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( )Anal scc
1. Case Presentation on anal
squamous cell carcinoma
Zerubbabael A. ( COR2)
Moderator
2. Contents of the presentation
• Case
• Staging of anal ca
• Clinical approach/diagnostic workup
• Management of anal SCC
• Prognostic factors
• Follow-up/ surveillance
• Case critics
• References
3. Clinical manifestations
• Mean age of diagnosis for anal SCC is = about 62
years
• The most common presenting complaint is rectal
bleeding
• Other symptoms may include tenesmus, pain,
local irritation, discharge, or change in bowel
habit
• Clinically enlarged LNs are present in 15% of
patients at presentation
• Late presentation may result in a fungating or
verrucous perianal mass
4. Clinical approach/diagnostic workup
Meticulous history and physical examination
DRE with tumor characterization (location, fixation, extent)
- Assessment of anal sphincter function
Endoscopy/proctoscopy information about the extent of
mucosal spread, including the relationship to the dentate
line, and facilitates biopsy
Biopsy from primary lesion
Examination of inguinal lymph nodes; consideration of
biopsy/ FNAC if deemed suspicious
Gynecologic examination in females to rule out vaginal
invasion as well as exclude gynecologic primary ( HPV
associated); include screening for cervical cancer
Basic lab tests : CBC, OFT, HIV test with CD4 count and viral
load ( if positive)
5. Imaging
Chest X- ray
CT scan of chest and abdomen, and pelvic CT or
MRI
MRI is considered the most accurate method for
assessing the primary cancer and pelvic nodes
Consider PET/CT scan
- Meta-analysis of twelve studies found that
FDG-PET resulted in a change in nodal staging
in average 28% of anal cancer patients.
6. Cont’d
Mistrangelo et al, confirmed the need for LN
biopsy who studied patients who underwent
both sentinel lymph node biopsy and PET
scans.
PET-CT scans detected inguinal metastases in
26% of patients .
Histological analyses of the sentinel lymph
nodes detected metastases in only 12% (4 of
27 false positive cases) of cases
7. Staging of Anal SCC
• Clinical staging is performed by a combination of clinical,
endoscopic, and radiographic examinations
8.
9. Management
Disease /patient classification
- Well differentiated early localized disease ( T1 N0)
-Locally advanced disease ( and including poorly differentiated
T1N0)
-Persistent or recurrent disease
- Metastatic disease
Treatment modalities
- Wide local excision ???
- Radiation therapy alone
- Concurrent chemoradiotherapy
- Radical surgery ( APR)
- Pallative chemotherapy
10. CHEMORADIATION—NIGRO
REGIMEN
It was developed empirically as preoperative neoadjuvant therapy in the 1970s,
has revolutionized the approach to its treatment and evolved to become the
standard of care for definitive therapy of anal canal SCC
Organ-preserving CCRT, using RT( 30 Gy EBRT), 5-FU , and mitomycin C with
surgery reserved for residual disease
The pathologic specimens in three of three patients failed to demonstrate any
viable tumor
The Nigro approach of chemoradiation has subsequently been evaluated in several
other small phase II studies with radiation doses ranging from 30 to 60 Gy.
Successful in approximately 70% of cases, and avoids a permanent colostomy
11. Radiation Vs CCRT
United Kingdom Coordinating Committee on Cancer Research
A Phase III Anal cancer Trial (ACT I): 577 patients with anal SCC (75%) or
anal margin SCC (23%) of patients.
Patients were randomized to radiation alone (45 Gy) Vs continuos infusion
5-FU (1,000 mg/m2 on days 1-4 or 750 mg/m2 on days 1-5) during the 1st
and last weeks of radiation (45 Gy) with MMC (12 mg/m2 on day 1.
If the primary tumor had not regressed by at least 50% by 6 weeks after
treatment (as occurred in 10% in each group), surgery was recommended.
otherwise, the patients received an additional 15 Gy in 6 fractions by a
perineal field or 25 Gy over 2 to 3 days by iridium-192 implant.
