Butt

Question 1

Basic epidemiology for anal cancer:

Answer 1

Relatively rare:
72 new cases/year in NZ = 0.2% of cancers in NZ
Average age at Dx is 50 to 60 (later age @ Dx in NZ data)
After age 50, anal cancer is slightly more common in women.
Incidence in men and women has increased over past 30 years.

Question 2

Risk factors for butt cancer:

Answer 2

HPV (most commonly HPV-16, but also 18, 31, 33, and 45).
High-risk HPV DNA has been detected in up to 84% of specimens in large-scale anal cancer studies.

Other (often related) risk factors include:
HIV infection, history of cervical, vulvar, or vaginal cancer (HPV-related), immunosuppression after organ transplant, smoking, and history of receptive anal intercourse.

Question 3

Key anatomic features of the anus

Answer 3

The anal canal: ~2.5-4 cm long, extends proximally from anal verge to anorectal junction

Anal verge = palpable junction between non–hair-bearing and hair-bearing squamous epithelium

Anal margin = skin within 5 cm of anal verge.

Dentate line (Pectinata) = line between simple columnar epithelium proximally to stratified squamous epithelium distally. Divides the upper 2/3 (derived from the embryonic hindgut) and lower 1/3 of the anal canal. Each side having different histology (stratified squam vs simple columnar), lymphatics,
and neurovascular supplies.

Question 4

Lymphatics of the anus:

Answer 4

Below Pectinata: Inguinal and external iliac nodes

Above: Inferior mesenteric nodes, internal iliac, and sacral nodes (and ischiorectal fossa nodes).

Question 5

Inferior mesenteric nodes drain to?
Sacral nodes drain to?

Answer 5

Inferior mesenteric nodes -> Superior mesenteric -> Para-aortic

Sacral nodes drain -> Common iliac.

Question 6

Common types of anal cancer (give %):

Answer 6

About 75% to 80% are squamous cell carcinoma.
Other, rarer anal cancers:
adenocarcinoma (poor concensus),
melanoma, neuroendocrine, carcinoid, Kaposi’s,
leiomyosarcoma,
and lymphoma.

Question 7

Broad steps in HPV mediated oncogenesis:

Answer 7

Infection -> Persistence (patient/host factors) -> Development of a high-grade precursor lesion/genome integration -> Invasion and malignant transformation

Question 8

Steps of HPV host genome integration:

Answer 8

1) Inserts into DNA (i.e DS-DNA virus), host expresses oncoproteins –
E5, E6, E7 (E5 is complicated and is involved in EGFR recycling and PDL-1 activation).
2) E6 protein binds to and facilitates degradation of p53 protein (tumour suppressor) → cell progress through G1/S check point with damaged DNA
3) E7 Phosphorylates Rb → Rb releases E2F transcription factor → E2F activated → transition of cell from G1 to S phase of cell cycle with damaged

Question 9

What is p16?

Answer 9

CDK inhibitor:
Slows progression of the cell cycle by inactivating the CDK2 that phosphorylates retinoblastoma protein (preventing E2F release).

When E7 binds Rb, E2F is free/active (pushing cell from G1 to S), p16 is a negative feedback on this process.
Therefore p16 is a marker of viral integration (E7 oncoprotein).

The criteria for tissue being p16 +ve: > 70% cells stain for p16

Question 10

The criteria for tissue being p16 +ve:

Answer 10

The criteria for tissue being p16 +ve: > 70% cells stain for p16

Question 11

Anal cancer prognostic and predictive factors:

Answer 11

Poor prognostic factors:
Male, positive nodes, and tumour size >5 cm were independently prognostic
for worse OS (RTOG 98-11).
P16 negative tumours are also a poor prognostic feature.
For exam: patient factors (compliance, immune status/compromise, age/frailty)

Predictive factors:
P16 and HPV in tumour cells are thought positive predictive factors. The evidence for p16 for anal cancer is mixed.
– recent follow up data of 78 patients suggested only presence of HPV in tumour cells was correlated with pCR. HIV status, wild type TP53, and p16 overexpression were not.

