Management of Carcinoma Rectum.pptx

Management of Carcinoma
Rectum
Dr. Kartik Kadia
MMIMSR, Ambala

Anatomy
The anatomy of the rectum is
usually divided into three
portions

The location of a rectal cancer is
identified by its distance from the anal
verge
•Low (distal) rectal cancers are located
4 to 8 cm from the anal verge,
•Middle rectal cancers 8 to 12 cm, and
•Upper (proximal) rectal cancers 12 to
15 cm.
Rectal cancer – By location

TNM– 8th EditionStaging
Micrometastases have been defined as clusters of
10 to 20 tumor cells or clumps of tumor on cut
section that measure > 0.2 mm in diameter

CLINICAL MANIFESTATIONS
•Gross red blood  mixed with stools/covering the stools
•Spurious diarrhoea
•Change in bowel habits  unexplained constipation/diarrhoea (>3 weeks)
•In locally advanced disease  urgency/inadequate emptying/tenesmus
•Urinary symptoms
•c/o Buttock/perineal pain  s/o Posterior extension
•Sciatic pain  involvement of sciatic notch

HISTORY
•FAMILY H/O COLORECTAL CANCER
•FAMILY H/O POLYPS

PHYSICAL EXAMINATION
•GENERAL CONDITION OF PATIENT
•DIGITAL RECTAL EXAMINATION:
SIZE
DIAMETER OF LUMEN
DIST. FROM ANAL VERGE
SPHINCTER FUNCTION

BLOOD TESTS
•COMPLETE HEMOGRAM
•LIVER FUNTION TEST
•KIDNEY FUNCTION TEST
•CEA - 0 to 2.5 ng/mL -
BASELINE
PROGNOSTIC FACTOR
FOLLOW-UP

RIGID PROCTOSCOPY
•TO ASSESS –
MOBILITY,
MIN. DIAMETER OF LUMEN,
DIST. FROM ANAL VERGE
•BIOPSY

COLONOSCOPY
•DETECT POSSIBLE SYNCHRONOUS COLORECTAL
NEOPLASM
•BIOPSY FROM UPPER PART OF RECTUM

EUS
•T STAGING ACCURACY: 85% - 95%
•MESORECTAL LN STAGING: 70% - 75%
•VERY USEFUL IN DETERMINING
EXTENSION IN ANAL CANAL
* Perez and Brady’s Principals of Radiation Oncology – 7th Edition

CT SCAN
•WITH I.V. AND ORAL CONTRAST
•DETECT POSSIBLE METASTASIS
•T STAGING ACCURACY: 65% - 75%
•MORE SPECIFIC FOR PARA-AORTIC/PELVIC LNs (75%-87%) THAN
PERI-RECTAL (45%)

PELVIC MRI
•BODY COIL ACCURACY: 85%-95%
•ENDORECTAL COIL ACCURACY: 80%-95%
•PHASED ARRAY MRI(TO DETECT LATERAL
EXTENSION OF DISEASE): 80%-97%
More reliable than CT for mesorectal fascia
involvement and for post op CRM margin
ENDORECTAL COIL

PET/CT
•NOT ROUTINELY INDICATED
•EQUIVOCAL FINDINGS ON CONTRAST CT/MRI
•TO RULE OUT OCCULT METASTASIS

Main Treatment Modalities
•Surgery
•Radiation therapy
•Chemotherapy

Goals of Treatment
•Cure of disease
•Maintaining Quality of Life
•Sphincter preservation
•Minimal Morbidity

Strategy
Surgery
pT1,T2 N0 pT3,T4 or N+
Observation/
adjuvant
Adjuvant
Treatment
cT3 or cT4
Preoperative
NACRT
Surgery and post-op
chemotherapy

•Management of cancer of the rectum has undergone dramatic changes in the last
two decades.
•Surgery has been considered the primary treatment modality, but in spite of
“curative” resections, historically, a significant proportion of patients developed LR of
disease (20% to 50%)*
TREATMENT
* Pilipshen SJ, et al. Patterns of pelvic recurrence following definitive resections of rectal cancer. Cancer
1984;53(6):1354–1362.