12. UKCCCR ( ACT I) trial
UKCCR- ACT I RT alone (n = 285) CCRT ( n= 292) P value HR
Complete CR 76 ( 30 %) 100 ( 39 %)
Partial CR ( > 50 %) 157 ( 62 %) 138 ( 53%)
Minimal CR ( < 50 %) 22 ( 9 %) 21 ( 8 %)
3 year local failure rate 164 ( 61 %) 101 ( 39 % ) < 0.0001
3 year OS 58 % 65 % 0.25
10 year locoregional
failure
59 % 34 % < 0.001 0.46
10 year colostomy free
survival
26 % 36 % significant Np
10 year DFS 24 % 36 % < 0.001 0.7
10 year OS 36 % 42 % 0.12 0.86
The authors concluded that chemoradiation provided a 46% reduction in local recurrence
compared with radiation alone
13. ACT I
Twenty patients (3%) required a palliative colostomy or anorectal excision
due to treatment-related morbidities
Subsequently, dose reduction of mitomycin C was recommended if the
patient was ≥70 years old or if deemed medically necessary
In a report after a median follow-up of 13 years LRC, CFS, DFS, and deaths
due to anal cancer all significantly favored chemoradiation.
The absolute difference in risk of dying from all causes was 5.1% lower in
the chemoradiation group at 5 years and 5.6% lower at 12 years(HR 0.86;
P = .12)
There were six (2%) deaths due to treatment in the combined-modality
arm and two (0.7%) in the irradiation-alone arm.
Acute non hematologic and late toxicities were considered comparable in
each group
14. EORTC
European Organization for Research and Treatment of
Cancer ( EORTC)
It randomized 103 patients with ( T3, T4 or pelvic node +ve
anal SCC) to radiation (45 Gy) with or without continuous
infusion 5-FU (750 mg/m2 on weeks 1 and 5) and mitomycin C
(15 mg/m2 on day 1).
After 6 weeks, boost irradiation of 15 Gy (if complete CR to
previous treatment had occurred) or
20 Gy (after partial response) given by external beam or
interstitial irradiation.
15. EORTC
EORTC RT alone ( n = 52) CCRT ( n= 51) P value
Complete response 54 % 80 %
3 year OS 65 % 72 % 0.17
5 year LRF 48 % 32 % 0.2
5 year CFS 40 % 72 % 0.002
5 year OS 53 % 58 % 0.17
One of 51 patients who received combined modality treatment died of toxicity.
Acute and late toxicity rates did not differ markedly
16. The Role of Mitomycin C
The RTOG and Eastern Cooperative Oncology Group (ECOG) study
was undertaken to determine whether MMC was a necessary
component of the protocol and whether the hematologic toxicity of
that drug could be avoided.
In this trial 291 patients with cancers of the anal canal of any T and
N category who did not have evidence of extrapelvic metastases
received 45 Gy to 50.4 Gy in 25 to 28 fractions over 5 weeks, plus 2
courses of 5-FU (1,000 mg/m2/d by continuous peripheral
intravenous infusion) over 4 days, with or without MMC (10 mg/m2
by bolus intravenous injection) on the first days 1 and 29
All patients underwent biopsy of the primary tumor site 6 weeks
after treatment
Patients with positive biopsies had the option of receiving an
additional 9 Gy in 5 treatments concurrently with a 4-day infusion
of 5-FU (1,000 mg/m2/d) and a single injection of cisplatin (CDDP)
(100 mg/m2) if it was thought that anal function might still be
salvaged
17. RTOG 8704/ECOG 1289
RTOG-8704/
ECOG- 1289
RT, 5 FU ( n= 145) RT, 5 FU, MMC
(n = 146)
P value
4 year LRF 34 % 16 % 0.0008
4 year CR 22 % 9 % 0.002
4 year DFS 51 % 73 % 0.0003
4 year OS 67 % 76 % 0.31
Complete response
tumor size > 5 cm
tumor size < 5 cm
86 % (115)
81 % ( 42)
90 % ( 73)
92 % ( 119)
86 % ( 42)
96 % ( 77)
0.135
0.02
0.002
Biopsies were positive in 15% of those who received 5-FU only and in 8% of those who
received both MMC and 5-FU (P = .14).