Question 12

Hx and Ex for a patient presenting with an anal lesion:

Answer 12

History:
HPV/HIV/risk, Immune compromise.
Obstructive Sx
Gynae Hx

Exam:
Digital rectal exam to determine extent of tumour and sphincter function
Inguinal nodes
GYN exam/cervical screening

Question 13

Investigations for patient presenting with an anal lesion:

Answer 13

Bloods:
FBC, U&E, LFTs, CEA,
HIV if there are risk factors (and CD4 if HIV+)
Tissue:
Anoscopy with biopsy of primary, excisional biopsy, or FNA of suspicious inguinal LNs and HPV status.
Sigmoidoscopy/colonoscopy often performed as well.
Imaging:
CT CAP, pelvis MRI + C, PET/CT.

Question 14

Anal cancer staging:

At which stage is ChemoRT indicated:

Answer 14

T1<2cm (“superficial” have option of local excision)
T2: 2 to 5cm (no invasion)
T3: > 5cm
T4: Invasion into adjacent organs.

> 2.1cm (T2-T3) is at least stage II
Invasive (T4) is at least stage IIIB
Node +ve is at lease stage III

Question 15

Define “superficial” SCC

Answer 15

NCCN says can consider excision alone if tumour “superficial SCC,” i.e <3 mm invasion past basement membrane and <7 mm horizontal spread

Question 16

The role(s) of surgery in anal SCC

Answer 16

1) Local excision “superficial SCC,” i.e <3 mm invasion past basement membrane and <7 mm horizontal spread

2) APR is used for salvage in setting of failure after definitive chemoRT.
Salvage surgery results vary widely due to small patient populations and selection bias:

A Netherlands of 47 patients undergoing salvage APR demonstrated negative margin resections in 81% with a 5-year OS rate of 42%.

Question 17

What is the benefit of concurrent chemo in anal cancer treatment?

Answer 17

The addition Chemo improves pCR rates, LC, CFS, and DSS, 2 large RCTs (Bartelink , ACT 1) failed to show OS benefit. Update of ACT I shows that benefit provided by adjuvant chemoRT persists at 15 years.

Question 18

Mnemonic for key Butt cancer studies

Answer 18

Nigro not included, butt:
ACT ACCORD(ing) to RTOG when thinking about bulk.

ACT (I and II) - benefit of concurrent chemo (everything but OS) + 72% of incomplete responses at 11 weeks have responded at 26wks.
ACCORD(ing) - 15Gy Boost and neoAdj chemo no benefit for T4.
to
RTOG when thinking about bulk:

• T3 or more get 54/30, +ve nodes>3cm also. +_ve nodes <3cm 50.4/30. Pelvis 45/30
  No bulk and node -ve = 50.4/28 to GTV (and canal), pelvis 42/28

Question 19

Give a brief outline of the history of anal cancer treatment, and the success of the previous approach:

Answer 19

Pre1970s anal ca was treated with APR and permanent colostomy.
Historical 5-year OS rates of 60% for T1/2 disease, 40% for T3 disease, and 20% for LN+ disease

In the 1970s: Nigro regimen was established after high pCR rates to neoadjuvant chemoRT were noted:
Retrospective Review of 45 pts (=>T2) treated with 5-FU (96 hrs) × 2 cycles days 1 to 4 and 29 to 32, as well as 1 cycle bolus MMC on day 1.
RT was 30 Gy/15# (3 weeks) AP/PA technique to pelvis and inguinal nodes.
All patients were intended to have APR, post, but this was abandoned when the 1st 4/5 pts had pCR@4weeks.

Question 20

What study forms the basis of the current standard of care chemo for anal ca?

What is the regime?

