CARCINOMA RECTUM MANAGEMENT

1. Ca.Rectum part II
Presenter: Dr. Masthan Basha
Moderator: Dr. B.V.Subramanian

3. surgery
• Surgery is the mainstay of treatment of RC.
• After surgical resection, local failures are common.
• Local recurrence after conventional surgery: 20%-50% (average of
35%)
• Recent results of national cooperative group studies and several
European randomized trials indicate that a multimodality treatment
approach, particularly neo adjuvant treatment, results in a
significantly better outcome than surgery alone

4. Surgery
• Surgical management depends on the stage and location of a tumor
within the rectum.
• APR or LAR combined with Total mesorectal excision is the standard
of care except for T1 lesions where a local excision might be
sufficient.
• Radial margin positivity bears an independent risk factor for loco
regional recurrence of the disease.
• On Pathological review an appropriate dissection should include a
minimum of 12 to 15 perirectal and pelvic LNs.

5. Types of surgery
• LOCAL EXCISION:
• Early rectal cancers can be resected with local excision techniques,
but patients should be carefully selected for these procedures.
• Trans anal excision, trans sphincteric excision (York-Mason), and a
posterior parasacral approach (Kraske) permit removal of the tumor
and adjoining rectum
• Local excision should be limited to tumors that are small (<4 cm),
clinically T1 (or favorable T2 patients in selected situations), well to
moderately differentiated, and involve <40% of the circumference
of the rectum.
• Properly selected T1 lesions have excellent results with local
excision alone, with 5-year LC ranging from 82% to 97% and OS
rates of 90% or better.

6. LOW ANTERIOR RESECTION( Sphincter
preserving surgery)
• Previously done in upper 1/3 rd of rectal cases
• Now, the availability of circular stapling devices has expanded the
role of LAR for middle- and lower-one-third cancers.
• Patients should have good anal sphincter continence prior to LAR
• Patient age, pelvic anatomy, gender, and body habitus can affect
suitability for sphincter preservation.
• A 2-cm distal margin of preserved normal rectum is considered
optimal for preservation of adequate bowel function.
• Several studies comparing results of LAR to APR generally reported
similar outcomes for local and distant recurrence rates and survival
as long as surgical margins are negative.
• The absence of a colostomy with a better quality of life

7. Abdominoperineal Resection
• APR has been considered the gold standard for surgical resection of
distal rectal cancer
• Requires removal of the primary tumor along with a complete
proctectomy, leading to a permanent colostomy.
• APR is associated with a slightly higher morbidity and mortality
than LAR and a worse quality of life.

8. Total Mesorectal Excision
• local failures are most often due
to inadequate surgical clearance
of radial margins.
• conventional resection violates
the mesorectal circumference
during blunt dissection, leaving
residual mesorectum.
• TME involves precise dissection
and removal of the entire rectal
mesentery as an intact unit.
• local recurrence with
conventional surgery averages
approx. 25-30% vs. TME 5-10 %
Total mesorectal excision specimen with
designation of the lower mesorectum
and upper anal canal
Upper anal
canal
Lower
mesorectum

9. Complications of Surgery
• Bleeding
• Infection
• Anastomotic Leakage
• Blood clots
• Anesthetic Risks

10. Adjuvant Therapy
• Advantage of postoperative radiation is the ability to selectively
treat patients at high risk of LF on the basis of pathologic criteria.
• Disadvantages include a potentially hypoxic postsurgical bed,
making radiation and chemotherapy less effective, and potentially
higher complications due to increased small bowel in the radiation
field.
• Postoperative treatments tend to require larger treatment volumes,
particularly in patients undergoing an APR where the perineal scar
may need to be covered.

11. Two trials of CRT demonstrating an improvement in OS
were the Gastrointestinal Tumor Study Group (GITSG) and
North Central Cancer Treatment Group (NCCTG) studies.
• The GITSG study was a four-arm trial of 227 patients with stage B2
and C rectal cancer who, after R0 resection, were randomized to
• (a) surgery alone
• (b) postoperative chemotherapy of bolus 5-FU (500 mg/m2 in
weeks 1 and 5 and methyl-CCNU [semustine] given day 1)
• (c) postoperative radiation treatment of 40 to 48 Gy split course
• (d) postoperative CRT of 40 to 44 Gy plus bolus 5-FU.

