Management of lower Gastrointestinal malignancies

Management of Lower GI Malignancies:
Colon, Rectum & Anal Canal
Dr Animesh Agrawal
21.02.17
Rectum +
Anal Canal
Dr Ram Manohar Institute of Medical Sciences, Lucknow

• Management options
• Stage wise management
• Radiotherapy techniques
• Follow up

Tx Tumor cannot be assessed
T0 No evidenceof priary tumor
Tis Carcinoma in situ: intraepithelial or invasion of lamina propria
T1 Tumor invades submucosa
T2 Tumor invades muscularis propria
T3 Tumor invades pericolorectal tissues
T4a Tumor penetrates to the surface of the visceral peritoneum
T4b Tumor directly invades or is adherent to other organs or structure
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1–3 regional lymph nodes
N1a Metastasis in one regional lymph node
N1b Metastasis in 2-3 regional lymph nodes
N1c Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or
perirectal tissues without regional nodal metastasis
N2a Metastasis in 4–6 regional lymph nodes
N2b Metastasis in > 7regional lymph nodes

M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confi ned to one organ or site (e.g., liver, lung, ovary,
nonregional node)
M1b Metastases in more than one organ/site or the peritoneum
Changes in the 8th edition; applicable from 2018
M0 No distant metastasis
M1 Distant metastasis
M1a Metastasis confined to one organ or site (e.g., liver, lung, ovary,
nonregional node) without peritoneal metastases
M1b Metastases in more than one organ/site or the peritoneum.
M1c Metastasis to the peritoneum with or without other organ involvement.
AJCC/UICC Staging System; 7th edition

Management depends on
Multimodality treatment
• Surgery
• Chemotherapy
• Targeted therapy
• Radiotherapy
Tumor related
• Stage
• Location
Patient related
• Age
• Performance status
• Medical comorbidities
• Molecular markers
Treatment options

Surgery
• Colectomy
- Principal treatment modality
- Accurate disease staging
- Guides adjuvant treatment
• Intent:
- Curative
- Palliative
• Indications:
- Stage 1 – 3
- Resectable stage 4

Aim of surgery
• Primary objective is an R0 resection: Considered curative
• Wide resection of involved colon segment + Lymphatics +
Mesocolon + en-bloc resection of neighbouring organs with
adequate margin f/b reconstituting bowel continuity
• Margin ~5 cm of normal bowel proximal and distal to tumor
considered adequate
• Minimum of 12 nodes removed, suspicious nodes outside field
of resection removed or biopsied.
• Positive LN left behind considered R2 resection.
• Inspect abdomen viscera, peritoneum, non-localized lymph
nodes for mets.
Guidelines 2000 for colon and rectal cancer surgery. J Natl Cancer Inst 2001; 93:583.

• Right/left Hemicolectomy
• Extended Right/left Hemicolectomy
• Transverse colectomy
• Segmental resection
• Total Abdominal Colectomy: UC, FAP Syndrome
Types of Colectomy

Extent of colectomy
• Dictated by the size and location
of lesions, vascular and lymphatic
supply.
• Lymphatics of the intraperitoneal
colon are found within the
mesentery of the bowel.

D
B CA
E F
A. Rt Hemicolectomy
B. Rt Extended
hemicolectomy
C. Transverse
colectomy
D & E. Lt
Hemicolectomy
F. Sigmoid Resection

Laparoscopic-assisted colectomy
• May be considered based upon the following criteria:
- Experience surgeon performing laparoscopically assisted
colorectal operations.
- No locally advanced disease.
- Not indicated for acute bowel obstruction or perforation.
• Thorough abdominal exploration to be done.
NCCN 2017

Laparoscopic vs Open colectomy
• Randomized/non randomized prospective study data suggest no
difference in oncologic outcome in open vs. laparoscopic resection.(1-5)
Advantages of Disadvantages
• Good abdominal exploration &
visualization of visceral structures
• Small incision
• Early return of bowel function
• Faster recovery& less hospital stay
• Inadequacy of resection margin
• Nodal sampling is difficult
• Risk of seeding port sites
• Cost
1. COST Study Group, NEJM 2004
2. Fleshman et al, Ann Surg 2007
3. Bonjer et al, Arch Surg 2007
3. Jackson et al, J Am Coll Surg 2007
4. CLASSIC study group. 2005, 2013

Pathologic report
Parameters to be reported:
• Depth
• Number of L.N evaluated
• Number of L.N positive
• Status of margin: proximal, distal, and radial
• Grade
• LVI
• PNI
• Extranodal tumor deposits
College of American Pathologists Consensus Statement; NCCN 2017

CAP Statement on Prognostic Factors
• Category I (factors definitively proven to be of prognostic importance)
1. Local extent of tumor assessed pathologically (pT stage).
2. Regional lymph node metastasis (the pN stage)
3. LVI
4. Residual tumor following surgery with curative intent
5. Preoperative elevation of CEA
• Category IIA (Factors studied extensively for prognostication, but not validated prospectively)
1. Tumor grade
2. Radial margin status (for resection specimens with nonperitonealized surfaces)
3. Residual tumor in the resection specimen following neoadjuvant therapy
• Category IIB (Factors studied for association, not fitting in I or IIA)
1. Histologic type
2. Histologic features associated with microsatellite instability (MSI) (ie, host lymphoid
response to tumor and medullary or mucinous histologic type)
3. High degree of MSI (MSI-H)
4. Loss of heterozygosity at 18q (DCC gene allelic loss)
5. Tumor border configuration (infiltrating vs pushing border)
Compton et al. Arch Pathol Lab Med 2000

• Category III (Factors not studied sufficiently to know prognostic value)
1. DNA content
2. All other molecular markers except loss of heterozygosity 18q/DCC and MSI-H
3. PNI
4. Microvessel density
5. Tumor cell–associated proteins or carbohydrates
6. Peritumoral fibrosis
7. Peritumoral inflammatory response
8. Focal neuroendocrine differentiation
9. Nuclear organizing regions
10. Proliferation indices.
• Category IV (Factors well studied; no importance)
1. Tumor size
2. Gross tumor configuration.
Compton et al. Arch Pathol Lab Med 2000
CAP Statement on Prognostic Factors

Results of surgical resection
• Resection results in excellent cure rates for
lesions limited to the bowel wall with
negative nodes (T1-T2 N0)
• With a single high-risk feature - extension
beyond colonic wall (T3+) or involved
nodes (N+), 5-year survival with surgery
falls below 75%, and adjuvant treatment
may be indicated.
• When both high-risk features (T3–4 N+),
5-year survival with surgery alone drops to
approximately 50% (T3 N+) and 35% (T4
N+), and adjuvant treatment is
recommended.
Stage
Mean 5 yr
survival (%)
T1N0 97
T2N0 85-90
T3N0 78
T4N0 63
T2N+ 74
T3N+ 48
T4N+ 35

Survival by N stage
in various T stages;
by number of nodes
examined. (Colon
cancer, 5 yr OS:
SEER database)
A-E: T1-T4b
(Each curve
represents an N stage)

Adjuvant Chemotherapy
In Resected Colon Cancer

• Stage I: No adjuvant treatment
• Stage II
• Role of adjuvant chemotherapy unclear.
• Risk estimation
- pT4
- Grade 3-4
- LVI +
- PNI +
- < 12 nodes examined
- Indeterminate, close or + margin
- obstruction, perforation
NCCN 2017

Stage II (contd)
May consider for high Risk IIA & Stage IIB, IIC
• FOLFOX
• mFOLFOX6
• Cape-Ox
• FLOX
Low Risk IIA
• Observation
• Clinical trial.
• May consider single agent Capecitabine or 5FU + leucovorin.
NCCN 2017

Stage III
Role of adjuvant chemotherapy established
Preferred
• FOLFOX
• CapeOx
Other options
• mFOLFOX6
• FLOX
May consider
• Capecitabine
• 5FU + LV
NCCN 2017

Evolution of chemotherapy regimen for Ca Colon
1. 5FU + Levamisole
2. 5FU + Leucovorin
3. oral 5 FU analogue
4. Addition of oxaliplatin to 5FU/LV
5. Addition of irinotecan to 5FU/LV
6. Capecitabine + oxaliplatin
7. Targeted agents

• 5-FU–based adjuvant therapy compared to surgery only shows a survival
benefit survival for stage III patients.1,2
• Six months of chemotherapy was sufficient, and no further benefit was
provided by extending treatment to either nine or twelve months.3,4
• Levamisole, an agent initially thought to be active, was, in fact inactive.5-7
• High-dose LV did not confer superior efficacy over low dose LV and
comparisons of various 5-FU/LV schedules did not demonstrate clear
superiority of one schedule over the other.
• Addition of Oxaliplatin to 5FU provides a significant improvement in DFS
and OS especially in Stage III disease8,9.
• Capecitabine may be used in lieu of 5FU with comparable outcomes.
• Addition of targeted agents (bevacizumab/cetuximab) in the adjuvant setting
has not shown any benefit.10,11
Summary of evidence for Adjuvant
Chemotherapy in CA Colon

Adjuvant regimens for Colon cancer
Roswell Park
(RP)
LV: 500 mg/m2, over 2 hrs
5FU: 500 mg/m2 bolus
On days 1, 8, 15, 22, 29, 35
Repeat 8 weekly x
32 weeks (4
cycles)
Mayo Clinic
(MC)
LV: 20 mg/m2 d1-d5
5FU: 425 mg/m2 bolus d1-d5
Repeat 4 weekly x
24 wks (6 cycles)
Capecitabine X: 850-1250 mg/m2 BiD PO d1-d14 Repeat 3 wkly
FLOX LV: 500 mg/m2 over 2 hours weekly
5FU: 500 mg/m2 weekly
Ox: 85 mg/m2 before 5FU/LV on d1, 15, 29
Repeat every 8
weeks for 24 wks
(3 cycles)
FOLFOX4 Ox: 85 mg/m2 on d1
5FU: 400 mg/m2 bolus → 600 mg/m2 continuous
infusion (CI) for 22h d1, d2
LV: 200 mg/m2 on d1-2 before 5FU
Repeat 2 weekly
for 24 weeks (12
cycles)
mFOLFOX6 Ox: 85 mg/m2 on d1
LV: 400 mg/m2 on d1
5FU: 400 mg/m2 bolus d1 → 2400 mg/m2 46h CI
Repeat 2 weekly
for 24 weeks (12
cycles)
CapeOx Ox: 130 mg/m2 d1
X: 850-1000 mg/m2 BID PO d1-d14
Repeat 3 wkly for
8 cycles

• Benefit of adding oxaliplatin to 5FU-LV.
• 2,246 patients randomly assigned to receive infusion LV5FU2
(n = 1123) or FOLFOX4 (n = 1123) for 6 months (12 cycles).
• Primary end point: DFS.
• Secondary end points:
- OS
- Safety
• Median follow-up of 81.9 months.
• The planned 12 cycles of CT received by 74.7% and 86.5% of
patients in FOLFOX4 and LV5FU2, respectively.
Improved Overall Survival With Oxaliplatin, Fluorouracil, and
Leucovorin As Adjuvant Treatment in Stage II or III Colon
Cancer in the MOSAIC Trial
Andre et al, JCO 2009

CONSORT diagram
A:3 pt. assigned to FOLFOX4 arm but did not receive oxaliplatin. Therefore, these patients
were considered in FOLFOX4 arm for efficacy analysis and LV5FU2 arm for safety
analysis.
B:1 pt. assigned to LV5FU2 arm received oxaliplatin. Therefore, this patient was considered
in the LV5FU2 arm for efficacy analysis and in FOLFOX4 arm for safety analysis.

