1) Preoperative chemoradiotherapy improves local control rates and tumor downstaging for rectal cancer compared to postoperative chemoradiotherapy or radiotherapy alone. 2) The addition of chemotherapy to radiotherapy, whether in the preoperative or postoperative setting, improves local control and disease-free survival compared to radiotherapy alone. 3) For patients who achieve a clinical complete response after preoperative chemoradiotherapy, observation without surgery may be feasible, with local recurrence rates of approximately 30% that can often be successfully salvaged.

1. Radiotherapy in Carcinoma
Rectum
Presenter : Dr Sagar N Raut
Moderator : Dr Rohit Mahajan
14/10/19

2. Contents
• Introduction
• Indications
• Evidence
• Short Course RT
• RT techniques

3. Introduction
• Trials comparing role of adjuvant radiotherapy compared to surgery alone.
• showed reduced LF with radiotherapy; however, no improvement in DFS, DM, or OS 1
• LF & OS rate for T3 or T4 or node-positive patients 2
• Surgery alone - >25% and 40% to 50% resp, whereas
• CRT - 10% to 15% and 50% to 60%.
1. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001;358(9290):1291–1304.
2. Perez & Brady 7th Ed.

4. • There is substantial incidence of locoregional failure with surgical therapy alone.
• Older studies - local failure rates of up to 50% in patients with T3 to T4 or N+
Devita 11th

5. Post-operative RT
• Indications
• pT3-4,
• pN1-2,
• positive margin,
• poor differentiation,
• LVI
• SM3 invasion (Submucosal invasion to the lower third of the submucosal level)
NCCN

6. • Advantages –
• Ability to selectively treat patients at high risk of LF on the basis of pathologic criteria.
• Disadvantages –
• Potentially hypoxic postsurgical bed, making radiation and chemotherapy less effective,
• Potentially higher complications due to increased small bowel in the radiation field.
• Larger treatment volumes, particularly in patients undergoing an APR where the
perineal scar may need to be covered.

7. •Preoperative RT
• Indications
• cT3-4 or
• cN1-2.
• Locally unresectable
• Medically inoperable
NCCN

8. • Neoadjuvant therapy is associated with
• Tumor downstaging,
• Improved resectability and tolerance (both acute and chronic), and
• Potential for expanded sphincter preservation options in the distal rectum.
Perez & Brady 7th Ed

9. • The role of radiotherapy as adjunct to surgery has evolved over the
decades with
• Changes in the timing (preoperative vs postoperative),
• Length (short course vs long course),
• Intent (neoadjuvant vs definitive), and
• Delivery 3D-CRT vs IMRT

10. Evidence

11. •What is the value of adding RT to CHT in adjuvant
setting?
• Multiple studies examined adjuvant role of pelvic radiation and collectively
found that adjuvant radiation alone decreased the risk of local recurrence but
did not significantly improve overall survival.
• The addition of adjuvant chemotherapy was noted to reduce the rates of
distant metastases while improving disease-free survival
1. Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal cancer: a systematic overview of 8,507 patients from 22 randomised trials. Lancet 2001; 358(9290):1291–304.
2. Thomas PR, Lindblad AS. Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol
1988;13(4):245–52. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3064191. Accessed October 9, 2016.
3. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324(11):709–15.

12. Wolmark, NSABP R-02
• PRT of 694 pts
• Dukes B (AJCC T3N0) and C (node-
positive) rectal cancer
• All female pts received 5-FU plus LV
CHT;
• male pts received either MOF or 5-
FU plus LV.
A) postoperative adjuvant
CHT alone
B) CHT with postoperative RT

13. • chemoRT significantly improved LC in arm.
Conclusion: Addition of RT to CHT improves LC but not OS.

14. •Does concurrent CHT improve outcomes over
long-course RT alone?

15. • PRT of 733 pts
• T3-4NxM0 rectal ACA,
• accessible to DRE
• 50% of pts in both arms received
adjuvant 5-FU CHT
A) Pre-op RT 45 Gy/25 fx
B) pre-op chemoRT with
bolus 5-FU + LCV on weeks 1
and 5

16. • ChemoRT reduced LF (8.1% vs. 16.5%, p < .05) and pCR (11.4% vs. 3.6%, p < 0.05) at
cost of increased grade 3-4 toxicity (15% vs. 3%, p < .05)
• No change in sphincter preservation.