12. • This trial was terminated early, due to significant benefits seen with
CRT.
• In a subsequent update, postoperative CRT improved 10-year OS,
45% versus 27% compared with observation after surgery.
• LF rate was decreased to 10% versus 25% with surgery alone.
• Therefore, this trial concluded that there was a significant OS
advantage (near doubling of survival) for pt who had CRT after
surgical resection.
• The severe acute toxicity was 61% in the combined modality
treatment arm, as compared to 31% with chemotherapy only and
18% with radiation only

13. The Mayo–NCCTG study compared postop RT Vs
postoperative CRT
• Two hundred four patients with T3/T4 or node-positive tumors
received one cycle of 5-FU and semustine before randomization.
• The radiation dose was 45 to 50.4 Gy to tumor bed and adjacent
lymph node regions.
• Bolus 5-FU (500 mg/m2) was administered concurrently with
radiotherapy.
• The 5-year local-regional failure was higher in the radiation-only
arm 25% versus 13%, and the 5-year OS was 40% versus 55% (in
favour of CRT).

14. • The NCCTG 86-47-51 study compared chemotherapy regimens to
be added to postoperative radiation therapy.
• 660 stage II or III patients were randomized to receive
chemotherapy (5-FU vs. 5-FU + semustine) and the method of
delivery (bolus vs. continuous infusion [CI] 5-FU).
• The bolus 5-FU dose was 500 mg/m2 on day 1 to 5 during weeks 1
and 5, and the CI 5-FU was 225 mg/m2 per day.

15. With a median follow-up of 46 months:
• There was a 27% improvement in RFS of 63% vs 53% in favor of CI
5-FU.
• The 4-year OS was 70% versus 60% in favor of CI.
• The time to relapse and the DM rate (31% vs. 40%) were also lower.
• There was no difference in LR.
• Bolus 5-FU had a higher rate of leucopaenia, whereas CI had more
acute severe diarrhoea, which did not persist after conclusion of
CRT.
• Semustine was of no additional benefit beyond 5-FU chemotherapy.

16. Neoadjuvant Therapy
• Although both preoperative and postoperative adjuvant therapy
can be effective, neoadjuvant treatment has emerged as the
standard of care.
• Neoadjuvant therapy is associated with tumor downstaging,
improved resectability and tolerance , and potential for expanded
sphincter preservation options in the distal rectum.

17. The Swedish Rectal Cancer Trial included 1,168 patients
accrued from 1987 to 1990 with resectable, Dukes A to C
rectal cancer.
• Patients were randomized to 25 Gy in five fractions in 1 week
followed by surgery 1 week later versus surgery alone.
• The 5-year LR (11% vs. 27%) and OS (58% vs. 48%) were superior
with preoperative radiation treatment compared to surgery alone.
• The LR and OS benefit persisted with long-term follow-up.
• At a median 13 years, LR was 9% versus 26% and OS was 38%
versus 30%, both in favor of preoperative radiotherapy, with all
stages benefiting.

18. • This trial set the standard of care in many European centers.
• One drawback of this study is that the surgery-alone arm did not
use TME.
• The dose of 5 Gy times five fractions may potentially contribute to
late toxicity, and the short interval between radiation and surgery
may not have allowed sufficient time for tumor regression
(downstaging) for improved sphincter preservation.

19. French trial, Lyon 90–01
• Justification for a longer interval after preoperative radiation treatment
before surgery was demonstrated in a French trial, Lyon 90–01, which
delivered 39 Gy as 3 Gy per fraction (no preoperative chemotherapy).
• 201 patients were randomized to surgery within 2 weeks versus 6 to 8
weeks of radiotherapy.
• The LC and OS after a median follow-up of 33 months were the same in
both arms of the study.
• However, the pCR was 7% versus 14% (p = NSS [not statistically
significant]), and the pathologic downstaging was 10% versus 26% (p =
.007) in favor of the longer interval before surgery.

20. Dutch
(CKVO 95-04) multicenter, phase III study
• This study of 1,861 patients was undertaken to evaluate the role of short-
course preoperative radiation with TME.
• Patients were randomized to TME alone versus 25 Gy in five fractions
followed by TME surgery.
• No fixed tumors were included in the study, and approximately half of the
patients had T1 or T2 disease.
• The 2-year OS was 82% in both arms of the study; however, the 2-year LR
was 8.2% in the TMEonly arm as compared to 2.4% in the preoperative
arm.
• This highlighted the value of radiation treatment, despite use of TME.

21. Dutch study
• Ten year follow-up indicates persistent benefit in LR of 5% (RT) vs.
11% (TME alone).
• Updated toxicity analysis indicates a higher incidence of sexual
dysfunction and slower recovery of bowel function, more fecal
incontinence, and generally poorer quality of life with preoperative
radiation.