Baseline patient and disease characteristics

II
III
FOLFOX (%) 5FULV2 (%) p
5 yr DFS (II + III) 73.3 67.4 0.003
6 yr OS (II + III) 78.5 76.0 0.046
6 yr OS (III) 72.9 68.7 0.023
6 yr OS (II) 86.9 86.8 0.986

• In stage II disease the difference between the two arms failed to reach
statistical significance for both DFS and OS.
• In contrast, both differences were significant in case of stage II disease.
Conclusion
• Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and
6-year OS in the adjuvant treatment of stage II or III colon cancer.

• Trial demonstrating OS advantage of XELOX over 5FU/LV.
• Randomized 1886 patients to Capecitabine plus oxaliplatin
(XELOX, n = 944) vs bolus FU/LV (n = 942, MC or RP) as
adjuvant therapy for stage III disease.
• Primary end point: DFS
• Secondary end points
• OS
• Relapse-free survival (RFS)
• Safety.
Capecitabine Plus Oxaliplatin Compared With Fluorouracil/
Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer:
Final Results of the NO16968 Trial.
Schmoll et al. JCO 2015

• Treatment-related grade 3/4 adverse events were 55% in XELOX group
and 47% in FU/FA group (p < 0.05).
• Overall, 69%of pts in XELOX grp and 85% of pts in the FU/FA grp (MC, 87%; RP,
79%) completed the planned number of cycles.
• Seven-year DFS rates were 63% and 56%
in the XELOX and FU/FA groups
respectively (HR 0.80; 95% CI 0.69 to
0.93; p = 0.004)
• Seven-year OS rates were 73% and
67% in the XELOX and FU/FA
groups respectively (HR 0.83; 95%
CI 0.70 to 0.99; P = 0.04)
XELOX is better than 5FU/FA as adjuvant
chemotherapy in Stage III Colon Cancer.

Adjuvant therapy in colon cancer:
Summary

• No conclusive evidence of benefit in Stage II without risk
factors.
• Indicated in stage III, & High risk stage II
• FOLFOX or CapeOx are preferred regimens.
Addition of oxaliplatin to 5FU increases benefit :
- FOLFOX is superior to5FU/LV in terms of DFS & OS.
- Benefit for the addition of oxaliplatin to 5-FU/leucovorin in
patients ≥ 70 not proven.
- Survival benefit not conclusively demonstrated in stage II
disease.
• Capecitabine/oxaliplatin is superior to bolus 5-FU/ leucovorin.
• Capecitabine equally effective to bolus 5-FU/LV.

Among the various 5FU/LV regimen
• Schedule of 5-FU/LV administration does not affect efficacy, but
toxicities may be different
- Mayo Clinic monthly regimen - more commonly associated
with leucopenia and stomatitis
- Roswell Park weekly regimen - more commonly associated
with diarrhea
- Infusional 5-FU/LV may have less toxicity vs. bolus
• Irinotecan no benefit in the adjuvant setting.
• No targeted agents are approved for use in the adjuvant setting.

Microsatellite Instability (MSI)
• Ribic et al found that adjuvant chemotherapy provide no
benefit in patients with a high frequency of MSI (MSI-H).
Patients with low frequency of MSI (MSI-L) or no MSI
(MSS) continued to derive benefit.1
• However a study by the NSABP2 and a meta-analysis by
Webber et al3 failed to show the same finding.
• Trials studied by Ribic et al all used 5FU only; positive
impact with addition of oxaliplatin is anticipated.
• ECOG 5202 results awaited to answer this question.
1. Ribic et al. NEJM 2003
2. Kim et al. JCO 2007
3. Webber et al. BMJ Cancer. 2015

Adjuvant Radiation therapy in colon cancer
Aim
• Tumor bed irradiation to decrease local failure.
• Conformal delivery to minimize small bowel toxicity

Rationale
• Local failure (LF) in colon cancer depends on stage & location
- Anatomic constraints on radial resection margins,
- Tumors adherent/ invading adjacent structures increases risk of LF
• LF high in ascending/descending colon
- Anatomically immobile,” limits wide surgical resection
• LF less in mid-sigmoid and mid-transverse colon
- Relatively “mobile,” with a wide mesentery, wide margins
• LF rates for ceacal, hepatic/splenic flexure, proximal/distal
sigmoid tumors are variable
- Depending on amount of mesentery present, tumor extension, and
adequacy of radial margins.

Indications Of RT
Adjuvant tumor bed irradiation with concurrent 5-FU–based
chemotherapy should be considered for patients with tumors
• Invading adjoining structures: T4
• Where incomplete resection is performed
• Those complicated by perforation or fistula
Perez & Brady's Principles and Practice of Radiation Oncology, 6th ed

Data evaluating the use of adjuvant radiation therapy in high-risk
colon cancer patients have largely been limited to single-
institution retrospective analyses.
• Massachusetts General Hospital (MGH)
• Mayo Clinic
• University of Florida

• 222 patients with completely resected : 1) T4 (any site), or 2) T3N+ (of
ascending or descending colon only).
• PORT 45-50.4 Gy / 25-28# with 5-FU/Levamisole; 5FU for a total 1 year in
both arms.
• Primary end point: Overall Survival.
- DFS
- Patterns of recurrence
- Toxicity.
• Study was closed early due to poor accrual (Initial goal:700 pts. Total accrual
222 patients between 1992-1996)
Adjuvant chemotherapy and radiation therapy compared
with chemotherapy alone in the adjuvant treatment of
colon cancer: Results of intergroup protocol 0130
Martenson et al. J Clin Oncol 2004

Results
• Median follow-up of living patients
was 6.6 years.
• No difference in OS or DFS was seen
between the two groups.

• Grade III or IV hematologic toxicity was higher in patients
receiving radiation therapy
• No significant difference in non hematologic toxicity.

• Information about pathologic radial margin status was not reliably
provided & not used in determination of protocol eligibility.
• No single method of determining the tumor volume to guide
radiation therapy planning
- Clip placement in only 18 (19%) of 94 patients.
- Preoperative radiologic imaging (i.e. barium enema or
abdominal/pelvic CT): 45 patients (48%).
- For 17 patients (18%), the tumor volume defined by operative
notes.
• 6/94 eligible patients assigned to receive chemo-RT refused RT.
Caveats

Interpretation of study results was handicapped by
• Decreased statistical power
• High ineligibility rates,
• Lack of appropriate target volume definition for Radiotherapy
planning
No definitive conclusion

Technique
• Bowel preparation
• Positioning: Supine, Prone or Lateral decubitus
• Immobilization
• Contrast: oral & iv
- Oral contrast aids in delineating small-bowel, may be useful to compare
films in decubitus & supine positions to determine bowel shift
• Simulation: Conventional/CT
• CT based planning preferred
- Facilitates defining tumor bed, beam orientation and estimating OAR doses

Treatment plans with patient in
(A) lateral decubitus and (B)
prone position.
A
B

Target volume delineation
Tumor Bed/Target
• Involved segment of colon and, when present, the adjacent structures to which it was
adherent or invading
• If adherent to partially resected organ: whole organ has to be treated if within tolerance
• If adherent to structure (pelvic side wall, psoas, diaphragm): 3-5 cm margins beyond area of
adherence
• Surgical clips aid in the identification of high-risk areas (i.e., positive margins) to assist in
target delineation
• The nodal basins in the mesentery beyond surgical margins are usually not treated .However
the final inclusion of local & regional nodal group is based on operative & pathologic
findings.
Margins
• Tumor bed covered with a 4- to 5-cm margin proximally and distally and with a 3- to 4-cm
margin medially and laterally to cover areas of potential residual disease

Field Arrangement
• Field arrangement will vary, depending on the site of the
primary disease, as well as on areas judged to be at high risk for
local recurrence
• Parallel opposed or other multifield techniques are used to treat
target & spare OAR: small bowel, kidney, liver, S.C

Para-aortic nodes may be at risk, due to tumor
adherence to posterior abdominal wall with
descending colon cancer.
External and common iliac nodes may be
at risk, from a proximal ceacal/ascending
colon cancer
Postop AP-PA Fields Of Extra pelvic Colon Cancer
(Tumor Bed And Nodal Regions).