Acute hematologic toxicity was more common in the patients who received MMC, but the
rates of other acute and late toxic effects were similar in each treatment group.
Four of 146 (2.7%) patients who received both 5-FU and MMC suffered fatal toxicity as did
1 of 145 treated with RT and 5-FU alone.
On the evidence from this trial, combination of MMC with 5-FU and RT is more effective
than is 5-FU alone with RT.
18. Neoadjuvant chemotherapy/ the
introduction of cisplatin
RTOG 98-11
The intention of the trial was to downsize the primary
tumor and nodal metastases prior to concurrent
chemoradiation
A large phase III multiinstitutional randomized trial for
locally advanced SCC of the anal canal that randomized 682
patients with T2 to T4 tumors and any nodal status
One Patient group received 5-FU/mitomycin C and
concurrent radiation (control arm)
The other group recived induction 5-FU/cisplatin followed
by radiation concurrent with 5-FU/cisplatin
19. RTOG 98-11
RTOG 98-11 RT, 5 FU, Cisplatin
( n = 324)
RT, 5 FU, MMC ( n= 325) P value
3 year CR 19 % 10 % 0.02
3 year DFS 54 % 60 % 0.17
3 year OS 70 % 75 % 0.1
5 year LRF 27 % 20 % 0.89
5 year CR 17 % 12 % 0.075
5 year DFS 58 % 68 % 0.004
5 year OS 71 % 78 % 0.021
Acute grade 3 or 4 non-hematologic toxicity rates were 75% in each arm, but
hematologic toxicity was higher in the MMC group (67% vs. 47%).
No treatment-related deaths were reported.
The rate of severe long-term toxicity was similar in each group (11% MMC vs. 10%
Cisplatin).
The investigators concluded that RT, 5-FU, and MMC should remain the standard
approach.
20. Mitomycin Versus Cisplatin and the
Role of Adjuvant Therapy
The UK ACT II trial is the largest phase III trial conducted in SCC of the anal
canal and is the first direct analysis of 5-FU/mitomycin C versus 5-
FU/cisplatin with concurrent radiation therapy.
It also evaluated whether maintenance (adjuvant) chemotherapy
following completion of chemoradiotherapy reduces recurrence-free
survival (RFS) .
Using a 2 × 2 factorial design, 940 patients ( anal and perianal SCC) with T1
to T4 node-negative and -positive disease were randomly assigned to
either 5-FU/mitomycin C or 5-FU/cisplatin administered concurrently with
continuous radiotherapy of 50.4 Gy.
Subsequently patients were further randomized in to two courses of 5-
FU/cisplatin consolidation chemotherapy or no further treatment
Treatment response was assessed at three time points from treatment
initiation: 11, 18, and 26 weeks.
The final assessment at 26 weeks included digital examination and CT
imaging.
21. UK ACT II trial
UK-ACT II RT,5 FU, Cisplatin
( n = 469)
RT, 5 FU, MMC
( n = 471)
No adjuvant
( n = 446)
Adjuvant
( n = 448)
P value
Complete CR at
6 months
90 % 91 %
3 year
colostomy rate
11 % 14 % 0.26
3 year DFS 75 % 75 % 0.42
3 year PFS 73 % 74 % 0.7
3 year OS 85 % 84 %
G 3 & 4
hematologic
toxicities
16 % 26 % 0.001
The role of maintenance (adjuvant) 5-FU/ cisplatin chemotherapy showed no added
benefit for RFS or overall survival
22. ACT II trial
At initial assessment (11 weeks), 64% were found to be in clinical
complete response, and by week 26 it increased to 85%
Of patients who did not experience complete response at 11
weeks, 72% went on to achieve such by week 26.