22. • Two meta-analyses of approximately 6,000 patients each were done to
explore the benefit of preoperative radiation treatment.
• One analysis included 14 randomized, controlled trials and reported that
neoadjuvant radiation treatment was associated with significantly fewer
local recurrences, improved specific survival, and an overall survival
benefit.
• The second meta-analysis, provided by the Colorectal Cancer Collaborative
Group, also reported on 14 randomized, controlled trials.
• They noted a significant reduction in the risk of local recurrence and death
from rectal cancer with preoperative radiotherapy.

23. Neoadjuvant ChemoRT
• The improvement in outcomes with CRT in the postoperative
setting led to adoption of this approach in the treatment of this
disease.
• More recently, in the United States neoadjuvant CRT has become
widely accepted, but in other parts of the world several groups
have undertaken studies to examine the potential benefit from
neoadjuvant CRT compared to radiation alone.

24. French study (Fédération Francophonedela Canérologie
Digestive 9203) – pre op RT Vs pre op CRT
• 733 patients with resectable T3 and T4 tumors randomized to 45 Gy of
radiation alone versus radiation with concurrent bolus 5-FU (350 mg/m2)
plus LV on days 1 to 5 during weeks 1 and 5.
• After surgery, four cycles of adjuvant chemotherapy were given.
• The primary endpoint was OS.
• Although there was no difference in 5-year OS between the two arms,
• pCR rates (11.4% vs. 3.6%) were higher and LR rates (8.1% vs. 16.5%) were
lower with CRT.
• Grade 3/4 acute toxicity was more frequent in patients receiving CRT, at
14.6% versus 2.7%.

25. • A similar study done by the European Organization for Research and
Treatment of Cancer (EORTC 22921) and got almost same results.
• A subsequent meta-analysis done including four trials and
compared results of preoperative radiotherapy with preoperative
CRT in patients with resectable stage II or III rectal cancer.
• The addition of chemotherapy significantly increased rates of grade
3/4 acute toxicity , higher rates of pCR and lowered the incidence of
LR
• No difference was seen in 5-year DFS or OS.
• Neoadjuvant CRT represents a reasonable standard of care

26. Long Course Neoadjuvant Chemoradiotherapy vs.
Short Course Neoadjuvant Radiotherapy
• Polish rectal cancer group did a study to determine whether a
short-course approach (5 Gy for five fractions) to neoadjuvant
therapy is better than a long course approach (50.4 Gy using 1.8- to
2-Gy # with concomitant bolus 5-FU/LV given during weeks 1 and 5)
• Although a higher pCR rate was seen with CRT (16% vs. 1%) and
considerable size reduction of the tumor (by approximately 1.9 cm),
no difference in the rate of sphincter preservation, LC, or OS was
seen.

27. The Australian Intergroup Trial
• 236 pts with cT3NxM0 rectal cancer were randomized to short course RT
(25 Gy in 5 fractions) with surgery within 1 week or long course CRT (50.4
Gy in 28 fractions with continuous infusion 5-FU 225mg/m2) with surgery
4-6 weeks following completion of CRT.
• Both regimens were followed by adjuvant 5-FU-based chemotherapy.
• Primary endpoint of this study was to compare LR rates at 3 years.
• With median follow up of 5.9 years, there was no difference in 3-year LR
(7.5% short course vs. 4.4% CRT), 5-year OS (74% short course vs. 70%
CRT) or late toxicity.
• Despite tumor downstaging, there was no difference in rates of sphincter
sparing surgery.

28. • The optimal neoadjuvant approach for resectable rectal cancer is
far from clear.
• Both short course RT (25Gy in 5 fractions) and long course CRT (50.4
Gy in 28 fractions with concurrent 5FU based chemotherapy)
represent reasonable therapeutic options.
• Many await long term data from these randomized trials to assess
for differences in late toxicities

29. • New drugs, including oral fluoropyrimidines (capecitabine),
oxaliplatin, and irinotecan, have been shown to be effective in the
treatment of metastatic colorectal cancer.
• Oral fluoropyrimidines, as part of a CRT regimen, are commonly
replacing infusional 5-FU.
• The incorporation of oxaliplatin and irinotecan into the neoadjuvant
regimen has been less promising.
Alternative Chemotherapy Regimens with
Neoadjuvant Radiotherapy

30. Capacitabine
• Capecitabine is an oral fluoropyrimidine prodrug that is readily absorbed
in the gastrointestinal tract and mimics the efficacy of CI 5-FU while
avoiding the risk of side effects and complications due to a central line for
CI 5-FU.
• Capecitabine requires the presence of thymidine phosphorylase (TP) for
conversion to the active form of 5-FU within the cells.
• TP is present in higher concentration in tumor cells, particularly colorectal
cancer than in normal tissues, and this potentially creates a therapeutic
advantage for capecitabine as compared to intravenous 5-FU.
• Capecitabine is generally given in two divided doses twice a day during the
course of radiation treatment.

