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EVIDENCE BASED
MANAGEMENT OF RECTAL
MALIGNANCY
Dr. Kanhu Charan Patro
M.D,D.N.B (RADIATION ONCOLOGY)
[EX.SR - TATAMEMORIAL...
Levels of evidence
 Level I=large double blind RCTs, or, metaanalysis of
smaller RCTs , with clinically relevant outcomes...
? ?
3
4
Rectal Cancer
Introduction
 Together with colon, it is third commonest cancer in
USA
 In India, it is not common but inc...
6
7
Introduction ..contd..
 Surgery is the mainstay of treatment
 Narrow confines of the pelvis limits the adequacy
of resec...
Preoperative staging
 Clinical
examination
 ERUS
 CT scan
 MRI
T2 sen Spe T3 sen
ERUS 94 86 90
CT 79
MR 94 69 82
For l...
TNM Staging
 T1 localised disease
 T2
 T3
 T4 Locally
 N1 Advanced
 N2
 Metastatic disease
Stage IIA T3, N0, M0
Sta...
 Likelihood of LN involvement
 pT1 – 5.6%
 pT2 – 10%
 pT3 – 36.7%
 pT4 – 77.7%
11
PET scan
Metabolic imaging
 Role in Detection of regional and metastatic
disease*
changed Rx in 17%
altered preop staging...
aims
 local control
 long-term survival
 preservation of
 anal sphincter
 bladder
 sexual function
 maintenance or ...
Mainstay treatment-
 Surgery
 AR
 LAR
 APR
 TOTAL MESORECTAL EXCISION
 MINIMUM OF 12 NODE DISSECTION
TEMPORARY/PERMA...
Non TME Surgery
Blunt intramesorectal dissection
Rectosacral fascia traction
Disruption of NVB
Dissection onto front of re...
16
 TME surgery-
 Principle- enbloc removal of
tumor within envelope of
endopelvic fascia
 Plane between visceral and
pari...
1.Heald : Lancet 1986
Retrospective
Local recurrence 32-35% with conventional surgery
4-9% with TME
Increase in overall su...
Incidence and predominant location on
recurrences after TME
IJROBP 2006 Roels S
5 subsites were noted as predominant
risk ...
20
Prognosis/Local Failure
 T stage
 Nodal involvement
 CRM – Quirke et al Lancet 1986 : 86% with CRM +ve developed LRR
c/...
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
S...
Rationale of Adjuvant Therapy
After surgery 20-50% patients develop
loco-regional recurrence (LRR)
Stage I : 5-15%
Stage ...
Radiation Therapy as Adjuvant
Therapy
Preoperative RT (Neoadjuvant)
Postoperative RT (Adjuvant)
Combined with Chemother...
Addition of radiotherapy
 Adjuvant
 Disadvantage
1) increased small bowel toxicity
2) Potentially radioresistant hypoxic...
NSABP R01
1977-86
 N=555
 3 arms-
 Post op Chemo improved
DFS
 Post op RT reduced LR not
OS
Postoperative Radiation an...
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 W...
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 ...
NIH consensus 1990
 Adjuvant CTRT in stage II and III rectal
Ca
 Standard of care
 Which type of chemo?
29
 5 FU
 Leucovorin
 Levamisole
Metastatic disease where 5-FU and leucovorin
improved response rate
Most regimens have us...
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%)...
 Infusional 5-FU is superior to bolus 5-FU and
is considered to be a standard adjuvant
therapy
32
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+le...
 Tumors located high in the rectum
 T1-2N or T3N0 disease,
 Tumors where the surgeon has been formally trained
to perfo...
Favourable Subset of patients
 Prognostic factors in stage T3N0 rectal cancer: do all patients require
postoperative pelv...
Resectable rectal cancer
algorithm
36
SURGERY
T1,T2-N0 >T1,T2-N0
OBSERVATION CT+RT
CT+RT[2 CYCLE CHEMORADIATION+CONCURREN...
Management of
Loco-regional Advanced
disease
37
Pre-op
CTRT
Post-op
CTRT
?