17. • PRT of 1,011 pts (≤80 y/o) with
• T3 or resectable T4 rectal ACA
• within 15 cm of anal verge
• TME not routine
A) pre-op RT 45 Gy/25 fx
B) pre-op chemo
C) pre-op RT and post-op CHT
D) pre-op chemoRT and post-op CHT

18. • 5-yr incidence of LR was 17.1%, 8.7%, 9.6%, and 7.6% per arms of study, respectively.
• There was no effect on OS.
• Conclusion: Preoperative chemoRT is superior to long-course RT alone with respect to LC.

19. Does concurrent CHT improve outcomes over
long-course RT alone?
• Addition of chemotherapy improves Local control

20. •Why is addition of chemoRT to surgery
standard for rectal cancer?

21. • PRT of 227 pts
• Dukes B2 and C rectal (T3-4 or N+)
ACA, R0 resection, no mets, distal
edge of tumor <12 cm from verge.
R
a
n
d
o
m
is
e
d
A) Surgery alone
B) post-op CHT (bolus IV 5-FU/M-CCNU)
C) post-op RT 40 or 48 Gy
D) post-op chemoRT: 40 or 44 Gy + 5-
FU 500 mg/m2 F/B adjuvant 5-FU/M-
CCNU as in CHT alone arm

22. • Overall, CHT reduced DM (20% vs. 30%) and RT decreased LR (16% vs. 25%).
• Conclusion: Adjuvant chemoRT improves LR and OS in rectal cancer.

23. Cont..
Results of GITSG 7175 Rectal Cancer
7-yr LR 7-yr OS
Surgery 24% 36%
Surgery + RT 27% 46%
Surgery + CHT 20% 46%
Surgery + chemoRT +
adjuvant CHT
11% 56%

24. Krook, NCCTG 794751
• PRT of 204 pts with
• T3-4 or N+,
• within 12 cm of anal
verge randomized
A) post-op RT 45 Gy/25 fx + 5.4
Gy boost to tumor bed and
adjacent LN
B) post-op chemoRT with 5-FU
bolus + semustine x1 month,
then bolus 5-FU 500 mg/m2
concurrent with RT, then 2 mos
consolidative 5-FU/semustine.
APR or AR

25. • ChemoRT improved OS, DFS, LR and rate of DM compared to RT alone.
• Conclusion: Adjuvant chemoRT is preferred to RT alone.

26. •What is the benefit of pre-op chemoRT over
postoperative chemoRT?

27. • PRT of 823 pts
• ≤75 years of age with cT3-4 or cN+ rectal ACA
with inferior margin ≤16 cm from anal verge,
• Compliance higher in pre-op arm 90% versus
~50% in post-op arm.
A) preo CRT 50.4 Gy/28 fx
with infusion 5-FU f/b TME in
6 wks f/b adj chemo
B) Postop chemoRT 50.4
Gy/28 fx with 5.4 Gy boost to
tumor bed 4 weeks following
surgery

30. • Conclusion: Preoperative chemoRT improves LC, tumor downstaging, reduces
late effects, and is preferred to postoperative chemoRT.

31. Long-term Results of German Rectal Study
10-yr LR 10-yr DM 10-yr OS 10-yr DFS Acute Grade 3-4 Late Grade 3-4
Pre-op
chemoRT
7% 29.8% 59.6% 68.1% 27% 14%
Post-op
chemoRT
10% 29.6% 59.9% 67.8% 40% 24%
p value .048 .9 .85 .65 .001 .01

32. • PRT of 267 pts (900 planned)
with
• cT3-4 or
• N+ rectal ACA,
• lesion <15 cm from verge,
• M0
A) pre-op 5-FU 500 mg/m2 and
leucovorin 500 mg/m2 x6 weeks F/B
chemoRT 50.4 Gy/28 fx with
concurrent 5-FU+LV
B) Postop chemoRT (same as
pre-op)

33. • Trial was underpowered with improved DFS with pre-op chemoRT
64.7% versus 53.4% p = .01 but no difference in OS.
• Trial had 15% pCR rate.
• Conclusion: Although underpowered, supports pre-op chemoRT as
preferred approach.