31. Preoperative Versus Postoperative Therapy
• The definitive phase III study by the German Rectal Cancer Group.
• 823 clinically staged T3/T4 or node-positive rectal cancers were
randomized to preoperative CRT followed by TME 6 weeks later or TME
followed by postoperative CRT.
• The radiation dose was 50.4 Gy in 28 fractions in all patients, with a 5.4-Gy
small-volume boost in the postoperative arm.
• 5-FU (1 g/m2 per day) was administered during the weeks 1 and 5 of
radiotherapy as a 120-hour CI.
• Both arms received four additional cycles of 5-FU (500 mg/m2 per day for
5 days every 4 weeks.

32. • The 5-year results revealed a pelvic recurrence rate of 6% versus
13% (p = .02) in favor of the preoperative arm.
• The distant recurrence rate was 36% versus 38% (p = NSS), DFS was
68% versus 65% (p = NSS), and OS was 76% versus 74% (p = NSS) for
preoperative radiation versus postoperative,respectively.
• There was significant tumor downstaging after preoperative CRT,
with an 8% pCR.
• The sphincter preservation rate in 188 patients with low-lying
tumors (declared by the surgeon prior to randomization to require
an APR) revealed that 39% versus 19% had a sphincter-preserving
low anterior resection (p = .004) in the preoperative versus the
postoperative arm.
Preoperative Versus Postoperative Therapy

33. • There were fewer acute (27% vs. 40%) and late toxicities (14% vs.
24%) in preoperative-treatment group.
• Thus, preoperative CRT resulted in half the LF and doubled the
sphincter preservation rate compared to postoperative therapy.
• In addition, compliance rates were significantly improved in the
preoperative arm.
• Of importance, there was no difference in OS or DFS between the
two arms.
• An update, with a median follow up of 11 years continues to
demonstrate an improvement in local control but no difference in
DFS or OS with preoperative therapy.
Preoperative Versus Postoperative Therapy

34. • MRC CR07 trial re-evaluated the role of radiotherapy.
• A total of 1,350 patients were randomized to preoperative radiotherapy
(25 Gy in five fractions) or upfront resection with selective postoperative
chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-FU) in
patients with a ≤1-mm circumferential resection margin.
• At median follow-up of 4 years the LR was significantly lower in the
preoperative radiotherapy group (4.4% vs. 10.6%).
• 3-year DFS was improved in the preoperative therapy group (77.5% vs.
71.5%), but there was no difference in OS.
• Both the MRC CR07 and German rectal trial established preoperative
therapy, either short-course (25 Gy in five fractions) or long-course
chemoradiotherapy (50 Gy in 1.8-Gy fractions with concurrent 5-FU–
based chemotherapy), as the current standard of care

35. Radiotherapy techniques
• PRONE POSITION:
• To reduce the volume of small bowel within the pelvis.
• Maneuvers to reduce the volume of small bowel include treatment with a
full bladder and the use of belly board
• A marker is generally placed at the anal verge and intravenous, rectal, and
small-bowel contrast is often administered at the time of simulation for
accurate target and normal tissue delineation.
• Portals
• 4 fields (AP, PA, two lateral fields)
• 3 fields (PA, Rt & Lt Lateral fields)

36. Field Arrangement
A : Posterior-anterior
Superior border: L5-S1 junction
Distal border: 3- 5 cm below the primary tumor for preoperative
cases and for postoperative cases the distal field edge is about 5 cm below
the best estimate of the preoperative tumor bed and (if an APR has been
performed) below the perineum
Lateral borders: 1.5 cm lateral to the widest bony margin of the true pelvic
side walls.
• B : Laterals
Posterior border:
should encompass the entire sacrum for adequate coverage
of the presacral space.
Anterior border:
T3 disease: Posterior margin of the symphysis pubis (to treat only the
internal iliac nodes).
T4 disease: Anterior margin of the symphysis pubis (to include the
external iliac nodes).