Answer 20

Nigro:
MMC/5-FU remains the standard of care, however, cisplatin/5-FU is also reasonable in pts in whom the toxicity of MMC may be unacceptable or where MMC is contraindicated (e.g idiosyncratic or hypersensitivity reactions, coagulation and bleeding disorders and thrombocytopenia).
1 Cycle concurrent w/RT (ACT 1 Trial):
Day 1: IV MMC + 5-FU (IV pump over 96 hours)
Day 29: 5-FU

Question 21

Alternative chemo for anal cancer:

Answer 21

Cisplatin – 5FU - ACT II Trial: replacement of MMC for cisplatin had equivalent response rates. BUT, still no trials to date have demonstrated an oncologic
benefit to the use of cisplatin.

MMC – Capecitabine: Equivalence of capecitabine to 5-Fu not yet been established. This protocol is not standard, may be considered in pts where continuous infusional fluorouracil is unsuitable (e.g. in patients with venous access related concerns).

Question 22

How important is MMC chemo (when is it given?) in anal cancer treatment?

Answer 22

The addition of MMC is important: Multiple prospective studies show adding MMC to 5-FU-based chemoRT improves LC, CFS - despite greater toxicity.

Given Day 1:
Day 1: IV MMC + 5-FU (IV pump over 96 hours)

Question 23

Does the addition of chemo to RT add much benefit for patients?

Answer 23

The addition Chemo improves pCR rates, LC, CFS, and DSS, 2 large RCTs (Bartelink , ACT 1) failed to show OS benefit. Update of ACT I shows that benefit provided by adjuvant chemoRT persists at 15 years.

Question 24

Outline the role of induction chemo in anal cancer:

Answer 24

In T4 disease:
Induction chemo (or 15Gy boost) for T4 disease does NOT improve outcomes (ACCORD Trial)

Question 25

Outline the role of RT boost in anal cancer:

Answer 25

Induction chemo or 15Gy boost for T4 disease does not improve outcomes (ACCORD Trial)

Question 26

Outline radiotherapy dosing strategy for anal cancer:

Answer 26

No prospective data exist to guide RT dosing strategies.
One common standard is from RTOG 0529:

Non-bulky (T1-T2) Node negative:
50.4 Gy/28# to primary, 42 Gy/28# to LNs (SIB)

Bulky (>T2) or Node +ve:
54 Gy/30# to primary, 45 Gy/30# to pelvis
Nodes:
≤3 cm: 50.4 Gy/28#
>3 cm: 54 Gy/30#

Question 27

Anal cancer target volumes for involved sites:

Answer 27

GTV primary: Gross disease as identified on exam and imaging ->expand 1cm CTV, encompassing entire canal from verge to junction include spincters exclude other muscle and bone.
GTVnode: 0.7cm CTV

PTV 1cm on CTV

Question 28

Anal cancer target volumes for at risk sites:

Answer 28

Low dose CTV includes High dose (i.e. SIB) +:
1) Mesorectum - 1cm ITV anterior border
2) Pre-sacral space
3) Ischiorectal fossa
4/5) int and external iliacs
6) inguinal nodes

PTV 1cm on CTV - trimmed off non-target skin

Question 29

When and how to assess for complete response post definitive chemo Rads for ass cancer:

Answer 29

ACT II: post-hoc analysis found there can be a delayed clinical response up to 26 weeks without negative impact on survival.

We perform:
Clinical “ass”essment by exam at 8-12 weeks post RT. If complete response, then: 3-6 months DRE, anoscopy, inguinal node exam for 5 years, with annual CT CAP +contrast yearly for 3 years.

IF clinical suspicion of residual -> can be watched for 6 months as long as no progression. If progression then Bx, and discussion of salvage APR

Question 30

A patient has definitive RT for an anal SCC.
1st post treatment assessment is performed at?

On assessment there is residual disease. What is your approach?

Name a relevant Trial.

Answer 30

Clinical assessement at 8-12 weeks.

SCCs can regress slowly in size for up to 26 weeks. ACT II - 72% of patients that did not have cCR at 11 weeks had it by 26 weeks.