38
Pre op treatment
Rationale / advantage
 1. downstaging
 2. decreased tumor seeding
 3. decreased acute toxicity
 4. mo...
Uppasala(Sweden)
40
Uppasala(Sweden)
 N= 471
 preoperative irradiation at
comparable, or even lower dosage
levels, is more efficient in redu...
Meta-analysis – benefit of preop
RT
Camma et al , JAMA 2000
14 RCTs
Overall survival benefit +
Colorectal Cancer Collabora...
Swedish Rectal Cancer Trial
 N=1168
 Surgery alone (notTME)
 25Gy/5# - Surgery
 21% benefit in OS (95%CI 8-34%)
IMPROV...
BUT
 Excessive acute and late toxicity ( 5Gy per fraction)
 Slower recovery of bowel function
 More bowel incontinence
...
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...
Swedish council of technology
assessment in health care 2003
 systematic review of radiation therapy trials
 25 351 pati...
Chemotherapy in preop setting
47
Chemotherapy
 With RT – enhance radiosensitivity
 Adjuvant – eradicate micro mets
48
EORTC 22921
Patients with T3
or resectable T4 M0
rectal cancer
(N = 1011) Preoperative RT-CT
45 Gy total with
Leucovorin (...
Results-
Preop CTRT was well tolerated c/w postop CTRT
(<50% complaince)
Chemoradiotherapy resulted in downsizing and down...
 So,
if RT is given, then 5FU based chemotherapy
given concurrently with RT prior to or
following surgery gives significa...
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...
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...
Results-
 Survival comparable between groups
 5yr OS 76% in preop group vs 74% in postop group (P = .80)
 5yr DFS 68% i...
Schedule of RT – polish study
 whether preop conventionally fractionated CTRT offers an
advantage in sphincter preservati...
Locally Advanced rectal cancer
algorithm
56
CT-RT
SURGERY
4 CYCLE CHEMO
6 WEEKS GAP
CT+RTRADIATION+CONCURRENT CHEMO]
Management for
metastatic disease
57
The main stay of
metastatic
colorectal cancer is
multi agent
chemotherapy
58
CHEMOTHERAPEUTIC
AGENTS FOR COLORECTAL
CANCER
 5FU
 LEVAMISOLE
 LEUCOVORIN
 ORAL 5FU AGENTS
 IRNOTECAN
 OXALIPLATIN
...
WHAT IS STANDARD
 Based on INT 0089 trial 5FU+LV for 7-8
month is standard treatment for stage
III colorectal cancer .the...
WHAT IS STANDARD
PROTOCOL FOR 5FU
ADMINISRTATION
 VARIOUS REGIMENS USED FOR 5FU+LV
ARE
DEGARMONT
NCCTG
LOKICH
ROSWELL...
ROSWELL PARK REGIMEN
 5FU----500mg/m2/WKX6WK
 LV-----500mg/m2/WKX6WK
 REAPT AT EVERY 8WK FOR 6 CYCLES
62
MAYO CLINIC REGIMEN
 5FU----425mg/m2/dX5d
 LV-----20mg/m2/dX5d
 REAPT AT EVERY 4WK FOR 6 CYCLES
63
What should be the standard
method of 5FU administration
 Lokich et.al compared 6 metaanalysis
of 5FU adminisration
RESU...
What should be followed
 Infusion regimens to be favored in Europe for
their safety and improved efficacy profile.
 in U...
CAPECITABINE
It is a orally absorbed flouro
pyrimidine not activated in gut
and absorbed as such and
converted to 5fu by ...
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 SAFE...
COMBINATION
CHEMOTHERAPIES
 FULFOX 1,2,3,4,6
 FULFIRI
 IFL
 bFL
 OXIRI
 IROX
 FULFOX ALTERNATING WITH FULFIRI
68
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
DOUL...
SURVIVAL
NOW IT IS CLEAR THAT WITH ALL
SUPPORTIVE CARE MEDIAN SURVIVAL IN
ADVANCED COLORECTAL CANCER IS 9
MONTH,WITH 5FU L...
CONCLUSION
AFTER GOLDBERG TRIAL THE PUBLISHED STATEMENT IN
JCO JAN 2004 TELLS THAT FOLFOX REGIMEN IS ACTIVE
AND COMPARITEV...