•Local tumor recurrence is highly correlated with both the
 depth of penetration of the tumor and
 number of regional nodes
•Recent results of national cooperative group studies and several European
randomized trials indicate that a multimodality treatment approach, particularly
neoadjuvant treatment, results in a significantly better outcome than does surgery
alone

SURGERY
• Surgery remains the mainstay of curative treatment for carcinoma of the rectum.
• Surgical management depends on the stage and location of a tumor within the
rectum.

• The general principles of a surgery:
 removal of all gross and microscopic disease with negative proximal, distal, and
circumferential margins
 Preserve intestinal continuity and the sphincter mechanism whenever possible
while still maximizing tumor control.

Local recurrence after conventional surgery:
20%-50% (average of 35%)

•Several retrospective studies have shown that distal intramural spread of tumor is
rare beyond 1.5 cm  2-cm distal margin is considered acceptable*
•The reduced requirement of 2-cm distal margin for adequate resection has led to a
significant increase in the likelihood of sphincter preservation procedures in this
disease
*Vernava AM III, et al. A prospective evaluation of distal margins in carcinoma of the rectum. Surg
Gynecol Obstet 1992;175(4):333–336.

Resection Margins
Intramural excision
2 cm of the distal margin intramural margin
5 cm of the proximal margin intramural margin
mesorectal excision
Upper rectal growth – 5cm
Mid and lower rectum – total mesorectum
Reference : Jemal A,Tiwari RC,murray T,et al . Cancer statistics2004.CA Cancer J Clin2004;54;8-29
Agarwal A,et al. Total mesorectal excision : In:GI Surg Annual ,ed T K Chattopadhyay 2001;(8):57-69.
Nelson H, Petrelli N, Carlin A, et al. Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst. 2001;93:583–596.

DIFFERENTIAL SURGICAL OPTIONS
For early cancers:
• Polypectomy
• Transanal excision
• Transanal endoscopic microsurgery (TEM)
For advanced cancers:
• Low anterior resection (LAR)
• Abdominoperineal resection (APR)
• Total Mesorectal Excision (TME)

Surgical procedures
Spincter saving :
Spincter compromise:
Anterior resection
Low anterior resection
Local excision
Colo-anal anastmosis
Abdominoperineal resection

Choice of surgery
Factors influencing sphincter preservation
Surgeon training
Neoadjuvant chemoradiotherapy
Factors associated with difficult sphincter preservation
Morbid obesity
Preoperative incontinence
Direct involvement of anal sphincter muscles with carcinoma
Bulky tumors within 5 cm from the anal verge

TRANSANAL EXCISION
When it can be done ?
• selected T1, N0 early-stage cancers.
• small length(<4 cm)
• well to moderately differentiated
tumors within 8 cm of the anal verge
• limited to less than 40% of the rectal
circumference
• mobile, polypoid, not ulcerated
• no evidence of nodal involvement
TRANSANAL EXCISION

Advantages:
Minimal morbidity
Sphincter sparing
Rapid post operative recovery
Limitation:
Absence of pathological staging/nodal involvement
TRANSANAL EXCISION

Properly selected T1 lesions, following Transanal excision have excellent results with
local excision alone, with 5-year LC ranging from 82% to 97% and OS rates of 90% or
better*
*Gall FP, Hermanek P. Cancer of the rectum–local excision. Surg Clin North Am 1988;68(6):1353–
1365.

Transanal endoscopic microsurgery (TEM)
•Special operating proctoscope that distends the rectum with
insufflated carbon dioxide and allows the passage of dissecting
instruments.
•This method can be used on lesions located higher in the rectum
and even in the distal sigmoid colon.
•It has not come into wide use yet because of a significant
learning curve and a lack of availability.

ABDOMINOPERINEAL RESECTION (APR)
• It was gold standard for surgical resection of distal rectal cancer
located within 6 cm of the anal verge.
• This procedure requires a tranabdominal as well as a transperineal approach
with removal of the entire rectum and sphincter complex.

A permanent end colostomy is created and the perineal wound either closed
primarily or left to granulate in after closure of the musculature

LIMITATIONS :
Higher morbidity and mortality than LAR.
Permanent Colostomy bag : worst quality of life.
Higher risk of positive margins with APR as the mesorectum is very thin in the
distal segment of the rectum.