At the 11-week assessment, patients with complete response had
a 5-year OS of 85% versus 75% without complete response;
however, by week 26, patients who failed to achieve a complete
response had a significantly inferior 5-year OS (87% versus 48%).
This confirms that delayed tumor response is frequent following
treatment and prolonged tumor regression occurs following
treatment, with prognostic significance at later time points
following completion
23. ACT II trial
Investigators failed to fulfill the primary end point of superiority for
the cisplatin-based regimen
The final results indicate that 5-FU/cisplatin is noninferior to 5-
FU/mitomycin C in achieving a CR and is associated with fewer
significant hematologic toxicities
Cisplatin should be used only for selected patients in whom
hematological toxicity may be truly significant, such as patients with
HIV/ AIDS-related complications or a history of complications (ie,
malignancies, opportunistic infections)
Based on these findings, at MDACC, 5-FU/cisplatin remains our
preferred regimen due to its efficacy and decreased
myelosuppression relative to 5-FU/mitomycin C.
This also allows for safer treatment of immunocompromised and
elderly patients who otherwise might not tolerate
myelosuppressive combinations
24. ACCORD 03
• French intergroup conducted a factorial-designed four-arm
trial (ACCORD 03) that evaluated the addition of induction
5-FU and cisplatin and of a higher dose of boost RT (20 Gy
to 25 Gy vs. standard 15 Gy).
• The baseline standard RT schedule was 45 Gy in 25
fractions in 5 weeks.
• The outcome has been reported in abstract only.
• The actuarial 3-year colostomy-free survival rate (the
primary study endpoint) ranged from 80% to 85% in the
four arms, with no significant advantages for either
experimental treatment.
• Local control, event free survival, and overall survival rates
were similar in each arm
25. Capecitabine in place of 5 FU ???
• The U.K. National Cancer Research Institute Anal Subgroup
conducted a phase II trial of RT (50.4 Gy in 28 fractions in
5.5 weeks), a single intravenous injection of MMC (12
mg/m2 on day 1) and oral capecitabine (825 mg/m2 twice
daily on each RT treatment day).
• The schedule was described as well tolerated with
acceptable compliance
• The overall tumor response rate after treatment was 90%
(complete in 24 of 31 and partial in 4 of 31).
• Although this use of oral capecitabine is promising and
removes the need for continuous intravenous infusions of
5-FU, at this time, delivery of both 5-FU and MMC
intravenously remains standard.
26. Cisplatine in Place of MMC???
• The EORTC conducted a randomized phase II trial
in which RT (36 Gy + 2-week gap + 23.4 Gy) was
combined with either MMC and 5-FU or MMC
and Cisplatin.
• The overall response rates at 8 weeks were 92%
to RT, MMC, and Cisplatin versus 80% to RT, 5-FU,
and MMC
• Greater compliance to the full regimen was seen
with RT, 5-FU, and MMC.
• It is not known whether this group has
proceeded with a planned phase III trial.
27. Summary
• Primary tumor control rates (excluding salvage
treatment) in most studies of RT, 5-FU, and
MMC are
T1 tumors = 90% -100%,
T2 tumors = 40% to 55%
T3, T4 tumors = 40% to 55%
An overall control rate of about 60 %
28.
29. Treatment in HIV positive patients
The numbers of HIV-infected patients with anal SCC are increasing with
marked preponderance of male patients.
The median age at diagnosis is in the fourth decade, about 20 years earlier
than in non–HIV-infected patients
HIV-infected patients were not eligible for any of the randomized trials
described earlier
Currently HIV status alone does not change the treatment option but there
is increased chance of toxicity and disease recurrence
Locoregional control rates of about 65% or better were described in some
series, similar to those in HIV-negative patients.
However, some investigators reported lower rates of local control and
sphincter preservation in HIV-positive patients, despite earlier-stage disease
and good initial tumor response
30. For patients with CD4 counts of 200/mL or less, increased morbidity may require
prolonged treatment breaks .