Dose prescription
• Total dose depends on the amount of suspected residual disease
and tolerance constraints of surrounding normal tissue.
• Initial dose of 45 gy/25 # at 1.8/# delivered through larger fields
to primary tumor and at-risk tissues followed by reduced boost
fields.
• For patients with t4 tumors, the general goal is to treat the tumor
bed to a total dose of 50.4-54gy
• Any treatment beyond 50 gy generally mandates exclusion of all
small bowel from the field

Critical normal (dose limiting) tissues
• Small intestine: 45-50 Gy
• Liver: 2/3rd of liver should get <30 Gy
• Kidneys: 2/3rd of one kidney should get < 20 Gy
• Spinal cord: Max dose to spinal cord < 45 Gy

Post treatment Surveillance
• History, physical examination & S.CEA:
- Every 3–6 month for 2 y, then every 6 month for a total of 5 yrs.
• Colonoscopy:
- In 1st yr:
 Normal: repeat in 3rd yr then every 5 yrs
 Abnormal repeat in one yr.
 If not done previously, 3-6 months post surgery.
• CT scan chest & abdomen:
- Annually for pts. with high risk for recurrence (eg. LVI/PNI, poorly
differentiated tumors).
NCCN 2017

Treatment Options for Metastatic Colon Cancer (Stage
IV) with synchronous liver only or lung only metastases
1. For resectable lesions
- Colectomy with synchronous resection of liver or lung metastases followed by
adjuvant chemotherapy with FOLFOX or CapeOx
- Neoadjuvant CT to increase curative resection rates
2. For unresectable lesions
- Treated with chemotherapy and evaluated every 2 months to assess
resectability of liver and/or lung metastases,colon resection if risk of
obstruction or significant bleeding.
- Combination chemotherapy for 2-3 months followed by chemo-radiation with
5-FU or capecitabine and then resection of metastases and primary
3. For patients that are able to undergo resection of metastatic disease
- 6 months of adjuvant therapy with an active regimen for advanced disease,
observation, or shortened course of palliative chemotherapy
NCCN 2017, ESMO 2014

Criteria for resectable metastases
• Lung, Liver
• Complete resection must be possible while leaving adequate tissue for
normal function
• Primary disease must have had/be amenable to an R0 resection
• If metastatic disease is unresectable, can consider 3-6 months of 5FU
based chemotherapy followed by reassessment for resection.
• Surgical resection preferred to ablative (eg. SBRT) techniques.
• Liver
• May consider portal venous embolization or staged resections when non-
resectability is based on inadequacy of remnant liver.
• Lung
• Extra-pulmonary resectable metastases is not a contra-indication.
NCCN 2017, ESMO 2014

Neoadjuvant Chemotherapy
i. FOLFIRI, CapeOx, or FOLFOX ± bevacizumab
ii. FOLFIRI or FOLFOX + panitumumab if KRAS wild type (WT)
iii. FOLFIRI + cetuximab if KRAS WT
Adjuvant First-Line Therapy Adjuvant Second-Line Therapy
Good Performance Status
• FOLFOX with or without
Bevacizumab.
• FOLFIRI with or without
Bevacizumab.
• 5-FU + Leucovrin with bevacizumab
If first line Irinotecan
• FOLFOX ±Bevacizumab.
• Irinotecan ±Cetuximab.
• Capecitabine or 5-FU + Leucovorin
Poor Performance Status
• Capecitabine or 5-FU + Leucovorin
± Bevacizumab.
If first line Oxaliplatin
• FOLFIRI ± Bevacizumab.
• Irinotecan ± Cetuximab.
Chemotherapy Options

Metastatic colon cancer: Chemotherapy
• Pts. with unresectable mCRC treated with BSC have poor prognosis
(median OS = 5 months).
• In contrast, pts. who receive CT have been shown to have a median
OS of ≈ 2 yrs.

Chemotherapy in metastatic colon cancer

Panitumumab
• Indicated in wild type KRAS metastatic colorectal cancer
• Approved for use in patients with mCRC refractory to FOLFIRI.
• All patients with mCRC should have tumor tissue genotyped for
RAS mutations performed in certified laboratories.
• The testing can be performed on the primary colorectal cancers
and/or the metastasis.
Bevacizumab
• Monoclonal antibody that binds to vascular endothelial
growth factor (VEGF).
• Can be added to either FOLFIRI or FOLFOX as first-line &
second line treatment of metastatic colorectal cancer.

Aflibercept
• Anti-VEGF molecule evaluated as a component of second-line
therapy in patients with metastatic colorectal cancer
• FOLFIRI + aflibercept is an acceptable second-line regimen for
patients who have failed with FOLFOX-based chemotherapy.
Cetuximab
• Monoclonal antibody against the epidermal growth factor
receptor (EGFR).
• Indicated in KRAS wild type, EGFR expressing colon cancer can
be added to either FOLFIRI or FOLFOX as first-line treatment
of metastatic colorectal cancer.
Patients with any known KRAS mutation should not be treated
with cetuximab or panitumumab as these render EGFR

Regorafenib
• Inhibitor of multiple tyrosine kinase pathways including VEGF,
PDGF, FGFR, B-RAF, RET, KIT
• Indicated in mCRC progressed on 5FU,oxaliplatin irinotecan &
bevacizumab, aflibercept, cetuximab & panitumumab based
chemotherapy.
Vemurafenib
• Active against the BRAF V600 mutated tumor
• BRAF V600 blockade upregulates EGFR.
• While not effective as single agent therapy1, in combination
with Cetuximab and irinotecan2 benefit in PFS was significant.
Absolute benefit, however, was small.
1. Kopetz et al, JCO 2016
2. SWOG 1406, JCO 2017

Targeted agents summary
Drug Dose / Indication
Bevacizumab 5-10 mg/kg, 2 weekly with
FOLFOX/FOLFIRI
Panitumumab 6 mg/kg 2 weekly with FOLFOX
Cetuximab 400 mg/m2 loading, f.b.
250 mg/m2 with FOLFIRI
Alifbercept 4 mg/kg with FOLFIRI
(after progression on oxaliplatin)
Regorafenib 160 mg OD 21d (q28 days)
After failure on above
Vermurafenib* 960 mg BD with cetuximab
• Benefit noted only in the metastatic setting.
* Not approved.

Strategies
Surgery
pT1,T2 N0 pT3,T4 or N+
Observation/
adjuvant
Adjuvant CMT
uT3 or cT4
Preoperative
CMT
Surgery and post-op
chemotherapy

Surgery
• Mainstay of treatment.
• Depends on
• Stage
• Site
• After surgical resection alone, local failure is common:
• 20% - 50% (average ~ 35%)

0: Absence of invasive carcinoma
1: Invasion into head of the polyp.
2: Invasion into neck of the polyp.
3: Invasion into stalk of the polyp.
4: Invasion into base of the polyp.
• Polypoid/malignant rectal
polyps (T1) based upon
the extent of invasion.
Haggitt’s classification

Surgical procedures for Rectal Carcinoma
• APR (Abdomino-Perineal Resection, sphincter
compromised)
• LAR (Low Anterior Resection)
• Proctectomy & colo-anal anastomosis
Radical
• Local excision:
- Transanal excision
- Post. Proctotomy
- Trans-anal endoscopic microsurgery(TEM).
Non Radical

Surgical techniques: Early rectal cancer
Local excision
• T1N0 or favourable T2N0 lesion <3cm in diameter
• <40% circumference of the lumen
• <10 cm from dentate line
• Well to moderately differentiated histology
• No evidence of lymphatic or vascular invasion on biopsy
• Mobile, exophitic or polypoid lesions
Early rectal cancer:
• T1-2N0 (TNM stage I)
• Tis and T1 (Japanese
classification)

• Low risk factors
- Submucosal invasion <1,000 µm
- Haggitt’s level 1-3
• High risk factors:
- Heggitt’s level 4
- Poorly differentiated
- LVI
- Tumor sprouting
• Independent poor prognostic
risk factors:
- Penetration of muscularis propria
- Definite vascular invasion
- High intensity tumor budding
• LN involvement rate
- No-risk (0.7%)
- One-risk (20.7%)
- Multiple-risk factor (36.4%)
• By T stage:
- T1: 5%
- T2: 20%
- T3: 65%
- T4: 80%
Ueno et al. Ann Surg, 2004
Sitzler et al. Dis Colon Rectum, 1997
Low Grade
tumor budding
High Grade
tumor budding

Local Excision Techniques
1. Transanal Excision. (<3 cm from the dentate line)
2. Posterior proctotomy. (<5 cm from the dentate line)
3. TEM (7-10 cm from the dentate line)
• Staging of such lesions should be performed using EUS to minimize
likelihood of doing a local excision for T3 tumors.
• Advantages:
- Rapid recovery,
- Minimal effect on sphincter function
- Relatively low perioperative morbidity and mortality.
• Disadvantages:
- Local failure

Transanal Excision Post proctotomy

Transanal Endoscopic Microsurgery (TEM)
• Special operating proctoscope that distends the rectum with
insufflated CO2 and allows the passage of dissecting
instruments.
• Can be used on lesions located higher in the rectum and even in
the distal sigmoid colon.
• Significant learning curve and a lack of availability.

Advanced Rectal Carcinoma: LAR
• For tumors in upper/mid rectum
allows preservation of anal sphincter
• Ocasionally, for lesions in the lower
third
• No pre-existing sphincter problems
• No evidence of extensive local disease
in the pelvis.
• Join colon to low rectum
• Permanent colostomy not required

• The colon is divided at the sigmoid-descending colon junction
• The operation entails full mobilization of the rectum, sigmoid
colon, and the splenic flexure.
• Mobilization of the rectum is by a technique called total
mesorectal excision (TME).

Total mesorectal excision
• Sharp dissection in the avascular plane
• Reduces positive radial margin rate.
• Specimen gross pathology:
- Bilobed
- Encapsulated
- Smooth & unbroken surface
• Local recurrence with conventional
surgery averages approx. 25-30% vs.
TME 4-7% by several studies.
• Disadvantage: anastmotic leak

Plane of dissection
TME Intra-mesorectal
excision
Muscularis
propria

Radiologic depiction of the TME
A. Axial
B. Coronal
C. Sagittal planes
B
A
C

Local Recurrence Following Surgery Alone
Clinical Colorectal Cancer, 2004;4(4):233-40.

Total Mesorectal Excision (TME)
Clinical Colorectal Cancer, 2004;4(4):233-40.