LOWER ANTERIOR RESECTION
• Now being performed not just for cancers
of the upper third of the rectum but also for
middle and lower third cancers.
• Preserving adequate anorectal function
becomes
a bigger problem, the more distal the level
of anorectal anastomosis.

Selection of patient for LAR:
• Good anal sphincter continence
prior to considering sphincter
preserving options
• A 2-cm distal margin of preservednormal
tissue.
• In carefully selected patients a functional
coloanal anastomosis can be achieved
with significantly reduced margins for
more distal cancers especially after
neoadjuvant therapy

•The high Local recurrence of disease following standard APR or LAR (15% to 30% or
more) has been believed by some to be due to blunt dissection that violates the
planes of the mesorectal circumference
TOTAL MESORECTAL EXCISION

•Lateral spread of disease has been shown to occur not only at the level of the tumor
but also distally within the mesorectum
•Heald et al* recommended en bloc removal of the tumor within the envelope of the
endopelvic fascia as necessary to obtain adequate lateral clearance of disease and
reduced likelihood of LR.
*Heald RJ, et al. Rectal cancer: the Basingstoke experience of total mesorectal excision, 1978–
1997. Arch Surg 1998;133(8):894–899.

Mesorectum: the structure that
contains the blood supply and
lymphatics for the upper, middle
and lower rectum.
In this procedure en bloc removal
of the mesorectum, including
associated vascular and lymphatic
structures is done.

Most of the involved LN for rectal cancer are found in the mesorectum:
T1: 5-7%
T2: 20%
T3: 65%
T4: 78%

Local Recurrence Following Surgery
Alone:
Clinical Colorectal Cancer, Vol. 4, No. 4, 233-240, 2004

Total Mesorectal Excision (TME):

•CIRCUMFERENTIAL RESECTION MARGIN
•RECORDING OF SURGICAL QUALITY
•TUMOR REGRESSION GRADING
POST SURGERY ASSESSMENT

CIRCUMFERENTIALRESECTION MARGIN
The completeness of resection can be scored as:
R0: negative margin
R1: microscopic involvement of margins
R2: gross residual tumour

Circumferential Resection Margin (CRM) is the most important margin that is
created around the mesorectum.
It can be involved directly or by LN that lie just under the mesorectal plane.

Circumferential Resection Margin (CRM)
The CRM is the distance in millimeters between –
•deepest point of tumor invasion in the primary
cancer and
•margin of resection in the retroperitoneum or
mesentery

If tumor is demonstrated at or within 1mm from the radial surgical plane of resection
i.e. CRM + then the local recurrence is increased greatly and survival is halved.

RECORDING OF SURGICAL QUALITY
Quirke introduced the concept of pathological audit of the quality of surgical
resection in MRC CR07 trial.
* Quirke P, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection.
Histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2(8514):996–999.

According to this the plane of surgery achieved:
Good: mesorectal
Intermediate: intramesorectal
Bad: muscularis propria plane
Plane of surgery was significantly associated with the risk of local recurrence
* Quirke P, et al. Local recurrence of rectal adenocarcinoma due to inadequate surgical resection.
Histopathological study of lateral tumour spread and surgical excision. Lancet 1986;2(8514):996–999.

Adjuvant Therapy and Neoadjuvant Therapy in relation
with Surgery
•Postop Chemoradiation Therapy
•Neoadjuvant RT alone
•Neoadjuvant CRT
•Long course NACRT v/s Short course NART
•Adjuvant Chemotherapy
•Total Neoadjuvant Therapy

Adjuvant treatment
Indication
•T1 lesion after local excision with poor risk (poorly differentiated, margin <3mm,
>3cm size, bad histology and +LVSI)
•T2 after local excision
•All T3-4 or node + after surgery

Post op Chemo-radiation therapy
The problem of unacceptably high LR after surgery has led to many studies exploring
the potential benefit of postoperative adjuvant therapy.

