1. Management of
Locally Advanced Rectal Cancer-An
evidence based approach
Prepared By
Ranjita Pallavi, MD
PGY-3, Department of Internal Medicine

2. TNM Staging-Rectal Cancer

3. Neoadjuvant RT in Rectal Cancer
• To lower local failure rates and improve survival in resectable cancers
• “Sterilization” of the mesorectal lymphatic channels, preventing dissemination of
viable tumor cells during mesorectal dissection
• Exclusion of the small bowel from the radiation field by the native rectum (after
resection, the small bowel can become tethered in the pelvis by adhesions where
it is then subject to repeat radiation exposure).
• Reducing tumor volume may facilitate resection and increase likelihood of a
sphincter-sparing procedure.
• Irradiating tissue that is surgery-naïve and thus better oxygenated may result in
increased sensitivity to RT.
• Preoperative radiation that includes structures that will be resected increases the
likelihood that an anastomosis with healthy colon can be performed (Superior
function of the nonirradiated neorectum).

4. Neoadjuvant Chemotherapy in Rectal Cancer

5. Is pre-op ChemoRT preferred over post-op?

6. Neoadjuvant Therapy Trials

7. German Rectal Cancer Study Group
Results:
• 421 patients were assigned to receive preoperative
chemoradiotherapy.
• 402 patients received postoperative
chemoradiotherapy.
• Median follow up 46 months.
• Primary end-point: Overall survival.
• Overall five-year survival rates were 76% and 74%
respectively (P=0.80).
• Five-year cumulative incidence of local relapse was
6% for patients assigned to preoperative
chemoradiotherapy and 13% in the postoperative-
treatment group (P=0.006).
• Grade 3 or 4 acute toxic effects occurred in 27% of
the patients in the preoperative-treatment group, as
compared with 40% of the patients in the
postoperative-treatment group (P=0.001); the
corresponding rates of long-term toxic effects were
14% and 24%, respectively (P=0.01).
N Engl J Med. 2004 Oct 21;351(17):1731-40.

8. German Rectal Cancer Study Group
N Engl J Med. 2004 Oct 21;351(17):1731-40.

9. German Rectal Cancer Study Group

10. German Rectal Cancer Study Group
Other favorable findings include:
• Evidence of tumor downstaging after preoperative chemoradiotherapy, in terms
of the rate of complete pathological response (8 percent, vs. 0 percent in the
postoperative-chemoradiotherapy group)
• Similar rates of sphincter preservation, despite the preponderance of distal
tumors in the preoperative-chemoradiotherapy group.
• Similar perioperative morbidity and mortality rates.
• Improved treatment compliance and decreased rates of severe acute and long-
term toxic effects in the preoperative-chemoradiotherapy group.

11. One disadvantage of preoperative chemoradiotherapy is the possibility of overtreating
early-stage tumors.
Sauer et al. found that in 18 percent of the patients randomly assigned to
postoperative chemoradiotherapy, the tumor had been overstaged during the initial
evaluation, despite the use of endorectal ultrasonography.
German Rectal Cancer Study Group

12. • Of 799 eligible patients, 404 were randomly
assigned to preoperative and 395 to
postoperative CRT.
• Median follow up of 134 months.
• According to intention-to-treat analysis,
overall survival at 10 years was 59.6% in the
preoperative arm and 59.9% in the
postoperative arm (P .85). The 10-year
cumulative incidence of local relapse was
7.1% and 10.1% in the pre- and
postoperative arms, respectively (P .048).
• No significant differences were detected for
10-year cumulative incidence of distant
metastases (29.8% and 29.6%; P .9) and
disease-free survival.
German Rectal Cancer Study Group – Follow up Data

13. German Rectal Cancer Study Group – Follow up Data

14. RT Regimens
• Two preoperative external beam RT (EBRT) regimens: short course and long
course.
• Short-course RT, also known as the 5 × 5 gray (Gy) regimen: offers 5 daily doses of
5 Gy (total of 25 Gy)
• It is usually followed by radical resection within one week of completing RT.
• Long-course regimens deliver daily doses of RT in significantly smaller fractions
(about 1.8 Gy-2 Gy) over a longer period of 25 days to 28 days.
• The total RT dose delivered by this regimen is 45 Gy to 54 Gy and seems to be
biologically equivalent to the 25 Gy short-course regimen.
• After long-course RT, radical surgery is delayed for 6 weeks to 8 weeks.
• The 2 regimens also differ with respect to concurrent CTx, which is typically offered
with long-course but not short-course regimens.