Choice of Surgical procedure
• Factors influencing sphincter preservation
- Surgeon training
- Neoadjuvant chemoradiotherapy
• Factors associated with difficult sphincter preservation
- Bulky tumors within 5 cm from the anal verge
- Direct involvement of anal sphincter muscles with
carcinoma
- Preoperative incontinence
- Morbid obesity
- Male sex

Abdominoperineal resection (APR)
• For tumors of distal rectum (lower 1/3rd) with distal edge up to
6 cm from anal verge
• This procedure involves:
- En bloc resection of the tumor, anal sphincters
- whole pelvic mesocolon, mesorectum , Wide Perineal
dissection
- Removal of the lymph nodes
- A permanent colostomy

Outcomes Complications
• 5-year survival rates
following an APR range
from*
- 78 to 100% for stage I
- 45 to 73% for stage II
- 22 to 66% for stage III
disease
• Urinary complications 50%
• Perineal wound infection 16%.
• Sexual dysfunction
• Stoma complications
• Anastomotic leak
• Fistula formation
* Varying with time and adjuvant treatment
APR

Pelvic Exenteration
• The surgeon removes the rectum as well as nearby organs such
as the bladder, prostate, or uterus if the cancer has spread to
these organs.
• A colostomy
• Urostomy
• Not routinely practiced.
• Mohan et al: Systematic review of 22 studies (1,575 patients)
- 4.2% perioperative mortality rate with morbidity of 42.5%
- The overall 5-year survival rate was 50.3% with worse outcomes in patients with
recurrent compared to primary disease (19.5% versus 52.8%).
- R0 resection was achieved in 79.5% of cases and, was the strongest factor
associated with long-term survival.
Mohan et al. Ann Sur Oncol 2013

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
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.

Circumferential Resection Margin (CRM)
• Circumferential radial margin (CRM) is an independent
predictor of both local recurrence and survival.
Nagtegaal ID, Quirke P. JCO, 2008
Quirke et al. Lancet, 2009
CRM Status LR Rate p value
> 2mm Negative 3.3% <0.0001
1to 2mm Close 8.5% 0.02
< 1mm* Positive 13.1% 0.08
* TNM definition of +ve margin is 0mm

• AJCC/UICC (7th edition)
Description Grade
No viable cancer cells 0 (Complete response)
Single cells or small groups of cancer cells 1 (Moderate response)
Residual cancer outgrown by fibrosis 2 (Minimal response)
Minimal or no tumor kill; extensive residual
cancer
3 (Poor response)
Adapted from Ryan et al; Histopathology, 2005
Tumor Regression Grade

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
Grade 10 – year DM P 10 – Year DFS P
0 - 1 39.6%
0.005
63%
0.0082 - 3 29.3% 73.6%
4 10.5 % 89.5%
Analysis from the German Rectal Cancer Trial. J Clin Oncol 2014;32(15):1554-62.

• Capirci et al found that in 566 patient who achieved a pCR
with neoadjuvant therapy, only 1.6% had a local recurrence
and 5 year DFS and OS were 85% and 90% respectively.1
• Others have also reported that patients with a pCR have
significantly lower LRR, better DFS and OS compared to
those without a pCR2-5.
A good pathological response is a good prognostic indicator.
1. Capirci et al. IJROBP, 2008
2. Kalady et al. Ann Surg 2009
3. Rodel et al. JCO 2005
4. de Campos-Lobato et al, Ann Surg Oncol 2011
5. Maas et al, Lancet Oncol 2010

Questions
• Is adjuvant/neoadjuvant treatment needed?
• Preop or Postop?
• Concurrent chemotherapy regimen?
• Long course or short course?
• Ideal gap between RT and surgery?
• Role of adjuvant chemotherapy
• Role of targeted agents

Adjuvant treatment
• Radiotherapy and/or Chemotherapy
• Indications:
- T1 lesion after local excision with poor risk (poorly
differentiated, margin <3mm, >3cm size and LVSI)
- T2 after local excision
- All T3-4 or Node positive after surgery

Drugs used:
• 5FU/Leucovorin
• Oxaliplatin
• Irinotecan
• Bevacizumab
• Cetuximab
Combinations
• FOLFOX
• Cap-Ox
• FOLFIRI
• Leucovorin/5FU
• Bevacizumab in combination
with the above regimens.

Adjuvant Therapy
Study Description Outcome
GITSG 7175
(1988)
4 arm trial
S/S+RT/S+CT/S+CRT
227 patients B2 ,
10 yr OS 45 % vs 27%,LRR 10% vs 25%
Significant benefit with CRT
NCCTG 79-47-
51 (1991)
Stage II –III
RT alone or CRT
(5FUX2> 5FU +RT>
5FUX2) (50% APR)
5-yr LR 14% (CRT) vs 25%
5-yr DM 29% vs 46%
5-yr OS 55% vs 45%
NSABP R-01
(1988)
3 arm RCT
500 patients (PT3/T4N+)
S/S+CT/S+RT
CT: Improved DFS & OS
RT: Reduction in LRR 16% vs 25 % favouring RT,
but no survival benefit.
NSABP -02
(1999)
2 arm RCT
Postop CT (5FU or MOF)
postop CRT
PORT: no benefit on DFS or OS, reduced the at 5
yr-LRR (13% to 8%) (P = .02).
Post-op CT: 5FU-LV better than MOF: DFS at 5 yr
(55% vs 47%; P = .009), 5-year OS (65% vs 62%; P
= .17).

NCI Consensus Statement (1990)
• CMT was the standard postoperative adjuvant treatment for all
patients with pT3 or N1-2 disease.
• Deliver 6 cycle of adjuvant CT (RT given with 3rd & 4th cycle of
chemotherapy).
• As most US trials used a 5FU continuous infusion based regimen,
this is the regimen of choice.

Neoadjuvant treatment
• Preoperative RT alone (Short/Long course)
• Pre-operative chemoradiotherapy
• Pre-operative chemotherapy

Preoperative approach: Pros and Cons
Pre operative RT Postop RT
Pros
• Tumour downstaging and better
resectability.
- Improved chances of sphincter
preservation.
• Better local control (esp in
patients with pCR).
Cons
• Risk of overtreatment as
pathological staging NA.
Pros
• Therapy is most effective when
tumor burden is minimal.
• Post op HPE known.
Cons
• More toxicity
- Bowel tethered in pelvis
- Perineal scar to be treated
• Anastomotic site irradiated, risk
of complications.

Pre-op vs post-op CRT
Trial Arms Acute tox
Gr 3+
LR OS Sphincter
preservation
GERMAN
cT3-4
cN+
Median FU:
134 mnths
Pre op CRT
421
Post op CRT
402
21/27
18/40
7.1%
10.1%
p=.048
59.6%
59.9%
p=0.85
45/116
37%
vs
15/78
19%
MRC
CR07/NCIC
C016
Preop 25 Gy/5# fb Surg
Surg + Post-op CRT
(if CRM+)
- 4%
11%
(SS)
4-yr
Similar -
NSABP
R03*
Preop (130)
Postop CRT (137)
34%
26%
5%
9%
74%
66%
47.8% (55/115)@
39.2% (47/120)
* Recruitment closed after 267/900 (slow accrual) @ Overall numbers; not reported by preop intent
• Preoperative CRT is better than post-op CRT in terms of tolerability, local control
and to some extent in sphincter preservation.
• For sphincter preservation usually follow long course RT schedule.

• 823 patients randomized to Preop (421) vs Postop (402) CRT
• Eligibility criteria
• Histopathologically confirmed, resectable adenocarcinoma with the inferior
margin within 16 cm from the anal verge.
• ERUS and CT scan of the abdomen and pelvis were performed to rule out
TNM stage I tumors and distant metastases.
• Primary end point: Overall Survival
• Secondary end point:
• Disease free survival
• Local and distant recurrences
• Postoperative complications, acute and long-term
• Toxic effects
• Sphincter preservation
Preoperative versus Postoperative
Chemoradiotherapy for Rectal Cancer

• Significantly lower incidence of LR;
similar OS and Distant failures
• Concluded that preoperative CRT
improves local control compared to
postoperative CRT.

Preoperative chemoradiotherapy vs RT alone
Trial N Randomisation F/U LR (%) OS
FFCD
9203
cT3-4
cN+
733 Pre op CRT f/b Sx
Preop RT f/b Sx
- 5yr
8.1%
Vs
16.5%
P = 0.048
5yr
NSS
EORTC
22921
4 arm
study
1011 Pre op RT → Sx → + CT
Preop CRT → Sx → + CT
10.4 Yrs
(7.8-
13.1)
18.4
11.8
p = 0.0017
(at 10 years)
22.4 & 14.5
11.8 & 11.7
49.4
50.7
p = 0.91
(at 10 years)

So far..
• Surgery (TME) should be followed by (when indicated)
adjuvant chemoradiotherapy.
• However, preoperative RT offers better local control than
postop RT though there is no demonstrable survival benefit.
• Concurrent chemotherapy should be given along with RT.

Optimizing Concurrent chemotherapy
Trial Chemo Sample RT pCR (%) Ac. Tox. 3+ (%)
STAR-01
5FU
5FU+Ox
379
368
50.4/28
16
15
8
24
ACCORD 12/
0405 PRODIGIE
Cap
Cap+Ox
295
291
45/25
50.4/28
14
19
11
23
NSABP R-04
(3 yr)
5FU+Ox
Cap+Ox
806
802
50.4/28
54/30 (T4)
17.8
20.7
28.2 & 40.1 (Ox)
32.9 & 41.9 (Ox)
CAO/ARO/
AIO-94 (50 mnth)
5FU
5FU+Ox
637
628
50.4/28
13
17
23
22
• Large randomized trials have failed to show any difference
between capecitabine & 5FU or benefit with adding oxaliplatin.
5 Fluorouracil (CI) or capecitabine are the
agents of choice in the concurrent setting.

Relative advantages of Neoadjuvant RT
Short-course Long Course
1. Shorter duration
2. No chemotherapy
3. Patient taken up for definitive
management earlier.
4. Less acute toxicity → Better
patient compliance
1. Downstaging of disease
2. Better chances of pCR
3. Time for recovery from
acute toxicity
4. Sphincter preservation
may be possible.

