5yr OS / DFS similar 67%
 Grade 3 or 4 acute toxicity was more frequent with
CTRT 15% VS 3%
 Compliance 93% in preop CTRT , 70% in post op CT
Preoperative Radiotherapy With or Without Concurrent Fluorouracil and Leucovorin in
T3-4 Rectal Cancers: Results of FFCD 9203 Gérard : JCO 2006
52

53. Pre op vs Post op CTRT
German rectal cancer group
Sauer R, et al. N Engl J Med, 2004;351:1731-1740.
Arm A*
(n = 415)
Arm B†
(n = 384)
Locally
advanced
rectal cancer,
T3, T4, or
node positive
(N = 823)
*Arm A: Preoperative chemoradiotherapy: 28 fractions (180 cGy/day, 5 x/wk) radiotherapy plus 5-
fluorouracil (5-FU) as 120-hr continuous infusion (1000 mg/m2/day) in Wks 1 and 5 of RT
Postoperative chemotherapy: bolus 5-FU (500 mg/m2 5 x/wk) every 4 wks for 4 cycles
†Arm B: Chemotherapy: bolus 5-FU (500 mg/m2/day) for 5 days, every 4 wks for 4 cycles
Follow-up
every 3 mos
for 2 yrs,
then every 6
mos for 3 yrs
Surgery
Wk 12
Preoperative
chemoradiotherapy
(6 wks)
Wk 0
Postoperative
chemotherapy
Wk 16
Wk 0
Surgery
Wk 16
Postoperative + 540 cGy boost
chemotherapy
53

54. Results-
 Survival comparable between groups
 5yr OS 76% in preop group vs 74% in postop group (P = .80)
 5yr DFS 68% in preop group vs 65% in postop group (P = .32)
 Preoperative treatment improved local control
 5-year local recurrence incidence 6% in preop vs 15% in postop group
(P = .006)
 Distant recurrence similar between groups
 Sphincter preservation rates in patients with abdominoperineal resection
before randomization
 Higher with preoperative chemoradiotherapy (39% vs 20% P = .004)
 Toxicity was less with the pre op group
 Acute 27% vs 49%
 Chronic 14% vs 24%
Sauer R, et al. N Engl J Med, 2004;351:1731-1740.
54

55. Schedule of RT – polish study
 whether preop conventionally fractionated CTRT offers an
advantage in sphincter preservation in comparison with preop
short-term RT
 resectable T3-4 rectal carcinoma without sphincters' infiltration
 preop 25Gy/5#/1wk TME performed within 7 days or CTRT to
50.4Gy/28# concomitantly with two courses of bolus 5FU-LV
followed by TME after 4-6 weeks.
 N=316
 pCR : CTRT 15% SCRT 1%
Sph Pre 58% 61%
<1 mm CRM 13% SCRT vs 4% in CTRT
No difference in LR, OS, DFS
55

56. Locally Advanced rectal cancer
algorithm
56
CT-RT
SURGERY
4 CYCLE CHEMO
6 WEEKS GAP
CT+RTRADIATION+CONCURRENT CHEMO]

57. Management for
metastatic disease
57

58. The main stay of
metastatic
colorectal cancer is
multi agent
chemotherapy
58

59. CHEMOTHERAPEUTIC
AGENTS FOR COLORECTAL
CANCER
 5FU
 LEVAMISOLE
 LEUCOVORIN
 ORAL 5FU AGENTS
 IRNOTECAN
 OXALIPLATIN
59

60. WHAT IS STANDARD
 Based on INT 0089 trial 5FU+LV for 7-8
month is standard treatment for stage
III colorectal cancer .then it is being
used since 1996
 Neither INT-0089 nor NSABP trial
showed that levamisole with 5FU+LV
is better than 5FU+LV
60

61. WHAT IS STANDARD
PROTOCOL FOR 5FU
ADMINISRTATION
 VARIOUS REGIMENS USED FOR 5FU+LV
ARE
DEGARMONT
NCCTG
LOKICH
ROSWELLPARK
MAYO CLINIC 61