15. Types of RT
• External Beam RT
• High dose endorectal brachytherapy
• Contact RT
• Intraoperative RT
• Stereotactic body RT

16. NCCN Guidelines

17. Neoadjuvant Therapy – Locally Advanced Rectal Cancer
• 139 uT3/T4 N0/N+ rectal
cancers were included.
• Dworak classification for
regression was used.
• Tumor downstaging
occurred in 46.7 percent.
• CONCLUSION: After
preoperative therapy, the
sterilized disease shows an
excellent prognosis.
• The minimal residual
disease has a much better
prognosis in comparison
with the gross residual
disease.
Dis Colon Rectum, October 2005

18. Neoadjuvant Therapy – Locally Advanced Rectal Cancer
CA: A Cancer Journal for Clinicians
Volume 62, Issue 3, pages 173-202, 9 APR 2012

19. Posttreatment Response Assessment
NCCN guidelines recommend grading tumor response after neoadjuvant therapy.
0-Complete response: No remaining viable cancer cells.
1-Moderate response: Only small clusters or single cancer cells remaining.
2-Minimal response: Residual cancer remaining, but with predominant fibrosis.
3-Poor response: Minimal or no tumor kill; extensive residual cancer.
Ryan et al. Histopathology 2005;47:141-146

20. Does neoadjuvant therapy increase chances of
sphincter preserving surgery?

21. Neoadjuvant Therapy – Locally Advanced Rectal Cancer
• Since 1976, the rate of sphincter saving
surgery has increased from 20% to 75%.
• In none of the 17 trials it was possible to
demonstrate a significant benefit of the
neo-adjuvant regimens on the rate of
sphincter saving surgery.
• The improvement in conservative surgery
appears to be the result of new
technologies and changes in surgical
concepts, such as incorporation of total
mesorectal excision (TME) and the
techniques for very low anastomosis.
• There was a reduction in the risk of 5-
year local recurrence partly due to these
neo-adjuvant treatments.
• These neo-adjuvant regimens had no
significant impact on the overall 5-year
survival.

22. Neoadjuvant Therapy – Locally Advanced Rectal Cancer

23. Can Capecitabine replace 5-Fluorouracil in peri-
operative ChemoRT?

24. • Between March, 2002, and December, 2007, 401
patients were randomly allocated.
• 392 patients were evaluable (197 in the capecitabine
group, 195 in the fluorouracil group), with a median
follow-up of 52 months (IQR 41–72).
• 5-year overall survival in the capecitabine group was
non-inferior to that in the fluorouracil group (76%
[95% CI 67–82] vs 67% [58–74]; p=0·0004; post-hoc
test for superiority p=0·05).
• 3-year disease-free survival was 75% (95% CI 68–81)
in the capecitabine group and 67% (59–73) in the
fluorouracil group (p=0·07).
• Similar numbers of patients had local recurrences in
each group (12 [6%] in the capecitabine group vs 14
[7%] in the fluorouracil group, p=0·67), but fewer
patients developed distant metastases in the
capecitabine group (37 [19%] vs 54 [28%]; p=0·04).
• Diarrhoea was the most common adverse event in
both groups.
• Patients in the capecitabine group had more hand-
foot skin reactions than did those in the fluorouracil
group, whereas leucopenia was more frequent with
fluorouracil than with capecitabine.
• Capecitabine could replace fluorouracil in adjuvant or
neoadjuvant chemoradiotherapy regimens for
patients with locally advanced rectal cancer.
Neoadjuvant Therapy – Locally Advanced Rectal Cancer