Short Course Preoperative Radiotherapy
Study Outcome
Swedish Rectal
cancer Trial
PreopRT vs Surg alone, cT1-3
• N = 1168
• 25Gy/5Fr/5days → Surg
• Med FU 13 years
• OS 38% vs 30%
p 0.008
• LRR 9%vs 26%
p 0.008
Dutch study
CKVO 95-04
PreopRT vs TME alone, cT1-3
• N = 1861 patients
• 25Gy/5Fr/5days→TME
• Median FU 12 years
OS 48%vs 49% p 0.86
LR 5% vs 11% p 0.0001
• RT alone; concurrent chemotherapy not given as ↑ toxicity anticipated.
• Swedish trial found an OS benefit while the Dutch trial didn’t; possibly
due to standardization of surgery.
- Generally higher OS and DFS in the TME study.

Short Course RT vs Long Course Chemoradiotherapy
Study No of
Patients
Randomis
ation
Median F/U 3 yr LRR 5 yr OS Toxicity
late
Australian
Intergroup
trial 2012
326
T3 N0-2
M0
SC – 163
LC – 163
5.9yrs 7.5%
Vs
4.4%
P – 0.24
74%
Vs
70%
P – 0.62
G 3-4
5.8 vs 8.2
P-0.53
Polish rectal
cancer group
2006
312 SC:156
LC 156
48 mths Higher
pCR in
CRT
67.2%
Vs 66.2%
10.1%
Vs 7.1%
• Tumour downstaging/higher pCR with CRT.
• No conclusive evidence of survival benefit/sphincter sparing;
both small trials.

Gap between NA-RT and Surgery
Neoadjuvant Chemoradiation
Lyon R90-01
1999
RCT
< 2 wks: 99
6-8 wks: 102
39 Gy / 13# 6-8 weeks
DS+
SS-
Moore
2004
RR
< 44 days: 82
> 44 days: 73
48.6 – 50.4
Gy / 26 – 28#
> 44 days
pCR+
SS-
Kalady
2009
RR
242
50.4 Gy / 28#
(median)
> 8 weeks
pCR+
LR+
Sloothaak
2013
RR
1593
50-50.4 Gy /
25 - 28#
> 16 wks
(for a maximal CR)
pCR+
RCT: Randomized Control Trial
RR: Retrospective review
PS: Prospective series
pCR: pathological Complete response
SS: Sphincter preservation
DS: Downstaging

Short Course RT
Stockholm
III
2017
RCT
SRT < 7 days: 228
SRT 4-8 wks: 227
CRT 4-8wks
SRT: 25 Gy / 5#
LRT: 50 Gy / 25#
4-8 wks pCR+
TRG+
CRM-
Pach et al 2012
RCT
SRT < 10 days: 77
SRT > 4 wks: 77
25 Gy / 5#
> 4 weeks; OS
benefit in DS+
DS+
SS-
Graf et al 1997 1316 25-25.5 Gy / 5-7# > 10 days DS+
Conclusion:
• 4-8 weeks gap is the present standard of care after CTRT, while <
7 days is the norm after short course RT.
• There is a case for increased interval after short course RT. More
evidence awaited.
Gap between NA-SRT and Surgery

Optimal fractionation of preoperative radiotherapy
and timing to surgery in rectal cancer: Stockholm III
• 3 types of treatment
• Short Course RT → Surgery (SRT)
• SRT → Delay (4-8 weeks) → Surgery (SRT delay)
• Long Course RT (LRT) → Delay (4-8 weeks) → Surgery (LRT-delay)
• Primary end point: Time to local recurrence
• Overall survival
• Frequency of postop mortality
• Frequency of postoperative complications
• Frequency of reoperations
• Frequency of late complications
• Radiation toxicity
• Frequency of Sphincter-preserving surgeries
Erlandsson et al. Lancet Oncol, 2017
• Resectable adenocarcinoma
• < 15cms from anal verge
• Total: 840 patients
• Median FU: 5.2 years

Stockholm III:
Trial design

• In patients with any LR, median time from randomisation to LR was 33.4
months (range 18.2-62.2) in the SRT group vs 19.3 months (8.5-39.5) in the
SRT-delay group. Median time to LR in the CRT group was 33·3 months
(range 17·8-114·3).
• Cumulative incidence of LR in the whole trial was 8 of 357 in SRT, 10 of 355
in SRT-delay, and 7 of 128 in CRT (p = 0.48)
• SRT-delay vs SRT: HR 1·44 [95% CI 0·41-5·11]
• SRT-delay vs CRT: HR 2·24 [95% CI 0·71-7·10]
• Acute RT toxicity was recorded in one patient (<1%) of 357 after SRT, 23
(7%) of 355 SRT-delay, and six (5%) of 128 after CRT.
• Frequency of postoperative complications was similar between all arms when
the three-arm randomisation was analysed, but in a pooled analysis of the two
SRT regimens the risk of postop complications was significantly lower after
SRT-delay than SRT (OR 0·61 [95% CI 0·45-0·83] p=0·001).

Local recurrence (A), distant metastases (B), recurrence-free survival
(C), and overall survival (D) in the three-arm randomisation with a
minimum of 2 years of follow-up

Local recurrence (A), distant metastases (B), recurrence-free
survival (C), and overall survival (D) in the pooled short-course
radiotherapy comparison with a minimum of 2 years of follow-up.

Conclusion
• Delaying surgery after short-course radiotherapy gives
similar oncological results compared with short-course
radiotherapy with immediate surgery.
• Quality of life outcomes and sphincter preservation rates yet
to be reported.

Neoadjuvant Therapy: Adding EGFR Inhibition
Rodel et al. Curr Opin Oncol, 2012

Neoadjuvant Therapy: adding VEGF Inhibition
Rodel et al. Curr Opin Oncol, 2012

Neoadjuvant therapy: Targeted agents
• As of now, not recommended outside a clinical trial.
(EGFR / VEGF inhibitors)
• Use in the adjuvant setting under evaluation.

Is adjuvant Chemotherapy needed for all patients?
• Adjuvant 5FU was associated with an improvement in
overall survival (OS) in patients with advanced disease from
the era preceding TME.
• Changes
1. Adoption of TME
2. Increasing use of neoadjuvant radiation
3. Improved staging accuracy
4. Addition of Oxaliplatin to standard regimens
Fisher et al. JNCI 1988
Petersen et al. Cochrane Database Syst Rev 2012

Modern trials evaluating adjuvant chemotherapy
Trial
Chemo
Regimen
Survival
data
DFS OS
C O p C O p
EORTC 229211 5FU/LV 10 years 47 44 .29 52 48 .32
CHRONICLE2 Cap-Ox 3 years 77 71 .56 88 89 .55
PROCTOR/
SCRIPT*3
5FU/LV or
Cap
5 years 63 55 .13 80 79 .73
Italian4 5FU/LV 5 years - - - 68 70 -
ADORE5 5FU/LV vs
FOLFOX
3 years 72 63 .047 - - -
C: Chemotherapy (adjuvant); O: Observation; p: p value
* Recruitment closed after 437/470 (slow accrual)
1. Bosset et al. Lancet Oncol, 2014
2. Glynne-Jones et al. Ann Oncol 2014
3. Breugom et al. Ann Oncol, 2015
4. Cionni et al. Radiother Oncol 2010
5. Hong et al. Lancet Oncol, 2014

Adjuvant chemotherapy: Conclusion
• For patients who have received neoadjuvant CRT, adjuvant
chemotherapy (6 months of FOLFOX or XELOX) is
recommended for Stage II disease and beyond.
• In an era with improved CMT, benefit needs to be re-
evaluated.
• Observation may be a reasonable approach for a subset of
patients with early disease (yp Stage II, node negative),
further follow up and outcome results needed.

Questions
Additional treatment needed? Yes
Preop or Postop? Preoperative
Concurrent chemotherapy regimen? 5FU or Cap
Long course or short course? ? Individualize
Ideal gap between RT and surgery? CRT: 6-8 weeks
SRT: < 7 days; ? > 4 weeks
Role of adjuvant chemotherapy Recommended*, may change
with further evidence.
Role of targeted agents Not recommended*
*NCCN 2017; FOLFOX/Cap-Ox

Unresectable Locally advanced rectal cancer
• T4 tumors with deep local invasion into adjacent structures,
which makes primary resection for cure difficult, invade into
pelvic sidewall or sacrum.
• Pre-operative chemoradiation
• IORT
• Pre-operative chemotherapy

Future directions
• Chemotherapy given before Surgery?
- PROSPECT: Recruiting T2N1, T3N0-1 and randomizing to NACT +
CTRT → Surg
- RAPIDO: Sequential SRT → NACT → Surgery.
• Delay after short course RT?
- Stockholm III suggests SRT-delay is a feasible option. Long term
outcomes and sphincter preservation rates awaited.
• Chemotherapy concurrent with Short course RT?

Strategy
Surgery
pT1,T2 N0 pT3,T4 or N+
Observation/a
djuvant
Adjuvant CMT
uT3 or cT4
Preoperative
CMT
Surgery and post-op
chemotherapy

Positioning
• Supine or Prone
position with belly
board
• Prone position displaces
bowel loops.
• Bladder distension
• Marker at anal verge
• Small bowel contrast

Pelvic subsites
Five subsites: predominant areas at risk for local recurrence:
• Mesorectal subsite (MS): less common as it gets totally
removed in TME
• Posterior pelvic subsite (PPS): most common site of nodal
recurrence 22 to 49% in various series.
• Lateral pelvic subsite (LPS): 21%
• Inferior pelvic subsite (IPS) : 3-11%
• Anterior pelvic subsite (APS): 5-17%

Field design
• PA portal with 6MV to decrease bladder dose
• Lateral portals may require higher energy (10/15 MV) to
increase depth dose and decrease dose to hip joints
• Portals
• 4 fields (AP, PA, two lateral fields)
• 3 fields (PA, two lateral fields)
• 2 fields (AP-PA)
• Typically a two phase treatment
• Phase I: Whole pelvis including nodes.
• Phase II: Boost to tumor (or tumor bed).

Field Arrangement: Whole pelvic field
AP-PA
• Lateral borders: 1.5 cm lateral to
the widest the true pelvic
• Inferior border: 3 cm below the
primary tumor or at the inferior
aspect of the obturator foramina,
whichever is the most inferior
• Superior border: L5-S1 junction.
• For APR patients, inferior border to be
shifted to include the post-op scar.