62. ROSWELL PARK REGIMEN
 5FU----500mg/m2/WKX6WK
 LV-----500mg/m2/WKX6WK
 REAPT AT EVERY 8WK FOR 6 CYCLES
62

63. MAYO CLINIC REGIMEN
 5FU----425mg/m2/dX5d
 LV-----20mg/m2/dX5d
 REAPT AT EVERY 4WK FOR 6 CYCLES
63

64. What should be the standard
method of 5FU administration
 Lokich et.al compared 6 metaanalysis
of 5FU adminisration
RESULTS
 Cont. inf increased response rate
 Cont. inf. Has modest survival benefit
 Protracted inf. Associated with greater
hand food syndrome
 Protracted inf. Associated with lesser
incidence of Gr—3,4 neutropenia.
 Protracted inf. Associated with
considerable inconvenience & disruption
of daily activities .
64

65. What should be followed
 Infusion regimens to be favored in Europe for
their safety and improved efficacy profile.
 in U.S.A bolus regimens followed for ease
administration
Conclusion– clinicians should
choose a regimen best suited to their patient
65

66. CAPECITABINE
It is a orally absorbed flouro
pyrimidine not activated in gut
and absorbed as such and
converted to 5fu by 3 step
enzymatic cascade. The last
enzyme that converts this to
5fu is thimidine phosphorylase
is significantly more active in
tumor tissue. 66

67. TRIALS ON
CAPECITABINE
 Hoff et.al.(2ooo) RR OS(M) TDP(M)
MAYO CLINC REG. 17% 12.8 4.7
CAPECITABINE 26% 12.9 4.6
THE SAFETY PROFILE OF CAPECITABINE WAS BETTER
IN ALL RESPECT TO 5FU+LV BUT HAND FOOT
SYNDROME IS MORE IN CAPECITABINE ARM.
CONCLUSION---
CAPECITABINE IS SUPERIOR RR TO 5FU/LV
67

68. COMBINATION
CHEMOTHERAPIES
 FULFOX 1,2,3,4,6
 FULFIRI
 IFL
 bFL
 OXIRI
 IROX
 FULFOX ALTERNATING WITH FULFIRI
68

69. STUDY PT REG RR(%) M,PFS(M) M,OS(M)
SALTZ et. al. 226 5FU/LV 21 4.3 12.6
EJM(2000) 231 IFL 39 7 14.8
226 IR 18 4.2 12
DOULLIER 198 5FU/LV 22 4.4 14.1
et. al.(2OOO) 188 FOLFIRI 35 6.7 17.4
DEGRAMONT 210 5FU/LV 22.3 6.2 14.7
et. al.(2OOO) 188 FOLFOX4 5O.7 9 16.2
GIACHETTI 100 5FU/LV 16 6.1 19.9
et. al.(2OOO) 188 FOLFOX6 53 8.7 19.4
GOLDBERG et. al. 264 IFL 29 6.9 14.1
JCO(2004) 267 FOLFOX 38 8.8 18.6
264 OXIRI 29 NA NA
69

70. SURVIVAL
NOW IT IS CLEAR THAT WITH ALL
SUPPORTIVE CARE MEDIAN SURVIVAL IN
ADVANCED COLORECTAL CANCER IS 9
MONTH,WITH 5FU LV IT IS 12 MONTH BUT
WHEN 5FU/LV COMBINED WITH IRINOTECAN
OR OXALIPLATIN THEN MEDIAN SURVIVAL IS
14 TO19 MONTH.
70

71. CONCLUSION
AFTER GOLDBERG TRIAL THE PUBLISHED STATEMENT IN
JCO JAN 2004 TELLS THAT FOLFOX REGIMEN IS ACTIVE
AND COMPARITEVELY SAFE . SO IT SHOULD BE
CONSIDERED AS A STANDARD THERAPY FOR ADVANCED
COLORECTAL CANCER
71

72. ALTERNATE FOLFOX with
FOLFIRI
 BASED ON GOLDIE COLDMNN HYPOTHESIS
RECHIA et.al(2004) CONDUCTED A PHASE II
TRIAL THAT COMPRISING FOLFOX
ALTERNATING WITH FOLFIRI SHOWED THAT
RR IS 69%, DISEASE STABILISATION IN 11%
OF CASES. IN ALL TOTAL 8O% GOT BENEFIT.
72

73. The DOCK Group
 DOCK
 [dissemination of knowledge in oncology club]
 landmark message
 Doubts
 case discussion
 Any other related queries
 TheDOCKgroup@yahoogroups.com
 drkcpatro@gmail.com
73

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74

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