One of the advantages of postoperative radiation is the ability to selectively treat
patients at high risk 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

Two trials of post-op CRT demonstrating an improvement in OS were –
•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, or
(d) postoperative CRT of 40 to 44 Gy plus bolus 5-FU
* 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):245–252.

•Postoperative CRT improved 10-year OS, 45% versus 27%, compared with observation
after surgery (p < 0.001)
•This trial was terminated early, given the significant benefit seen with CRT.
* 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):245–252.

•The Mayo–NCCTG study compared postoperative radiation therapy against
postoperative CRT.
•234 patients with T3/T4 or node-positive tumors
•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.
*Krook JE, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med
1991;324(11):709–715

•The 5-year locoregional failure was higher in the radiation-only arm, 25% versus 13%
•The 5-year OS was 40% versus 55% - p <0.032 (in favor of CRT)
*Krook JE, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med
1991;324(11):709–715

Adjuvant Radiation Therapy:

Neoadjuvant RT alone
•Although both preoperative and postoperative adjuvant therapies can be effective,
neoadjuvant treatment has emerged as the standard of care.
•Neoadjuvant therapy is associated with tumor downstaging, improved resectability
and tolerance (both acute and chronic), and
potential for expanded sphincter preservation options

Grade Regression Fibrosis
0 No All cells are viable
1 Minor < 25% fibrosis
2 Moderate 26 – 50% Fibrosis
3 Good >50%
4 Total No Viable Cells
Neoadjuvant Therapy
Tumor Regression Grade
J Clin Oncol 32:1554-1562. © 2014

•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 surgery was rated as curative if margins were negative.
*Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J
Med 1997;336(14):980– 987.

•The 5-year OS (58% vs. 48%) was superior with preoperative radiation treatment compared
to surgery alone.
•At a median of 13 years,
LR was 9% versus 26% and
OS was 38% versus 30%,
•both in favor of preoperative radiotherapy, with all stages benefiting.
*Swedish Rectal Cancer Trial. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J
Med 1997;336(14):980– 987.

•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/fraction (no preoperative chemotherapy)
•201 patients were randomized to surgery within –
2 weeks versus
6 to 8 weeks of radiotherapy.
*Francois Y, et al. Influence of the interval between preoperative radiation therapy and surgery on
downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01
randomized trial. J Clin Oncol 1999;17(8):2396.

The OS after a median follow-up of 33 months was the same in both arms of the
study.
However, the pathologic downstaging was 10% versus 26% (P = .007) in favor of the
longer interval before surgery.
*Francois Y, et al. Influence of the interval between preoperative radiation therapy and surgery on
downstaging and on the rate of sphincter-sparing surgery for rectal cancer: the Lyon R90-01
randomized trial. J Clin Oncol 1999;17(8):2396.

•The TME experience by Heald et al suggested that TME alone may be sufficient for
achieving low LR rates*
•A Dutch (CKVO 95-04) multicenter, phase III 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
*Heald RJ, Husband EM, Ryall RD. The mesorectum in rectal cancer surgery—the clue to
pelvic recurrence? Br J Surg 1982;69(10):613–616.

•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 TME-only arm as compared to 2.4% in the
preoperative arm (p <0.005)
•This highlighted the value of radiation treatment, despite the use of TME.
*Dutch (CKVO 95-04) multicenter, phase III study

Neoadjuvant Chemoradiation
• Preoperative radiation therapy was compared with combined preoperative CRT in a
French study (Fédération Francophone de la Canérologie Digestive 9203)*
• 733 patients with resectable T3 and T4 tumors accessible by DRE were 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.
* Gerard JP, et al. Preoperative radiotherapy with or without concurrent fluorouracil and
leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24(28):4620–4625.

•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% (p
< 0.01)
* Gerard JP, et al. Preoperative radiotherapy with or without concurrent fluorouracil and
leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24(28):4620–4625.

•A similar study undertaken by the European Organization for Research and Treatment
of Cancer (EORTC 22921) randomized >1,000 patients to four arms (2 × 2 design):
•45 Gy alone versus
•45 Gy plus 5-FU (350 mg/m2) plus LV followed by surgery,
with patients further randomized to –
•adjuvant therapy with 5-FU/LV or
•no adjuvant therapy.
*Bosset JF. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med
2006;355(11):1114–1123.