Laterals
• Posterior border: 1 to 1.5 cm
behind the anterior bony sacral
margin.
• Anterior border: Posterior or
anterior margin of the
symphysis pubis
• Placing it anteriorly includes the
external iliac nodes within the
field.
Field Arrangement: Whole pelvic field

• Intent: Treat the primary tumor bed plus a 3-cm margin.
• After an abdominoperineal resection:
• 1.5-cm margin beyond the post-op scar to be treated.
• Therefore, scar to be marked with radio-opaque wire during simulation.
• Blocks are used to spare the posterior muscle and soft tissues
behind the sacrum and small bowel.
Field Arrangement: Boost field

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

Dose
• Preoperative radiotherapy
• Short course: 25 Gy in 5 daily fractions of 5 Gy given in 5 days.
• Long course
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
• 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.

Rectal Cancer Contouring Guidelines
• New definitions for subsites:
• PS: Pre-Sacral Nodes
- Abdominal
- Pelvic
• M: Mesorectum
• LLN: Lateral Lymph Node
- Anterior
- Posterior
• EIN: External Iliac Nodes
• IN: Inguinal Nodes
• IRF: Ischio-rectal fossa
• SC: Sphincter Complex
Valentini et al, Radiother Oncol 2016

• Mesorectum (M)
• Cranial: Bifurcation of the IMA in SA and SRA
• Caudal: Insertion of the levator ani muscle into the
external sphincter muscles (disappearing of the
mesorectal fat around the rectum)
• Anterior:
• Superior: 7 mm beyond SRA excluding bowel structures
• Mid/inferior: mesorectal fascia, posterior border of the anterior
pelvic organs
• Posterior: Anterior surface of the sacrum and coccyx to
the level of IRF (including the medial part of the PS)
• Lateral:
• Upper/mid: Mesorectal fascia if visible or medial border of the
LLN and EIN
• Lower: medial edge levator ani muscle

Pre-sacral nodes (PS) are divided into an abdominal and a
pelvic part, because the abdominal part doesn’t have to be
treated in all patients.
• Limits:
• Abdominal
- Cranial: Aortic bifurcation/5mm above cranialmost positive
node
- Caudal: Sacral promontory
- Anterior: 1 cm ventral to lumbar vertebrae
- Posterior: Lumbar vertebrae anterior wall
• Pelvic
- Cranial: Bifurcation of the common iliac arteries/promontory
- Caudal: Caudal border of Mesorectum (M)
- Anterior: 1 cm ventral to lumbar vertebrae
- Posterior: Lumbar vertebrae anterior wall

• Lateral Lymph Nodes (LLN) correlate with a triangular area
between the pelvic wall and mesorectum.`
• Divided into an anterior and a posterior part; this division is at
a virtual coronal plane crossing the anterior wall of the ureters
when they join the bladder and the posterior aspect of the
external iliac vessels cranially.
• Posterior group corresponds to the internal iliac nodes.
• It is suggested that for early disease (pT3N0 with MRF-) the
cranial limit of the internal iliac nodes (i.e. Posterior LLN)
may be lowered at the level of the bifurcation of IMA.
Lateral Lymph Nodes

• Cranial: Bifurcation of common iliac artery
• Caudal: Insertion of the levator ani muscle into the external sphincter
(pelvic floor)
• Anterior
• Upper pelvis: 7 mm around the vessel.
• Mid pelvis: a virtual coronal plane crossing the anterior wall of the ureters
when they join the bladder and the posterior aspect of the external iliac vessels
cranially
• Inferior pelvis: posterior limit of the obturator fossa
• Posterior: Lateral edge of the sacro-iliac joint
• Medial:
• Upper: Above the M add 7 mm around the vessel, excluding normal anatomic
structures
• Mid/lower: Mesorectal fascia, pelvic organs
• Lateral
• Upper: iliopsoas, pelvic bones
• Mid-lower: medial edge of the pelvic wall muscles (pyriform and internal
obturator muscles)
Borders for the posterior LLN

• The posterior border is the same as the anterior border of the posterior LLN:
• Upper pelvis: 7 mm around the vessel.
• Mid pelvis: a virtual coronal plane crossing the anterior wall of the ureters
when they join the bladder and the posterior aspect of the external iliac
vessels cranially
• Anterior
• Mid pelvis: posterior wall of the EIN
• Low pelvis (when external iliac vessels leave the pelvis): anterior surface of
obturator artery
• The cranial, caudal and lateral borders remain the same.
Borders for the anterior LLN
Anterior border of the posterior lateral node
when the ureters join the bladder
Include when:
• Positive nodes in the posterior LLN
• cT4
• Multiple positive nodes (N2)

External Iliac Nodes (EIN)
• Located around the external iliac vessels
• Borders:
• Cranial: bifurcation of common iliac artery into internal and external
iliac arteries
• Caudal: Where the deep circumflex vein crosses the external iliac
artery. Alternatively between the acetabulum roof and the superior
pubic rami
• Anterior: 0.7 cm anterior to the vessels. 1.5 cm antero-laterally along
the iliopsoas muscle to include the antero-lateral nodes
• Posterior: posterior border of the external iliac vein
• Medial: 7 mm medial to the vessel, excluding pelvic organs
• Lateral: the iliopsoas muscle

• To be included when:
- cT4
- positive anterior LLN
Caudal border of the
external iliac nodes
(orange), where the deep
circumflex vein crosses
the external iliac artery
External Iliac Nodes (EIN)

Inguinal Nodes (IN)
• Cranial: Where the deep circumflex vein crosses the external iliac artery.
Alternatively (if difficult detection on CT images) between the acetabulum
roof and the superior pubic rami (i.e. continues below where the EIN end)
• Caudal: Where the great saphenous vein enters the femoral vein
• Anterior: at least 20 mm margin around inguinal vessels including any
visible lymph nodes or lymphoceles
• Posterior: the femoral triangle formed by iliopsoas, pectineus and abductor
longus muscles
• Medial: 10-20 mm margin around the femoral vessels including any
visible lymph nodes or lymphoceles
• Lateral: medial edge of the sartorius or iliopsoas muscles
To be included in • Positive IN
• Anal canal/external anal sphincter infiltration
• cT4 with infiltration of the lower third vagina

Ischiorectal Fossa (IRF)
• IRF is the fatty triangular area framed by the levator ani muscles, the
obturator and gluteus muscles and the ischial tuberosity.
Borders
• Cranial: Where the inferior pudendal artery leaves the pelvis
• Caudal: Oblique plane joining the inferior level of SC and the ischial
tuberosity.
• Posterior:
• Mid-superior: Major gluteus muscle
• Inferior: Virtual line tangent to the posterior level of the sphincter
• Medial: Levator ani muscles
• Lateral: Ischial tuberosity, internal obturator muscle, Gluteus maximus
muscle

• Included when there is infiltration of the external anal
sphincter or the ischio-rectal fossa.
Cranial border of the ischio-rectal
fossa (blue), where the inferior
pudendal artery leaves the pelvis
Caudal border of the ischio-rectal
fossa (blue), at the inferior level of
the sphincter complex and the
ischial tuberosity
Ischiorectal Fossae

CTV
• Always treated: M, pelvic PS and the posterior LLN
• Optional: anterior LLN, the SC, the IRF and the IN depends
on tumor stage and tumor location.

Organs at risk (OAR) : Dose constraints
Small bowel Bladder Femoral head
V180cc < 35 Gy
V100cc < 40 Gy
V65cc < 45 Gy
V40 < 40 Gy
V15 < 45 Gy
V40 < 40 Gy
V25 < 45 Gy

Intra-Operative Radiotherapy (IORT)
• IORT delivers a concentrated dose of radiation therapy to a tumor
bed during surgery
• Dose range from 1250-2000cGy.
• Reserved for pts. with early-stage disease.
• Delivered immediately after tumor is removed, helping to destroy
the microscopic tumor cells that may be left behind
• Spares healthy tissues and organs
• Shortened treatment times.

Endocavitary Radiation
• Alternative to local excision/conservative treatment
• Selection criteria:
- Small T1
- Mobile T2 lesion
- Less than 10 cm from the anal verge
- No larger than 3 cm.
• A total of 6 application of high-dose (20Gy to 30 Gy), low-
voltage radiation (50kV) is given over the course of 6 weeks.
• Dose at 1 cm depth = 1/3 rd of surface dose

Treatment cones for Endocavitary radiotherapy

• Cumulative surface dose might be high but well tolerated.
• The overall survival rate is 83%, although the local
recurrence rate as high as 30%
• In combination with EBRT may be considered in medically
unfit patient for surgery.
• Drawbacks :
• Not suitable for tumors extending into anal canal
• May develop transitory superficial ulcer

Staging
T Stage
Tx Primary tumour cant be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ (Bowen's disease, high-grade squamous
and anal intraepithelial lesions)
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 5 cm in greatest
dimension
T3 Tumor more than 5 cm in greatest dimension
T4 Tumor of any size that invades adjacent organ(s); e.g.,
vagina, urethra, bladder
AJCC/UICC 7th edition
Carcinoma in situ (Bowen's disease, high-grade squamous
and anal intraepithelial lesions) HSIL

T1
T3
T2
T4
2-5 cm
>5 cm
T Staging

Staging
N Stage
Nx Regional lymph nodes cant be assessed
N0 No regional nodal metastases
N1 Metastasis in perirectal lymph node(s)
N2 Metastasis in unilateral internal iliac and/or inguinal lymph
node(s)
N3 Metastasis in perirectal and inguinal lymph nodes and/or
bilateral internal iliac and/or inguinal lymph nodes

Staging
N Stage
Nx Regional lymph nodes cant be assessed
N0 No regional nodal metastases
N1 Regional lymph node(s) metastases
N1a Metastasis in mesorectal, inguinal or internal iliac lymph
node(s)
N1b Metastasis in external iliac lymph nodes
N1c External iliac lymph nodes with any N1a nodes

N1a
N1b
N1c

Overall Stage

Management Algorithm
Gunderson 4th edition

Surgery: APR
• Standard of care for the primary treatment of anal carcinoma
before the adoption of CRT.
• Average 5-year OS with APR alone reportedly were 50% (range,
25%-75%).
• LRR and distant failure occurred in up to 35% and 10% patients,
with higher rates for positive pelvic or inguinal lymph nodes.
• High morbidity and rates of recurrence; now reserved for salvage.