25. How much time should elapse between pre-
operative ChemoRT and definite surgery?

26. • The patients were divided into two groups according to
the neoadjuvant–surgery interval: ≤7 weeks (group
A, n = 48), and >7 weeks (group B, n = 84).
• The median interval between chemoradiation and
surgery was 56 days (range 13–173 days).
• There was no in-hospital mortality.
• The pCR and near pCR rates were higher with longer
interval: 17% in group A, 35% in group B (P = 0.03).
• Patients operated at an interval >7 weeks had
significantly better disease–free survival (P = 0.05).
• Surgery type, operative time, number of intraoperative
blood transfusions, postoperative complications, and
length of hospitalization were not influenced by the
interval length.
• A neoadjuvant–surgery interval >7 weeks was
associated with higher rates of pCR and near pCR,
decreased recurrence and improved disease–free
survival.
Neoadjuvant Therapy – Locally Advanced Rectal Cancer

27. NCCN guidelines recommend an interval of 5-12 weeks following
completion of full-dose 5 ½-week chemoRT prior to surgical
resection in order to allow for patient recuperation from
chemoRT-associated toxicities.
Neoadjuvant Therapy – Locally Advanced Rectal Cancer

28. Can neoadjuvant treatment response be an early
response indicator?

29. • 725 patients were classified by tumor
response: complete (ypT0N0) (131; 18.1%),
intermediate (ypT1-2N0) (210; 29.0%), and
poor (ypT3-4 or N+) (384; 53.0%).
• Age, sex, cN stage, and tumor location
were not related to tumor response.
• Tumor response
(complete v intermediate v poor) was
associated with 5-year RFS
(90.5% v 78.7% v58.5%; P < .001), 5-year
DM rates (7.0% v 10.1% v 26.5%; P < .001),
and 5-year LR only rates
(0% v1.4% v 4.4%; P = .002).
• Treatment response to neoadjuvant
chemoradiotherapy among patients with
locally advanced rectal cancer undergoing
radical resection is an early surrogate
marker and correlate to oncologic
outcomes.
Neoadjuvant Therapy – Locally Advanced Rectal Cancer

30. • A total of 21 eligible RCTs were identified and used for
meta-analysis purposes.
• Overall, 16,215 patients with colorectal cancer were
enrolled, 9,785 being affected with rectal carcinoma.
• Considering patients with rectal cancer only, 4,854
cases were randomized to receive potentially curative
surgery of the primary tumour plus adjuvant
chemotherapy and 4,367 to receive surgery plus
observation.
• 11 RCTs had been performed in Western countries and
10 in Japan.
• All trials used fluoropyrimidine-based chemotherapy
(no modern drugs - such as oxaliplatin, irinotecan or
biological agents - were tested).
• The meta-analysis of these RCTs showed a significant
reduction in the risk of death (17%) among patients
undergoing postoperative chemotherapy as compared
to those undergoing observation (HR=0.83, CI: 0.76-
0.91).
• There was a reduction in the risk of disease recurrence
(25%) among patients undergoing adjuvant
chemotherapy as compared to those undergoing
observation (HR=0.75, CI: 0.68-0.83).
Adjuvant Therapy – Locally Advanced Rectal Cancer

31. NCCN Guidelines

32. NCCN Guidelines

33. A 4-Tiered Process
The development and execution of a treatment plan is really a 4-step
process that is conducted at 2 time points if nCRT is provided: before and
after treatment.
The 4 tiers of assessment are:
1) Conventional therapy: identification of stage-directed, standard
therapy for the tumor;
2) Qualified therapy: modification of the conventional therapy plan based
on evaluation of tumor features that define higher or lower oncologic risk
within the stage grouping or present particular surgical challenges;
3) Tailored therapy: recommendations based on assessment of patient
factors that influence the feasibility or suitability of the qualified therapy
plan;
4) Actual therapy: the treatment that is actually provided

34. NCCN Guidelines

35. NCCN Guidelines

36. Thank You