•Results of the study were similar to those of the French study, with increased tumor
downstaging (14% vs. 5.3%; P = .0001) and lower rates of LR (9% vs. 17%) but no
difference in 5-year OS (65% in both arms).
•This information suggests that although there are lower rates of recurrence, there is
no conclusive evidence that combined treatment offers a survival benefit compared
to radiation alone in the neoadjuvant setting.
•There is, however, a higher incidence of acute toxicity associated with combined CRT
*Bosset JF. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med
2006;355(11):1114–1123.

Long-Course Neoadjuvant Chemoradiotherapy Versus
Short-Course Neoadjuvant Radiotherapy
In the Australian Intergroup Trial, 326 patients with cT3NxM0 rectal cancer within 12
cm of the anal verge were randomized to –
Short-course RT alone (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 225 mg/m2)
with surgery 4 to 6 weeks following completion of CRT.
Both regimens were followed by adjuvant 5-FU–based chemotherapy
* Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-
course chemoradiation comparing rates of local recurrence in patients with t3 rectal cancer: trans-
tasman radiation oncology group trial 01.04. J Clin Oncol 2012;30(31):3827–3833.

•The primary endpoint of this study was to compare LR rates at 3 years.
•Over 90% of patients were clinically staged with pelvic MRI or EUS.
•With a 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.
* Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-
course chemoradiation comparing rates of local recurrence in patients with t3 rectal cancer: trans-
tasman radiation oncology group trial 01.04. J Clin Oncol 2012;30(31):3827–3833.

The more recently published Stockholm III trial evaluated both fractionation and
timing after radiation therapy to surgery*
Patients with resectable rectal cancer were randomized to -
(1) 5 Gy × 5 # followed by surgery within 1 week,
(2) 5 Gy × 5 # followed by surgery after 4 to 8 weeks, and
(3) 50 Gy in 25 fractions followed by surgery after 4 to 8 weeks.
*Erlandsson J, Holm T, Pettersson D, et al. Optimal fractionation of preoperative radiotherapy and timing to
surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, noninferiority trial.
Lancet Oncol 2017;18(3):336–346.

•The primary endpoint was time to LR
•Outcomes were similar between all three treatment arms.
•Although there was noted to be an increase in radiation-related toxicities in the short-
course RT arm with delay to surgery, there was a significant decrease in postoperative
complications in these patients.
•The authors suggest that short course RT with delay may be an alternative to
conventional short-course RT followed by immediate surgery.
*Erlandsson J, Holm T, Pettersson D, et al. Optimal fractionation of preoperative radiotherapy and timing to
surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, noninferiority trial.
Lancet Oncol 2017;18(3):336–346.

•The optimal neoadjuvant approach for resectable rectal cancer remains far from
clear.
•Both short-course RT (25 Gy in 5 fractions) and
• long-course CRT (50.4 Gy in 28 fractions) with concurrent 5-FU–based
chemotherapy represent reasonable therapeutic options.

Adjuvant Chemotherapy
Adjuvant chemotherapy is recommended for all patients with stage II/III rectal cancer
following neoadjuvant chemoRT and surgery if they did not receive neoadjuvant
chemotherapy regardless of the surgical pathology results

•Although conclusive data on the benefits of adjuvant therapy in patients with stage
II/III rectal cancer are lacking, the NCCN panel recommends its use.
•Choice of regimen depends on initial clinical staging and predicted CRM status, with
FOLFOX or CAPEOX as preferred options

Alternative Chemotherapy Regimens with
Neoadjuvant Radiotherapy
•There is considerable variability in the administration of chemotherapy in many of
the trials undertaken and those that are ongoing.
•5-FU has been used concurrent with radiation because of its well-established
potentiating effect with radiation.
•However, several studies have used bolus 5-FU, whereas others have administered
LV-modulated 5-FU during the first and last weeks of radiation.