• Till the late 1970s, the treatment for anal cancer was an APR.
• Nigro et al1 first reported on 3 consecutive patients planned
with Chemo-RT followed by APR, who all achieved a pCR.
This was updated for 28 patients2, with 23 attaining a pCR.
• With a FU of 1-9 years, 22/28 patients were alive and 19 were
disease free (12 APR, 14 excisions, all 6 deaths in APR patients).
The Nigro Regimen
1. Nigro et al, Dis Colon Rectum 1974
2. Nigro et al, Cancer 1983
External Irradiation:
• 3000 rads to anorectal and
local nodal areas on d1 - 21.
• 200 rads/day/15 days
Systemic Chemotherapy
A. 5-FU: I000 mg/m2;24 hr as a continuous
infusion for 4 days. Start on day 1.
B. Mitomycin C: 15 mg/m2 bolus on day 1.
C. 5-FU: Repeated day 20 to 31.

Chemo-RT vs. RT Alone
• UKCCCR ACT I
• EORTC

UKCCCR Anal Cancer Trial (ACT) 1
• 577 patients randomized to RT alone (285) or CRT (292).
• 45 Gy phase I → 6 week break → 15 Gy boost OR Salvage APR
• MMC 12 mg/m2 d1; 5FU 1g/m2 d1-4 and d29-32
• Primary end point: Local Failure
• Secondary end point: 5 year survival
• Initially calculated sample size was 130 per arm to show a 60%
reduction in local failure; 585 patients were recruited.
• Median FU: 13 years
UKCCCR. Lancet 1996; upd. Northover et al, Br J Cancer 2010

• Updated results after 13 years of follow-up showed a non
significant survival advantage for the chemoradiation arm, but
cancer specific survival was significantly improved.
• In patients who underwent an APR, 5 yr survival was > 50%
for node negative patients vs 20% for N+.
CR LC DM OS
CRT 39 61 10 65
RT Alone 30 39 17 58
P 0.08 < 0.001 NR 0.25
* All values in percentages
UKCCCR. Lancet 1996; upd. Northover et al, Br J Cancer 2010
Conclusion
• Chemoradiation was superior to RT alone for almost all evaluated
end points, and should be the standard of care.

CT-RT vs RT Alone: a Phase III EORTC trial
• 110 patients T3-4N0-3 or T1-2N1-3 (locally advanced ds)
• CRT: 52 patients (45 Gy → 6 week break → 15–20 Gy boost,
concurrent 5FU 750mg/m2 d1-4, d29-32 + mitomycin C 15
mg/m2 d1) vs RT alone: 51 patients.
• End points
- Overall Survival
- Colostomy free survival
- Local Control
- Event Free Survival
- Severe toxicity free interval
• Salvage surgery for < 50% reduction; patients achieving a CR
with salvage surgery were deemed treatment successes.
Bartelink et al. JCO 1997

• 3 factors were significantly associated with poorer survival -
Skin ulceration, nodal involvement and male sex.
(Prognosis did not differ by N1 vs N2 stage).
Conclusion:
• The combination of RT and CT resulted in an improvement
in local control and a reduction in the need for colostomy in
patients with locally advanced anal cancer.
CR* 5 yr LC CFS PFS OS
ChemoRT 80 68 72 61 57
RT Alone 54 50 40 43 52
p NR 0.02 0.002 0.05 0.17
All values in percentages; * CR: Complete remission.
Bartelink et al. JCO 1997

Concurrent Chemotherapy Regimens
Is MMC necessary: RTOG 87-04/ ECOG 1289
CDDP or MMC: ACT II, RTOG 98-11

Role of MMC: RT + 5FU + MMC
RTOG 8704 / ECOG 1289
• 291 patients (any T, any N), 146 MMC arm and 145 to test arm.
• End points
- Negative postinduction biopsy
- Incidence of Positive salvage biopsy
- Local regional control
- Time to colostomy
- Colostomy-free survival
- Disease-free survival
- Overall survival
- Toxicity rate
• Patients with residual disease post RT were considered failures.
• Median follow up: 3 years
Flam et al, JCO 1996

A. Two-field (AP-PA) technique. Superior border lowered to bottom of SIJ at 30.6 Gy and
lower corner blocks were not used. At 36.0 Gy, 10- x 10-cm fields with unchanged
inferior borders were used.
B. When inguinal nodes were involved, anterior field flared to include both inguinal regions.
Shaded area was boosted by electrons or photons to bring nodal dose at 3-cm depth to
50.4 Gy.

-ve Biopsy +ve Biopsy Colostomy CFS PFS OS
5FU +
MMC
92 8 9 71 73 78
5FU 86 14 23 59 51 71
p 0.135 0.135 0.002 0.014 0.0003 0.32
• Patients with primary tumors less than 5 cm achieved a 93% -ve biopsy
rate vs with 83% for patients with bigger primary tumors (p = .02).
• The impact of MMC on colostomy rate reduction was most significant in
T3/T4 primary tumors (p = .019) vs T1/T2 primary tumors (p = .141).
Conclusions:
• Adding MMC to 5-FU and RT improves postinduction biopsy
rates, colostomy rates, CFS and DFS.
Flam et al, JCO 1996

2x2 trial
Cisplatin vs MMC: the ACT II trial
• Primary end point: Complete response (at 26 weeks)
- colostomy-free survival
- in-field recurrence rate
- cause-specific survival
- Overall survival
- Progression-free survival
Median follow up
5.1 years

RT:
Phase I: 30.6 Gy / 17#
Phase II: 19.8 Gy / 15#
5FU: 1000 mg/m2/d, d1–4 & 29–32.
Mitomycin C: 12mg/m2, d1 (max 20mg)
Cisplatin: 60mg/m2, d1 & d29 (max 120mg)
Adjuvant: CDDP 60mg/m2, 5FU 1000mg/m2
• Stage T1–T2 (50%), T3–T4 (43%), LN-(62%), LN+ (30%)
• Stratified by site, T and N stage, sex, age & renal function
• 90.5% patients in the MMC arm vs 89.6% in the CDDP arm
had a CR at 26 weeks (p = 0.64).
• 3 year PFS was 74% (CDDP) vs 73% (MMC); p = 0.63).
• 3-year CFS was 73%, 75%, 75% and 72% in the MMC
/maintenance, CDDP/maintenance, MMC/No maintenance and
CDDP/No maintenance groups respectively.

• Overall, toxic effects were similar in each group [71%]
mitomycin vs [72%] cisplatin).
• MMC patients had more acute grade 3/4 hematological toxicities (25 vs.
13%).
Conclusion: 5-FU + MMC with RT remains the standard of care.
PFS OS

• Patients with T2-T4, any N anal carcinoma (65% T2, 70% N0, 48% Stage I)
• Stratifications: Sex, nodal status and tumor diameter.
Cisplatin vs MMC: RTOG 98-11
Ajani et al
• RT: 45 Gy (30.6 Gy Phase I, 14.4 Gy Phase II)
• 5FU 1000 mg/m2 on d1-4, d29-32 MMC arm; additionally on d57-60 and
d85-88 CDDP arm
• CDDP 75 mg/m2 on days 1, 29, 57, 85
• MMC 10 mg/m2 on days 1 and 29
NACT (2 x CDDP/5FU) fb
Chemoradiotherapy
• Concurrent 5FU/CDDP
CR Follow up
T3. T4, N+ or
residual T2
Boost
10-14 Gy
Chemoradiotherapy
• Concurrent 5FU/MMC
versus
320
324

Ajani et al. JAMA 2008
AP-PA fields
Four field

• Primary end point: 5-year disease-free survival
• overall survival
• Time to relapse
DFS OS Colostomy LRR DM
Hemat
toxicity
MMC 60 75 10 25 15 61
CDDP 54 70 19 33 19 42
p 0.17 0.10 0.02 0.07 0.17 < 0.001
NR: Not reported; all values in percentages
Ajani et al. JAMA 2008
• Severe acute hematologic toxicity was worse in the MMC
arm, but all other toxicities were comparable. Long term
toxicity was also similar.

RTOG 98-11: Long term update
Gunderson et al. JCO 2012
• DFS and OS were statistically better for MMC versus CDDP (5-year DFS,
67.8%v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026).
• CFS (P = .05), LRF (P = .087) and CF (P = .074) were numerically better.
Conclusion
• CCR with FU/MMC remains the standard of care for Anal SCC.

Other approaches
• Radiotherapy intensification: ACCORD 03
• Neoadjuvant chemotherapy: CALGB 9281, ACCORD 03
• Targeted agents

Induction Chemotherapy and RT Dose Intensification:
the UNICANCER ACCORD 03 study
Peiffert et al. JCO, 2012
2x2 factorial design
ICT: Induction Chemo; RCT: Chemoradiotherapy; SD: Standard dose; HD: High dose
• ICT: 5FU 800 mg/m2/d CI, d1-4 & 29-32; CDDP 80 mg/m2 d1 & d29
• RCT: 45 Gy / 25# / 5 wks; 5FU * CDDP during weeks 1 and 5
• HD: 20-25 Gy
• SD: 15 Gy
• 307 Patients with Tumors ≥ 40 mm or node positive
Median FU: 50 months

Conclusion
• Using CFS as primary end point, there was no advantage for
either ICT or HD radiation boost in LAACC.
Peiffert et al. JCO, 2012
CFS OS LC
Induction vs
No Induction
76.5 vs 75
P = 0.37
74.5 vs 71
P = 0.81
80.3 vs 81
P = 0.65
Standard Dose
vs High Dose
73.7 vs 77.8
P = 0.067
71 vs 74
P = 0.43
78.2 vs 83.1
P = 0.28
• Primary end point: Colostomy Free Survival
- Overall survival (OS)
- Local control (LC)
- Cancer-specific survival

CALGB 9281
• Phase II - 45 patients.
• NACT (T3/T4 and/or N2/N3)
.
• 2 week break included.
• Four-year data: OS 68%, DFS 61, 23% colostomy rate.
• No evidence to suggest improvement
- May be used in cases of abscess or fistula.
Meropol et al, JCO 2008
2 x NACT:
CDDP/5-FU
EBRT 45 Gy
2 x Concurrent MMC/5-FU
Single cycle CDDP/5FU
+ 9 Gy boost

