NEOADJUVANT TREATMENT IN CARCINOMA RECTUM

1. NEOADJUVANT TREATMENT IN
CARCINOMA RECTUM
Dr Joneetha Jones
Assistant Professor
Dept of Radiation Oncology
Malabar Cancer Centre

2. • Surgery is the cornerstone in management
However

3. LOCAL
RECURRENCE

4. REASONS
• Close proximity of
rectum to adjacent
organs
• Absence of serosa
covering rectum
• Technical difficulties in
obtaining wide surgical
margins at resection
• NCCN guidelines 2018
PELVIC SUBSITES FOR LOCAL
RECURRENCE
Memorial Sloan Kettering group

5. PELVIC SUBSITES FOR LOCAL
RECURRENCE
CENTRAL Anastomotic, mesorectal (residual
mesorectum) or perirectal soft
tissue or perineum
ANTERIOR (5-17%) Genitourinary tract
POSTERIOR (22-49%) Sacrum and presacral fascia
and sacral root sheaths
LATERAL (21%) Muscles (piriformis, levator), soft
tissue of the pelvic sidewall, lymph
nodes, major iliac vessels, sacral
nerve plexus and lateral bony pelvis

6. Local recurrence after conventional surgery:
15%-45% (average of 28%)

7. HOW THIS LOCAL RECURRENCE
CAN BE REDUCED?

8. Role of Combined Modality
Therapy
• Surgery followed by adjuvant treatment
• Ability to selectively treat patients at high risk
of local failure on the basis of pathologic
stage

9. Adjuvant Therapy
Post-op Chemo, RT, and/or
ChemoRT ?

10. Adjuvant Therapy of Rectal
Cancer
• 1990 US NIH Consensus Conference
– Postoperative chemoradiotherapy =
standard of care for RC Stage II,III
• The consensus statement was based upon the
results of three randomised trials

12. CONCLUSIONS
• ChemoRT arm improved local control ,DFS
and OS.

13. Post-op ChemoRT – what chemo??
• INT/NCCTG 86-47-51
(1986-90) O’Conell
1994
– Bolus
5Flurouracil
– Continuous
infusion
– 5FU + semustine
• INT 0144
• (a) bolus 5-FU alone
• (b) 5-FU and leucovorin
• (c) 5FU plus levamisole
• (d) 5-FU and leucovorin
plus levamisole.

14. CONCLUSIONS
• Chemo
– 5FU is the main drug.
– No additional benefit of semustine/Levamisole
– Continous infusion 5FU is better than bolus 5FU

15. Disadvantages of adjuvant treatment
• Potentially hypoxic postsurgical bed, making
radiation less effective
• Higher complications due to increased small
bowel in the radiation field
• A larger treatment volume, especially if the
patient undergoes an APR and the perineal
scar needs to be covered

16. NEOADJUVANT TREATMENT
• Studies from Europe have demonstrated that
appropriate neo adjuvant preoperative
radiation results in improvement of both local
control and survival

17. NEOADJUVANT TREATMENT
• Down staging, hence increased resectability
• Decreased risk of dissemination during
surgery.
• Radiation more effective with tumour cells
highly vascular.
• Less serious bowel toxicity due to easy
exclusion.
• Possibility of increasing sphincter
preservation in borderline cases.

18. • Preop RT Short course RT 25GY/5 fractions
• Preop ChemoRT Long course RT 50.4Gy/28
fractions along with concurrent
chemotherapy.

19. Pre-op RT vs. surgery alone

20. Pre-op RT vs. surgery alone
Surgery alone arm did not utilize TME
PRE TME ERA

22. • Late effects suggested more bowel movement
frequency, incontinence, urgency, small bowel
obstruction and soiling in the preoperative
radiation treatment arm, although overall
quality of life was rated good.
• Short interval between radiation and surgery
may not have allowed sufficient time for
tumor regression (downstaging) for improved
sphincter preservation.

24. Total Mesorectal Excision
(TME)
• Initial studies reported local-regional failure
rates of less than 5% after TME without the
use of any adjuvant therapy
• These excellent results could not be
replicated in larger population-based studies.

25. This study highlighted the value of radiation
treatment, even with TME

26. CONCLUSION
• Pre-operative RT improves survival for
patients with locally advanced disease treated
without total mesorectal excision.
• For patients treated with total mesorectal
excision, the baseline risk for local recurrence
is reduced and pre-op RT improves local
control but not survival.

27. Pre-op Long course RT vs Pre-op
ChemoRT

29. LONG COURSE RT
• Pre-op chemoRT increased the rate of pCR (5 vs
15%)and LC (80–85% vs 90%),
• But not sphincter preservation(50%) or OS (65%)
compared with pre-op RT alone.
• More acute toxicity
• PREOP CHEMORT BETTER THAN PREOP LONG
COURSE RT ALONE

30. Pre-op RT vs Post-op ChemoRT

31. ALL GROUPS BENEFITTED FROM
PREOP RT

32. Preop ChemoRT vs Postop
ChemoRT

33. T3/T4/N+
Rectal Cancer
n=823
Surgery (TME) ChemoRT
Surgery (TME)
50.4Gy/28Fr/5.5 wks
1995-2002 Sauer 2004
ChemoRT
55.8Gy/31Fr/6wks
5FU (CI D1-5) wk1
and wk5
5FU based adjuvant chemotherapy x 4
5FU (CI D1-5)
wk1 and wk5
German Rectal Cancer Study
33

34. • LC significantly better with pre op chemo RT
(LF 8% vs 13%)
• OS not different
• Pre op chemo RT had significantly less acute
toxicity (27% vs. 40%) and late toxicity (14%
vs. 24%)
• increased sphincter preservation (39% vs 19%),

35. • There was significant tumor downstaging after
preoperative CRT, with an 8% pCR.
• The sphincter preservation rate was 39%
versus 19% in preop CRT arm

36. • NSABP R-03 (Roh JCO 2009): Phase III, closed
early due to poor accrual.
• Confirmed findings of the German Rectal
Cancer Study.