•The results of the Intergroup study demonstrating a superiority of low-dose continuous-infusion (CI)-
FU were extrapolated to the neoadjuvant setting, and it appears to be a preferred approach to
treatment*
•New drugs, including oral fluoropyrimidines (capecitabine), oxaliplatin, and irinotecan, have been
shown to be effective in the treatment of metastatic CRC.
•Oral fluoropyrimidines, as part of a CRT regimen, are commonly replacing infusional 5-FU.
•However, the incorporation of oxaliplatin into the neoadjuvant regimen has been less promising.
* O’Connell MJ, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion
fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331(8):502–507.

•A German trial compared capecitabine to infusional 5-FU
•Patients in the capecitabine group were scheduled to receive two cycles of capecitabine
(2,500 mg/m2 days 1 to 14, repeated day 22), followed by chemoradiotherapy (50.4 Gy plus
capecitabine 1,650 mg/m2 days 1 to 38), and then three cycles of capecitabine (post surgery)
•Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m2 days 1
to 5, repeated day 29), followed by chemoradiotherapy (50.4 Gy plus infusional fluorouracil
225 mg/m2 daily), and then two cycles of bolus fluorouracil (post surgery)
* Hofheinz ED, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil
for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
Lancet Oncol 2012;13:579–588.

•Five-year OS in the capecitabine group was noninferior to that in the fluorouracil group (76%
[95% CI 67 to 2] vs. 67% [58 to 74]; P = .0004; post hoc test for superiority P = .05).
•Similar numbers of patients had LRs in each group (6% in the capecitabine group vs. 7% in the
fluorouracil group, P = .67), but fewer patients developed distant metastases in the
capecitabine group (19% vs. 28%; P = .04).
•Patients in the capecitabine group had more hand–foot skin reaction, fatigue, and proctitis
than did those in the fluorouracil group, whereas leukopenia was more frequent with
fluorouracil arm
* Hofheinz ED, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine versus fluorouracil
for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial.
Lancet Oncol 2012;13:579–588.

•A second study, the NSABP R-04, compared the efficacy of four chemotherapy regimens.
•More than 1,600 patients were randomized to –
•5-FU (225 mg/m2, 5 days/week) or
•Capecitabine (825 mg/m2, twice a day, 5 days/week)
with radiation therapy with subsequent randomization to
±oxaliplatin (50 mg/m2/week ×5)
•For patients who received 5-FU versus capecitabine, there were comparable rates of tumor
downstaging, pCR, and sphincter preservation
* O’Connell MJ, Colangelo LH, Beart RW, et al. Capecitabine and oxaliplatin in the
preoperative multimodality treatment of rectal cancer: surgical end points from
National Surgical Adjuvant Breast and Bowel Project trial R04. J Clin Oncol
2014;32(18):1927–1934.

•The ACCORD 12 (NACRT) study randomized approximately 600 patients with
resectable T2 to T4 rectal cancer to CRT (45 Gy) with –
•Capecitabine (800 mg/m2 twice daily) versus
•Capecitabine and Oxaliplatin (50 mg/m2 weekly) delivered with 50- Gy radiation.
The addition of oxaliplatin increased grade 3+ acute toxicity (25% vs. 11%) and did not
significantly improve pCR or sphincter preservation rates.
*Gerard JP, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced
rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010;28(10):1638–
1644

•A number of retrospective studies suggest a benefit with the addition of irinotecan to
neoadjuvant CRT
*Gollins S, et al. Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan
in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long-term
clinical outcomes. J Clin Oncol 2011;29(8):1042–1049
*Willeke F, et al. A phase II study of capecitabine and irinotecan in combination with concurrent
pelvic radiotherapy (CapIri-RT) as neoadjuvant treatment of locally advanced rectal cancer. Br J
Cancer 2007;96(6):912–917.

•The RTOG conducted a randomized, phase II study of neoadjuvant CRT for distal rectal cancer
•103 patients with T3 or T4 distal rectal cancer ( <9 cm from the dentate line) were randomized to –
o CI 5- FU plus hyperfractionated radiation treatment of 55.2 to 60 Gy (1.2 Gy twice a day) versus
o CI 5-FU and irinotecan with conventional fractionation radiation of 50 to 54 Gy (1.8 Gy/fraction)
f/b surgery
•The response rate between the two arms was similar, with a pCR of 28%.
*Mohiuddin M, et al. Randomized phase II study of neoadjuvant combined modality
chemoradiation for distal rectal cancer: Radiation Therapy Oncology Group Trial 0012. J Clin Oncol
2006;24(4):650–655.