34. What is the benefit of pre-op chemoRT over postop
chemoRT?
• Preoperative chemoRT for cT3, T4, N+ tumours improves LC, tumor
downstaging, reduces late effects, and is preferred to postoperative
chemoRT

35. •Does increased interval of time between pre-op
chemoRT and surgery impact pCR rates?

36. • PRT of 265 pts from 24 centers. cT3/4 or cN+ pts in mid or lower rectum were
eligible. ChemoRT included 45 to 50 Gy with 5-FU or capecitabine.
• ChemoRT, then randomized to surgery at either 7 or 11 weeks.
• Primary endpoint was pCR rate.
• 82% of tumors were cT3.

37. • Overall, 47 pts (18.6%) achieved pCR.
• pCR rates were not different between 7 and 11 weeks (15% vs. 17.4%, p =
.598).
• However, morbidity was significantly increased in 11-week group (44.5% vs.
32%, p = .04) and quality of TME was also worse (complete mesorectum
78.7% vs. 90%, p = .02).
Conclusion: Waiting 11 weeks after chemoRT did not increase rate of pCR.
Longer waiting period may be associated with higher morbidity and more
difficult surgical resection.

38. •Since pCR is associated with improved outcomes, can
additional CHT after pre-op long-course chemoRT
increase pCR rates?

39. • Phase 2, nonrandomized study with four consecutive groups:
• Group 1 underwent chemoRT followed by surgery 6 to 8 weeks later;
• Groups 2 to 4 received two, four, or six cycles of mFOLFOX6, respectively, after long-
course chemoRT followed by surgery.
• Primary endpoint pCR.

40. • 292 pts registered,
• pCR rates:
• Study group was independently associated with pCR (p = .011).
• Grades 3 and 4 toxicities were increased with neoadjuvant therapy: group 2
(3%), group 3 (18%), group 4 (28%).
• Conclusion: mFOLFOX6 prior to surgery is being evaluated for nonoperative
management of rectal cancer.

41. •In pts who achieve cCR after pre-op therapy,
can surgery be omitted?

42. • RR of 265 pts with distal rectal adenocarcinoma (cT2-4, 24% node-positive)
treated with 50.4 Gy/28 fx and 5-FU/LCV.
• 71pts (26.8%) developed cCR and additional 8.3% were pT0 on resection.
• Pts with cCR had 100% 5-yr OS and in pT0 group 5-yr OS was 88%.

43. • Review and RR of 173 pts from 1991 to 2009 treated with neoadjuvant
chemoRT 50.4 to 54 Gy with concurrent 5-FU; 63% cT3/T4, 21% cTxN1-2.
• MFU of 65 mos. 67 pts (39%) developed cCR.
• Of these 67 pts, 13% underwent rectal biopsy and 87% were managed
without surgical procedures.

44. • Recurrences were observed in 15 pts (21%): 8 pts developed local only
recurrence and 7 developed DM.
• Median time to recurrence was 38 mos.
• Of 8 pts who recurred locally, seven were successfully salvaged.
• 5-yr OS was 96% and 5-yr DFS was 72%.
Conclusion: Early retrospective data suggests it may be feasible to reserve
surgery for salvage after cCR to chemoRT.

45. • 259 pts were included of which 228 underwent surgery and 31 (12%) had
complete CR and underwent watch and wait.
• Additional 98 pts with clinical CR were included via national registry for total
of 129 pts managed by watch and wait.
• MFU 33 mos.

46. • 44 (34%) had LR and 36 of 41 pts were salvaged.
• In matched analysis, there was no difference in non-regrowth DFS between
watch and wait and immediate post-chemoRT surgery (88% and 78%, p =
.04).
• No difference in 3-yr OS (96% vs. 87%, p = .02).
• Improved 3-yr colostomy-free survival in watch and wait (74% vs. 47%).
• Conclusion: Watch and wait can be considered in many pts without
detriment in 3-yr OS.

47. •Can RT be omitted in pts with cT3N0 rectal
cancer?

48. • RR review of 188 pts with cT3N0 rectal cancer who underwent preoperative
chemoRT followed by resection.
• Despite pCR rate of 20% in pts, 22% of pts had pathologically involved
mesorectal lymph nodes.