ALTERNATE FOLFOX with
FOLFIRI
 BASED ON GOLDIE COLDMNN HYPOTHESIS
RECHIA et.al(2004) CONDUCTED A PHASE II
TRIAL THAT COMP...
The DOCK Group
 DOCK
 [dissemination of knowledge in oncology club]
 landmark message
 Doubts
 case discussion
 Any ...
? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?
? ? ? ? ? ? ? ...
75
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RECTUM CANCER MANAGEMENT

RECTUM CANCER MANAGEMENT

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RECTUM CANCER MANAGEMENT

  1. 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. 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. ? ? 3
  4. 4. 4
  5. 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. 6
  7. 7. 7
  8. 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. 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. 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. 11.  Likelihood of LN involvement  pT1 – 5.6%  pT2 – 10%  pT3 – 36.7%  pT4 – 77.7% 11
  12. 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. 13. aims  local control  long-term survival  preservation of  anal sphincter  bladder  sexual function  maintenance or improvement in QOL. 13
  14. 14. Mainstay treatment-  Surgery  AR  LAR  APR  TOTAL MESORECTAL EXCISION  MINIMUM OF 12 NODE DISSECTION TEMPORARY/PERMANENT COLOSTOMY 14
  15. 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. 16
  17. 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. 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. 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. 20
  21. 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. 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. 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. 24. Radiation Therapy as Adjuvant Therapy Preoperative RT (Neoadjuvant) Postoperative RT (Adjuvant) Combined with Chemotherapy 24
  25. 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. 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. 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. 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. 29. NIH consensus 1990  Adjuvant CTRT in stage II and III rectal Ca  Standard of care  Which type of chemo? 29
  30. 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. 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. 32.  Infusional 5-FU is superior to bolus 5-FU and is considered to be a standard adjuvant therapy 32
  33. 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. 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. 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. 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. 37. Management of Loco-regional Advanced disease 37
  38. 38. Pre-op CTRT Post-op CTRT ? 38
  39. 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. 40. Uppasala(Sweden) 40
  41. 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. 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. 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. 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. 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. 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. 47. Chemotherapy in preop setting 47
  48. 48. Chemotherapy  With RT – enhance radiosensitivity  Adjuvant – eradicate micro mets 48
  49. 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. 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. 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. 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. 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. 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. 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. 56. Locally Advanced rectal cancer algorithm 56 CT-RT SURGERY 4 CYCLE CHEMO 6 WEEKS GAP CT+RTRADIATION+CONCURRENT CHEMO]
  57. 57. Management for metastatic disease 57
  58. 58. The main stay of metastatic colorectal cancer is multi agent chemotherapy 58
  59. 59. CHEMOTHERAPEUTIC AGENTS FOR COLORECTAL CANCER  5FU  LEVAMISOLE  LEUCOVORIN  ORAL 5FU AGENTS  IRNOTECAN  OXALIPLATIN 59
  60. 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. 61. WHAT IS STANDARD PROTOCOL FOR 5FU ADMINISRTATION  VARIOUS REGIMENS USED FOR 5FU+LV ARE DEGARMONT NCCTG LOKICH ROSWELLPARK MAYO CLINIC 61
  62. 62. ROSWELL PARK REGIMEN  5FU----500mg/m2/WKX6WK  LV-----500mg/m2/WKX6WK  REAPT AT EVERY 8WK FOR 6 CYCLES 62
  63. 63. MAYO CLINIC REGIMEN  5FU----425mg/m2/dX5d  LV-----20mg/m2/dX5d  REAPT AT EVERY 4WK FOR 6 CYCLES 63
  64. 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. 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. 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. 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. 68. COMBINATION CHEMOTHERAPIES  FULFOX 1,2,3,4,6  FULFIRI  IFL  bFL  OXIRI  IROX  FULFOX ALTERNATING WITH FULFIRI 68
  69. 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. 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. 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. 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. 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
  74. 74. ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?? 74
  75. 75. 75 2/9/2021 1:40:17 AM

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