Although reports of the addition of bevacizumab and cetuximab to conventional
preoperative regimens appear tolerable, the benefit remains unclear, and no phase III
evaluation of these agents has been performed

Addition of targeted agents
•At this time the NCCN panel does not endorse the use of bevacizumab, cetuximab,
panitumumab with concurrent radiotherapy for rectal cancer
•But the targeted agents according to the mutation panels, can be used along with
traditional chemotherapy drugs as post op regimens

Preoperative Versus Postoperative Therapy
•A Korean trial randomized 240 patients with locally advanced (cT3/T4 or N+) rectal
cancer to preoperative or postoperative CRT
•CRT consisted of 50 Gy in 25 fractions with concurrent capecitabine (1,650
mg/m2/d).
•Standard surgical procedure was TME.
*Park JH, et al. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with
capecitabine for locally advanced rectal cancer. Cancer 2011;117(16):3703–3712.

•Patients also received four cycles of adjuvant chemotherapy with either capecitabine
(2,500 mg/m2/d for 14 days followed by a 1-week break) or bolus 5-FU (375
mg/m2/d)/LV (for 5 days every 4 weeks) in both arms
•The 5-year DFS, OS, and LR rates were no different between the two arms.
•Patients with low-lying rectal tumors (<5 cm from the anal verge) had higher rates of
sphincter preservation in the preoperative arm (68% vs. 42%).
*Park JH, et al. Randomized phase 3 trial comparing preoperative and postoperative chemoradiotherapy with
capecitabine for locally advanced rectal cancer. Cancer 2011;117(16):3703–3712.

•The definitive phase III study in favor of preoperative radiation therapy was the
CAO/ARO/AIO-94 study performed by the German Rectal Cancer Group
•823 clinically staged T3/T4 or node-positive rectal cancers were randomized to
opreoperative CRT followed by TME 6 weeks later or
oTME 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/d) was administered during the weeks 1 and 5 of radiotherapy as a 120-
hour CI.
*Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N
Engl J Med 2004;351(17):1731–1740.

•Both arms received four additional cycles of 5-FU (500 mg/m2/d for 5 days every 4
weeks).
•All surgeons were trained in the use of TME and were asked, prior to treatment, to
evaluate the possibility of sphincter preservation.
•The 5-year results revealed a recurrence rate of 6% versus 13% (P = .02) in favor of
the preoperative arm
•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.
*Sauer R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N
Engl J Med 2004;351(17):1731–1740.

•In the era of improved surgical technique, staging, and histologic assessment, the
MRC CR07 trial reevaluated the role of radiotherapy
•A total of 1,350 patients were randomized to –
o preoperative radiotherapy (25 Gy in five fractions) or
oup-front resection with selective postoperative chemoradiotherapy (45 Gy in 25
fractions with concurrent 5-FU) in patients with a ≤1-mm circumferential resection
margin
* Sebag-Montefiore D, et al. Preoperative radiotherapy versus selective postoperative
chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre,
randomised trial. Lancet 2009;373(9666):811–820

•At median follow-up of 4 years, the LR was significantly lower in the preoperative
radiotherapy group (4.4% vs. 10.6%).
•Although 3-year DFS was improved in the preoperative therapy group (77.5% vs.
71.5%), there was no difference in OS
* Sebag-Montefiore D, et al. Preoperative radiotherapy versus selective postoperative
chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre,
randomised trial. Lancet 2009;373(9666):811–820

Both the MRC CR07 and German rectal trial established –
preoperative therapy,
either shortcourse (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

•Despite preoperative CRT and complete surgical resection, LR rates remains an issue
in locally advanced CA Rectum
•In situations in which the margin of resection is compromised, IORT offers the
possibility of improved LC.
•The IORT experience at MGH was reviewed by Nakfoor et al*
* Nakfoor BM, et al. The impact of 5-fluorouracil and intraoperative electron beam radiation therapy on the
outcome of patients with locally advanced primary rectal and rectosigmoid cancer. Ann Surg 1998;228(2):194–
200.