49. • Although overstaging and overtreatment are possible with preoperative
treatment, a larger number of patients would be understaged and require
postoperative therapy.
• Thus, there is likely a limited subset of patients with T3 N0 rectal cancer who
might have an excellent outcome with surgery alone, but there are no
randomized data to support the omission of (neo) adjuvant therapy for this
group of patients at the present time.
Perez & Brady 7th Ed.

50. NCCN
• Observation can be considered in pT3N0 in
• Well differentiated or moderately differentiated
• Invading <2mm in mesorectum
• Without lymphatic or venous vessel involvement
• Located in upper rectum

51. Short-course RT

52. •Is short course of preoperative RT effective
compared to surgery alone?

53. • PRT of 1,168 pts with
• resectable rectal carcinoma,
• age <80,
• planned abdominal surgery,
and
• no mets
A) 25 Gy/5 fx followed by
surgery within 1 week
B) surgery alone

54. • Conclusion: Pre-op RT is associated with significantly improved LC and OS
compared to surgery alone.
• Comment: non-TME surgery, increase risk of late small bowel obstruction in
RT group.

55. •If TME is performed, is short-course RT still
beneficial?

56. • PRT of 1,861 pts with
• clinically resectable adenocarcinoma of rectum, M0
• inferior tumor margin <15 cm from anal verge randomized to
• 25 Gy/5 fx followed by TME or
• TME alone.

57. • 10-yr LR was reduced from 11% to
5% (p < .0001) with no change in
OS or DM.
Conclusion: Preoperative RT with 25 Gy/5 fx significantly improves LC,
even with good surgery (TME), but does not improve OS

58. •Is pre-op short course better than post-op
chemoRT?

59. • PRT of 1,350 pts with
• resectable rectal ACA, (distal tumor <15 cm from verge), M0
• (a) 25 Gy/5 fx followed by surgery or
• (b) surgery followed by post-op chemoRT (45 Gy/25 fx with concurrent 5-FU)
for those with positive circumferential margin.

60. • Most node-positive pts received
adjuvant CHT.
Conclusion: Pre-op short course is superior to selected post-op chemoRT.

61. •How does pre-op long-course chemoRT
compare to short-course pre-op RT?

62. • PRT of 312 pts with
• cT3-4 with no evidence of
sphincter involvement
A) 25 Gy/5 fx followed by
TME within 7 days
B) 50.4 Gy/28 fx with
concurrent bolus 5-FU+LV
followed by TME 4 to 6 weeks
later

63. • No difference in sphincter preservation, LR, OS, or DFS.
• Conclusion: Long-course chemoRT did not increase OS, LC, or late toxicity
compared to short-course RT.
• Comment: Limitations to this study include clinical staging (no US or MRI),
no standard post-op chemotherapy, not all TME, and no RT QA.

64. • PRT of 326 pts with
• cT3N0-2M0 rectal ACA,
• within 12 cm of verge (US or
MRI staged)
A) 25 Gy/5 fx (given in 1 week),
surgery in 3 to 7 days, six cycles 5-FU
with folinic acid
B) 50.4 Gy/28 fx + CONTINUOUS
INFUSION 5-FU (225 mg/m2), surgery
in 4 to 6 weeks, four cycles of 5-FU
with folinic acid

65. • No differences in LR, DR, OS or late grade 3-4 toxicity (Table 34.10).
• For distally located tumors, LR 12.5% in arm 2 vs 3% in arm 1, p = NS.
• Conclusion: Short-course pre-op RT is equivalent to pre-op chemoRT
without increased late toxicity. Unclear if short course is equivalent to long
course for distally located tumors.

66. •How long after short-course RT should surgery
be performed?

67. • Polish study of 154 pts randomized to early surgery (7–10 days) versus
delayed (4–5 weeks) after short-course RT.
• Significantly higher rate of downstaging was achieved, (44% vs. 13%), for
those who underwent delayed surgery.

68. • No differences were seen in sphincter sparing procedures, LC or OS.
• Conclusion: In limited size prospective trial, delayed surgery after short course
RT is feasible and associated with higher rate of downstaging.