37. CONCLUSION
• WITH THIS EVIDENCE PRE OP CHEMORADIATION
HAS BECOME THE STANDARD OF CARE FOR
OPERABLE T3/T4/N+ RECTAL CANCERS

38. Pre-op Short-Course vs Pre-op
Long-Course ChemoRT

39. ;
Short
course
RT
Long
course
CRT
Local Rec 9% 14.2%
DFS 58.4% 55.6%
DM
OS 67.2% 66.2%
Acute Tox 3.2% 18.2%
Late Tox 10.1% 7.2%
• ChemoRT did not
increase OS, LC,or late
toxicity.
• Patients treated with
chemoRT were likely to
have higher pCR rates
and lower pathologic
stage and radial margin
involvement.
39Equivalent

40. • 3-year LR rates were
non significantly
reduced with long-
course CRT (7.5% vs
4.4%,p = 0.24).
• No difference in distant
recurrence or overall
survival.

41. These trials had modest
sample sizes,
which limit their ability to
detect small differences
between groups
New trials evaluating sequential
neoadjuvant short-course RT and
chemotherapy are ongoing.
Long term data needed

42. • As of now preop chemoradiation followed by
surgery is the standard of care in T3/T4 /Node
positive cases.

44. Conclusions
o Short course RT with or without delay compared with Long
course RT with delayed Surgery has a similar outcome.
o Long-course RT with delay is similar to both short-course RT
regimens, but prolongs the t/t time substantially.
o Delaying surgery after short-course RT gives similar
oncological results compared with shortcourse radiotherapy
with immediate surgery.
o Short-course RT with delay had less postoperative
complications.
o Short-course RT with delay to surgery is useful alternative to
conventional short-course RT

45. Sphincter preservation
Theoretical potential for sphincter preservation in low lying tumors
where an APR would otherwise have been done
2 Metanalyses however could not find any evidence for
sphincter preserving benefits from RCTs comparing
neaodjuvant RT/CRT vs. Sx alone, regardless of the
timing of surgery. (Bujko 2006, Gerard 2012)

46. WHAT IS THE OPTIMAL TIMING OF
SURGERY AFTER NEOADJUVANT
CHEMORADIATION

49. o Longer waiting
interval (more
than the classical
6-8 weeks)
increases the rate
of pCR by 6%.
1. Waiting 11 weeks
after CT-RT did not
increase the rate of
pCR after surgical
resection
2. Longer waiting period
may be associated
with higher morbidity
and more difficult
surgical resection
7-10 WEEKS

50. FUTURE SCOPE CAN WE
AVOID
SURGERY?

51. FUTURE SCOPE
• THE WATCH AND WAIT
• The “watch and wait” approach was first
proposed by Dr. Angelita Habr-Gama in Brazil
in 2009
• Those patients with cCR are followed with
close surveillance physical examinations,
endoscopy, and imaging

52. Habr Gama story…
RT 50.4 Gy / 1.8 Gy
5-FU/LV
361
6-8 weeks
cCR
DRE, Proctoscopy,
biopsy, MRI, ERUS
Stage 0
If sustained cCR
for 12 months
90(27.4 %)
Monthly F/U
Proctoscopy, CEA;
CT,X Ray 6 months
Habr-Gama et al, Ann Surg 2004
30 June 2018What we learnt from ESTRO 52
90 (49%) patients achieved cCR. Of
these, the 5-year LRFS rate was 69% and salvage
therapy was possible in 93% of failures (primarily R0
resection).

53. LOCAL EXCISION VS TME

54. TARGET VOLUME
• Site of local involvement
• Spread to other organ - sacrum, vagina or
prostate
• Whole of the sacrum

57. 3DCRT/IMRT
• The GTV includes all gross tumour seen on the
planning CT scan with reference to information
from diagnostic endoscopy, MRI and DRE
• Any involved lymph nodes, extrarectal extension,
or extranodal deposits seen on MRI should be
included
• CTV should include peri-rectal, pre-sacral,
internal iliac regions and margins for GTV
• PTV margin should be ~0.7 to 1.0 cm,

58. • 3DCRT
• Currently, IMRT is not
recommended for
routine use.
• IMRT can be used in re
irradiation for
recurrence

59. DOSE
• PREOPERATIVE RADIOTHERAPY
• Short course: 25 Gy in 5 daily fractions of 5 Gy given
in 1 week.
• Long course
• Phase 1
• 45 Gy in 25 daily fractions of 1.8 Gy given in 5 weeks.
• Phase 2
• 5.4 in 3 daily fractions of 1.8 Gy
• POSTOPERATIVE RADIOTHERAPY
• Phase 1
• 45 Gy in 25 daily fractions of 1.8 Gy given in 5 weeks.
• Phase 2
• 5.4–9 Gy in 3–5 daily fractions of 1.8 Gy.

60. Take home messages
• Radiotherapy adds to local control with both TME and non-
TME surgery
• Concurrent chemotherapy adds to the local control benefit
of long course RT
• Preop chemo RT is better than post op chemo RT
• Short course RT may be a simple and equally effective
alternative to mid and upper rectal cancers that do not
require downstaging/downsizing
• Short-course RT with delay to surgery is useful alternative to
conventional short-course RT.
30 June 2018 60

61. THANK YOU