Role of Cetuximab
• 23 patients in a phase 2 study of chemoradiation with 5FU, cisplatin, and
cetuximab.1
• RT: 55 to 59 Gy over 6.0 to 6.5 weeks.
• Response rate of 95%, but closed early:
- 6 (26%) episodes of thrombosis/embolism
- 52% grade 3 or 4 radiation dermatitis
- 44% grade 3 or 4 diarrhea.
• ACCORD 16 phase 2 trial evaluating cetuximab concurrently with
chemoradiation for anal cancer was closed early because of excessive
toxicity.
• At present, no role in definitive setting. May be used in metastatic
disease in combination with cytotoxic agents.2
1. Olivatto LO et al Cancer. 2013
2. Lukan et al. Oncology 2009

Impact of OTT on outcomes:
Pooled analysis of RTOG 8704 and 9811
• Univariate analysis
• Significant association between
Rx duration and
• Colostomy failure HR 1.51
• Local failure HR 1.52
• Locoregional failure HR 1.51
• Time to failure HR 1.40
Patients with a median Rx time more than
53 days had a significantly higher rate of
locoregional failure.
Ben-Josef et al. JCO 2010

Local Failure

Overall Survival

Adjuvant therapy after APR
• No data to suggest indications of adjuvant therapy after
surgery.
• Generally extrapolated from other sites:
- T3/T4
- Node +ve
- Margin +ve
- High risk features: poor differentiation, LVSI, ulcerative lesions, male
sex, HIV+/MSM

Summary
• Definitive chemoradiation (EBRT 45-54 Gy + 5FU/MMC) is
the management of choice for anal SCC.
- Treatment breaks to be avoided as far as possible.
• APR reserved for salvaging treatment failures/ recurrences.
• No benefit with neoadjuvant or adjuvant chemotherapy.
• No benefit with a higher dose boost.

Patient Positioning & Simulation
• Supine with arms across the chest or prone in a belly board
• If using the prone setup for primary fields, may consider supine
positioning for the boost
• Due to high rates of moist skin desquamation
• Contrast agents and markers
- Oral contrast to delineate small bowel
- Barium enema
- IV contrast to delineate the tumor and LN.
- Anal marker to delineate the anus.
- Wire to involved inguinal LN.

Field Design: Principles
• Large AP/PA fields that include the inguinal lymph nodes will
deliver the full radiation dose to the femoral head and neck.
• Patients treated in this way may be at risk for radiation-induced
fracture.
• Lateral inguinal lymph nodes generally treated only through
anterior fields. The posterior field is designed to treat only the
primary tumor and the pelvic lymph nodes.
• Minimize the dose to the femoral head and necks.
• If necessary, electron fields are used to supplement the dose to
the lateral superficial inguinal nodes that are not included in the
posterior photon field.

Whole Pelvic Field
AP-PA Fields
• Superior border
- L5/S1 junction for the first 30.6 -36 Gy.
- Lowered to lower margin of SIJ / 3 cm above the cranial extent of disease
to 45 Gy.
• Inferior border: > 2-3 cm below the anal verge or the inferior extent of
the primary tumor - whichever is lower.
• Lateral borders:
- PA field: 1.5-2 cm lateral to widest portion of the pelvic brim.
- AP field to include inguinal nodes till ~ 36 Gy, matched to PA thereafter.
- Clinically positive nodes should be outlined with radio-opaque wire.
• Generally includes the entire femoral heads.
Conventional field borders

• Wide anterior (A) and narrow
posterior (B) photon fields.
Electron fields are used to
dose the lateral inguinal
nodes not included in the
narrow posterior photon field
(C and D).
• The medial border of each
electron field is placed at the
posterior photon field’s lateral
exit point on the anterior
abdominal wall.

Anteroposterior treatment portal film. Nigro et al, Cancer 1983.

Conventional field borders
• Anterior border: Posterior margin of the symphysis pubis (to
treat only the internal iliac nodes).
• Posterior border: 1-1.5 cm behind the anterior body sacral
margin
• Superior/ Inferior borders: Same as AP-PA fields.
Lateral Fields
- Not always employed; may be used as part
of a 3 field design or a 4 field box

Perineal Boost
• Prone or supine; prone usually difficult due to skin toxicity
from Phase I
• Two,3 or 4 field design may be employed
• 2.5-3 cm margin to be taken on gross disease (AP and lateral)
- Clinical + radiological

Dose / Fractionation
• Phase 1: 36 Gy
- Whole Pelvic Fields (wide AP + narrow PA)
• Phase 2: 9 Gy (36 → 45)
- Whole pelvis, with AP fields matched to PA fields
- May lower the cranial border to lower end of SIJ
• Phase 3: 5.4 - 9 Gy* (45 → 50.4 - 54)
- Boost additional 5.4 to 9 Gy depending on T/N size & clinical response.
- May be omitted for early lesions (T1/T2, node negative).
• Inguinal fields: 9-18 Gy (photon or electron)
- Prescription depth ideally CT defined/3-4cms
* no evidence in favour of high dose boost

Conformal Radiotherapy
Target Volume Definitions
• GTV: Primary tumor + positive LN on planning CT (>1 cm short
axis diameter).
• CTV
- Nodes at risk include common iliac, external iliac, internal iliac,
presacral, perianal, and inguinal.
- CTV_A = 2.5 cm expansion on primary tumor and 1 cm
expansion on involved nodes
- CTV_B (Whole Pelvis CTV) = CTV_A + Nodal areas at risk
• PTV: Setup margins on CTV as per institutional protocol

Planning Objectives
• 95% of the PTV should receive at least 95% of the prescription
dose.
• Dose limitations
• Small bowel: V40-45Gy < 200 cc
• Femoral Head: D50 < 30-35 Gy
• Bladder: D50 < 35-40 Gy
• Marrow: V10 < 90%, V20 < 80%
• External genitalia: D50 < 20 Gy, D5 < 40 Gy

Brachytherapy
• In most series, patients received 30 to 55 Gy of EBRT + 5-FU/MM-C or
cisplatin followed by a 15 to 25 Gy boost with Ir192 afterloading catheters.
• Delivered intraluminally, through a rectal applicator that has direct contact
with the tumor, or through interstitial catheters.
• Papillon and Montbarbon reported a series of 276 patients of whom 222
underwent CRT (30 - 42 Gy) → 2 month break → 15-20 Gy Ir 192 interstitial
template based boost.
• Followed for at least 5 years, 65% DFS was noted, with a 7.4% failure rate in the
inguinal nodes.
• Other authors have also reported encouraging results; however it is yet to be
compared directly against an EBRT boost.2
1. Papillon et al. Dis Colon Rectum. 1987
2. Niehoff P, Kovacs G. Gastrointest Oncol 2014

Salvage Therapy for Local Recurrence
• Most patients undergo an APR and a permanent colostomy.
• Local structures invasion requires multivisceral resection to
achieve negative margins.
• Reported 5 year results: OS 30% - 64%, DFS 30% - 40%.
• The most important prognostic factor of survival after resection
is margin status, and patients with negative margins (R0) have
up to >50% long term survival.

AIN (Anal Intraepithelial Neoplasia)
• Transanal excision.
• Microinvasive disease: if incompletely excised, reexcision is required once
the surgical site is fully healed.
Topical options
• Imiquimod, a nucleoside analog has local proinflammatory and antiviral
properties and has shown good results in the eradication of AIN III.
• Fluorouracil has been shown to have high efficacy but causes significant
side effects, such as burning, irritation, and pain.
Other options
• Infrared coagulation,
• Cryotherapy,
• CO2 laser ablation, and 5-ALA/photodynamic therapy.
• High rates of recurrence, esp. in high risk groups.

Anal Margin Cancers
T1N0 > T2
Node +ve /
Advanced
• WLE with 1cm
margin
• If positive margins:
• Re-excision
• If re-excision not
feasible, RT + CT
• Chemoradiation • Combined modality
treatment
• APR + adjuvant treatment

Squamous Cell Cancer Of The Anal Margin
• Papillon and Chassard reported
on 8 patients with T1/T2 lesions
treated with either radium implant
brachytherapy alone (6 patients)
or in combination with external-
beam radiation (2 patients) .
• Local control rate was 100%. An
additional 36 patients were
treated with EBRT + 5-FU/MMC.
Cure rate for T1, T2, and T3
lesions were 100% , 84% & 50%.
• Cummings compared radiation
alone versus chemoradiation
retrospectively in 29 patients
• Median 7 yr follow-up, the local
control rate was 64% for the
radiation group and 88% for the
chemoradiation group. The local
control rate was inversely
associated with larger cancers
(T1-T2, 100 % ; T3 5-10 cm,
70%; T3 > 10 cm, 40%).

Adenocarcinoma Of The Anal Canal
• Extension of rectal cancer into the anal canal far commoner
than de novo adenocarcinoma of the anal canal.
- May arise from anal glands or anal fistulae.
- Occasionally in patients with Inflammatory Bowel Disease who have
ileal pouch-anal anastomosis.
• APR should be offered for early-stage disease.
• Locally advanced disease (T3+ or N+): Combined Modality

Melanoma Of The Anorectal Region
• The 5 -year OS rate is generally less than 20% . The initial stage at
presentation largely determines OS.
• Ross et al from the M. D. Anderson Cancer Center reviewed a series of 32
patients with melanoma treated with either APR or local resection.
• Local recurrence was lower in the APR group (29% APR vs 5.8%).
However, there was no difference in OS (19.5 months for APR; 18.9
months for local resection).
• Given available data, local excision advisable if adequate margins
possible; else APR should be done.
- Adjuvant therapy to be decided along the lines of melanoma.
Ross et al. Arch Surg, 1990
Singer M, Mutch MG. Clin Colon Rectal Surg, 2006

Management of advanced/metastatic disease
• Approximately 10%–20% patients
• Poor prognosis; 2 year survival less than 25%.
• No consensus on the standard chemotherapy treatment;
NCCN recommends combination chemotherapy with
CDDP + 5FU as 1st line.
• Other options:
• Taxanes, carboplatin, doxorubicin, irinotecan (alone or in
combination).
• Cetuximab (KRAS wild)
NCCN 2017

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