69. • PRT (noninferiority) of 840 pts
• resectable rectal
adenocarcinoma without
evidence of metastasis.
A) short-course RT (25 Gy/5 fx), then
surgery (within 1 week),
B) short-course RT then surgery (4–8
weeks after RT)
C) long-course RT only (50 Gy/25 fx)
then surgery (4–8 weeks after RT)

70. • LR was 2.2%, 2.8%, 5.5% per arms of study, respectively (p = NS).
• Postoperative complications were similar between three arms of study.
• However, when evaluating only short-course pts, risk of postoperative complications
was lower in arm (2) compared to arm (1) (41% versus 53%, p = .001).
• Conclusion:
• Oncologic outcomes were similar between immediate surgery and delayed surgery after short-
course RT.
• Similarly, long-course RT is similar to both short-course regimens.
• Postoperative complications were lower in pts who underwent delayed surgery after short-
course RT.

72. Radiotherapy Techniques

73. Adjuvant post-operative Irradiation
• Performed 4-6weeks after radical surgery in cases with pT3, T4, N1,
N2)
• Target Volume: Posterior pelvis
• Technique: Four field box technique
• Localization: Marks on perineal scar, anal margin and/or vagina

74. Patient Position
• Supine with body immobilization or
• Prone with use of a belly board for
anterior displacement of bowel

75. Simulation (Cont..)
• Oral contrast 30 min prior to simulation -differentiate small bowel/large bowel
• Bladder Protocol
• Planning CT scan of abdomen and pelvis is obtained at 3-mm intervals (Inferior
edge of the L2 through mid-thigh)
• IV contrast -delineate GTV and pelvic blood vessels
• Place fiducials at anal verge
• Diluted rectal contrast helps in tumour delineation

76. Field Margins
Posterior and anterior fields
Upper Limits
Upper Rectum:
L5-S1
Lower Limits
3-5cm below palpable tumor
After APR: Lower extremity of perineal scar
After AR: 5cm Below best estimate of preoperative
tumor bed
Lateral Limits
1.5-2cm from Pelvic rim

77. Lateral Field
• Upper and lower limits: as AP-PA
• Posterior limits: 2cm behind
anterior bony sacral margin
• Anterior limit: 4cm anterior to
rectum (ensuring adequate
coverage of mesorectum)

79. Guidelines for target delineation
• RTOG
• International Working Group

80. RTOG
• CTVA: always treated for rectal cancer: internal iliac, pre-sacral, and
peri-rectal
• CTVB: external iliac nodal region
• CTVC: inguinal nodal region

81. International working group subsites
• Pre-sacral nodes (PN)
• Mesorectum(M)
• Lateral lymph nodes (LLN),
• External iliac nodes (EIN)
• Ischio-rectal fossa (IRF)
• Sphincter complex (SC)
• Inguinal Nodes (IN)

84. • •Includes rectum and its mesentery& internal iliac region
• •Margin for bladder variability.
• •Post & latmargins should extend to pelvic sidewall musculature or,
where absent, bone.
• •Anteriorly extending~1 cm into post. bladder, Include post. portion
of internal obturator vessels

85. Boost Volumes and Planning Target Volumes
• Boost CTV extend to entire mesorectum and pre-sacral region at involved
levels, including ~1–2 cm cephalad and caudad in the meso-rectum and ~2
cm on gross tumor within the anorectum.
• PTV margin should be ~0.7 to 1.0 cm as per institutional protocol and
technique employed
• At skin, where it be trimmed to ~2–5 mm within the skin surface.

86. International working group (2016)
• CTV for elective irradiation of all regional lymph node levels

88. • Image from TPS

90. • Anterior border of the posterior lateral node
(purple), when the ureters join the bladder (red
line).

93. • Cranial border of the ischio-rectal fossa (blue), where the inferior pudendal
artery leaves the pelvis going into the Alcock’s canal.

94. SC: Sphincter Complex
• Limits:
• From the anal-rectal junction.
Around the sphincter
• Recommendations
• To include in case of sphincter
infiltration

97. Organ At Risk (OAR)

98. Take Home Message
• Indications Post-op RT - pT3-4, pN1-2, positive margin, poor differentiation,
LVI
• Standard is CRT, dose depends on margin status
• Indications of pre-op RT – cT3, T4, N+
• Short course RT similar to long course CRT in preop
• Selected pT3N0 – RT can be avoided

99. • Preop Short course RT equivalent to long course CRT
• Optimal Duration of Surgery post CRT 6-8 weeks, post Short course 1
week or can be delayed

100. Thank You