37. Fig B: For a T4N1M0 rectal
cancer 8 cm from the anal
verge. Since the tumor was a
T4, the anterior field is at the
anterior margin of the
symphysis pubis (to include
the external iliac nodes).
Fig A: Treatment fields after a low anterior
resection for a T3N1M0 rectal cancer 8 cm
from the anal verge. The distal border is at
the bottom of the obturator foramen and the
perineum is blocked. Since the tumor was a
T3, the anterior field is at the posterior
margin of the symphysis pubis (to treat only
the internal iliac nodes).
Fig C: Treatment fields following an
abdominoperineal resection for a T4N1M0
rectal cancer 2 cm from the anal verge,
because the tumor was a T4, the anterior
field is at the anterior margin of the
symphysis pubis (to include the external
iliac nodes). Since the distal border is
being extended only to include the scar
and external iliac nodes, the remaining
normal tissues can be blocked

38. 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 (optional)
5.4–9 Gy in 3–5 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 (optional)
5.4–9 Gy in 3–5 daily fractions of 1.8 Gy.

39. CTVA: For this atlas, defined to be the regions that would always be
treated for rectal cancer: internal iliac, pre-sacral, peri-rectal.
CTVB: external iliac nodal region
CTVC: inguinal nodal region
For anal cancers, the elective regional target volume would include all
three.
For rectal cancer, in most cases, CTVA would be the only volume to
receive elective radiation.
However, for certain presentations (e.g. extension into GU structures,
extension to the peri-anal skin) one could consider adding the external
iliac (CTVB) and even the inguinal regions (CTVC).

40. • The case utilized for this atlas was a clinical T3 N2 rectal cancer
located 7 cm above the verge.
• with the presence of multiple peri-rectal lymph nodes, without
major distortion of the mesorectum .

41. Group Recommendations: CTVA (peri-rectal, pre-
sacral, internal iliac regions)
• Lower Pelvis: The caudal extent of this elective target volume should be a
minimum of 2 cm caudal to gross disease, including coverage of the entire
mesorectum to the pelvic floor.
• The group agreed that, unless there is radiographic evidence of extension
into the ischiorectal fossa, extension of CTVA does not need to go more
than a few millimeters beyond the levator muscles.
• For very advanced anal or rectal cancers, extending through the
mesorectum or the levators, the group’s recommendation is to add ~1-2
cm margin up to bone wherever the cancer extends beyond the usual
compartments.

42. • Mid pelvis:
• The posterior and lateral margins of CTVA should extend to lateral pelvic
sidewall musculature or, where absent, the bone.
• Anteriorly, the group recommended extending CTVA to ~1 cm into the
posterior bladder, to account for day-to-day variation in bladder position.
Also in the mid pelvis, the group recommended including at least the
posterior portion of the internal obturator vessels (which lie between the
external and internal iliacs in the mid pelvis) with CTVA.
• Upper pelvis:
• The recommended superior extent of the peri-rectal component of CTVA
was at whichever is more cephalad: the rectosigmoid junction or 2 cm
proximal to the superior extent of macroscopic disease in the rectum/peri-
rectal nodes.
• The most cephalad aspect of CTVA should be where the common iliac
vessels bifurcate into external/internal iliacs (approximate boney
landmark: sacral promontory).

43. Group Recommendations: CTVB (external iliac region)
and CTVC (inguinal region)
• Indications for elective irradiation: The consensus group felt that elective
coverage of the inguinal and external iliac regions should be routine for
anal carcinoma. There was some disagreement as to the indications for
covering these regions for rectal carcinomas. For rectal carcinomas
extending into gynecologic or genitourinary structures, the group agreed
that the external iliac region should be added (i.e. elective nodal coverage
= CTVA + CTVB for these cases). Some, but not all, of the committee would
also include the external iliacs for rectal cancers that extend into the anal
canal. Similarly, the group was divided on whether to electively irradiate
the inguinal nodal region for rectal adenocarcinomas that extend to the
anal verge or peri-anal skin.
• Caudad extent of elective target volumes: The group recommended that
the caudad extent of the inguinal region (CTVC) should be 2 cm caudad to
the saphenous/femoral junction. The transition between inguinal and
external iliac regions (CTVC to CTVB) is somewhat arbitrary, but the group
recommended the level of the bottom of the internal obturator vessels
(approximate bony landmark: upper edge of the superior pubic rami).

44. • Margin around blood vessels: The group recommended a 7-8 mm margin
in soft tissue around the external iliac vessels, but one should consider a
larger 10+ mm margin anterolaterally—especially if small vessels or nodes
are identified in this area. The inguinal/femoral region should be
contoured as a compartment with any identified nodes (especially in the
lateral inguinal region) included.
• Group Recommendations: Boost Volumes
• The group did recommend that any boost clinical target volumes extend to
entire mesorectum and presacral region at involved levels, including ~2 cm
cephalad and caudal in the mesorectum and ~2 cm on gross tumor within
the anorectum.
• Similarly this atlas does not present planning target volumes (PTVs). It was
generally agreed that the PTV margin should be ~0.7 to 1.0 cm, except at
skin.

58. THANK U