•Preoperative CRT - CI 5-FU plus 50.4 to 54 Gy of radiation was given, followed by a 4- to 6-
week break and surgery.
• No IORT was given if metastases were present at surgical exploration, if there were adequate
margins >1 cm, or if there was less than T4 disease
o10 to 12.5 Gy was given for complete resection,
o12.5 to 15 Gy for microscopic residual disease, and
o17.5 to 20 Gy for gross residual disease.
•The 5-year LC was 90%, 65%, and 55%, and
•disease-specific survival at 5 years was 65%, 45%, and 15%, for these three dose levels,
respectively
* Nakfoor BM, et al. The impact of 5-fluorouracil and intraoperative electron beam radiation therapy on the
outcome of patients with locally advanced primary rectal and rectosigmoid cancer. Ann Surg 1998;228(2):194–
200.

Total Neoadjuvant Therapy
•Several small trials have tested the utility of a course of neoadjuvant chemotherapy
preceding chemoRT and resection
•This approach is referred to as a total neoadjuvant therapy (TNT) approach.

•In the Spanish GCR-3 randomized phase II trial, patients were randomized to receive
CAPEOX either before chemoRT or after surgery.
•Similar pathologic complete response rates were seen, and induction chemotherapy
appeared to be less toxic and better tolerated

•A pooled analysis of two phase II trials, EXPERT and EXPERT-C, assessed the safety and
efficacy of neoadjuvant chemotherapy followed by chemoRT and surgery.
•Of the 269 patients who were included,
•91.1% completed chemotherapy,
•88.1% completed chemoRT, and
•89.2% underwent curative surgery.
•Five-year PFS and OS rates were favoring Total NACT arm

Management of Recurrent Rectal Cancer

•Recurrent rectal cancer is often approached in the same way as T4 disease, often
with an aggressive treatment plan of CRT, surgery, and adjuvant chemotherapy.
•At the time of surgery, IORT may be considered.
•Recurrences may occur along the pelvic sidewall or in nonpelvic sidewall areas such
as the uterus, prostate, or vagina.

•In patients with no prior history of radiation, neoadjuvant CRT followed by surgical
resection is a reasonable treatment approach.
•In one series, 123 patients with locally recurrent CRC received a course of EBRT (45 to
54 Gy) either before or after surgical resection and IORT*
•Five-year OS in patients undergoing gross total resection was 24%, compared to 18%
in patients with gross residual disease.
*Haddock MG, et al. Intraoperative electron radiotherapy as a component of salvage therapy for
patients with colorectal cancer and advanced nodal metastases. Int J Radiat Oncol Biol Phys
2003;56(4):966–973.

•Long-term results of reirradiation for patients with recurrent rectal carcinoma were
reported by Mohiuddin et al.
•103 patients who developed LR after surgery with preoperative or postoperative
radiation treatment (median dose, 50.4 Gy) were reirradiated with concurrent CI 5-
FU.
•Patients were treated with opposed laterals or three-field technique (PA/L lateral/R
lateral) to the presacral area and gross tumor volume with 2- to 4-cm margin
*Mohiuddin M, Marks G, Marks J. Long-term results of reirradiation for patients with
recurrent rectal carcinoma. Cancer 2002;95(5):1144–1150.

•Patients received 30 Gy (1.2 Gy twice a day) or 30.6 Gy (1.8 Gy every day), followed by
a boost of 6 to 20 Gy to gross tumor volume (2-cm margin).
• 41 patients were surgically explored after treatment and 34 underwent resection,
with 6 patients undergoing sphincter-sparing surgery.
•With a median follow-up of 2 years, the 5-year OS rate was 19%

•Patients who underwent resection had a higher survival rate, with tolerable acute and late
toxicity.
•22 patients experienced late toxicity, including –
osevere, persistent diarrhea (18 patients),
osmall-bowel obstruction (15 patients),
ofistula formation (4 patients), and
ostricture (2 patients).
•Palliation of bleeding was achieved in 100% of patients.

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