Hoffman et al. reported that patients with CD4 count ≥200/mm3 tolerated
combined therapy (5-FU/MMC/radiation) better (decreased likelihood of toxicity)
compared with patients who had CD4 counts <200/mm3
Most recent reports indicate that it is not necessary to electively modify standard
protocols of RT (with respect to dose, fractionation, or volume) and chemotherapy
(either 5-FU and MMC or 5-FU and Cisplatin ), but modifications should be based
on the severity of side effects in each individual patient
In a study of 40 HIV-positive patients, the 5-year overall survival rate was similar to
that in 81 HIV-negative patients, but the major cause of death in HIV-positive
patients was anal cancer, in contradistinction to the HIV-negative patients in whom
causes other than cancer predominated
With the use of HAART, CRT (even if the CD4 count is less than 200/mL) may be
given safely at conventional doses to patients who are HIV positive with
comparable CR rates to patients who are HIV negative
31. In patients with low CD4 counts that are not on HAART, decreasing
chemotherapy doses, not delivering mitomycin or replacing it with
cisplatin, or giving a lower dose treatment (30 Gy) may be considered
Carefully examine the patient’s performance status and CD4 count before
initiation of treatment
Adherence to standard treatment is frequently jeopardized in patients
who are HIV positive who were at risk of not obtaining the optimal
treatment (longer RT duration, lower equivalent dose, and less mitomycin-
based therapy).
In addition, patients who are HIV positive required higher doses of
inguinal RT more often because of advanced disease, which can further
contribute to toxicity
Blood counts should be monitored weekly during CRT for all patients with
a low threshold to suspect neutropenia, especially in a patient who is HIV
positive.
32. Two factors may predict for heightened acute normal tissue toxicity or
poor cancer control:
CD4 count <200/μL at the start of treatment
the presence of active AIDS
Local control and long-term sphincter preservation remaines problematic.
Current practice is to make sure that patients who are HIV positive are
currently taking HAART and to include the patient’s infectious disease
and/or primary care team in his or her multidisciplinary management
33. The role of surgery
Prior to the mid-1970s, the standard surgical approach to anal cancer was APR,
which required a permanent colostomy
Collectively, long-term DFS results with a surgery alone approach were
approximately 50%.
A review at the Mayo Clinic of 118 anal cancers treated with APR reported an
OS rate of 70% and overall recurrence rate of 40%.
34. Local excision
Usually restricted to small well-differentiated squamous cell cancers that
have not invaded the sphincter muscles and are located distal to the
dentate line
This approach is based on the finding in surgical series that pararectal or
superior hemorrhoidal system lymph node metastases were associated with
<5% of well-differentiated squamous cell cancers <2 cm in size
For lesions that have residual microscopic disease or have close surgical
margins <1 mm, further local excision, if technically possible, may be
pursued, or adjuvant chemoradiation should be considered
However, if resection margins are positive or considered inadequate, and
further local excision is not possible, the patient should receive
chemoradiation or RT alone.
Wide local excision with a 1-cm margin is recommended for all histologic
types, provided anal continence can be preserved
35. Radical surgery
Retains only a limited place in the initial management of primary invasive anal
cancer
It is mainly reserved for salvage therapy of persistent or loco-regionally recurrent
disease
For management of complications after conservative therapy
Inguinal dissection for inguinal recurrence
For permanently incontinent patients:
- few patients (<5% in most series )are incontinent for solid stool at
presentation.
This is usually due to extensive tumors that have destroyed the competence of the
anal sphincters or fistulized into the vagina
Eradication of cancer by RT, with or without chemotherapy, does not restore
continence in such patients, likely because the cancer is replaced by fibrous tissue
rather than the specialized muscle of the anal sphincters.
In a recent study that included 31 patients that failed chemoradiation, those who
underwent surgery with curative intent had a 5-year OS of 66% compared to those
only 13.5% who those who had palliative treatment.
DFS rates ranging from 30% to 40%
36.
37. Radiotherapy
• Radiation alone is now recommended mainly to
patients who are unable to undergo CCRT or for the
treatment of smaller cancers up to about 3 to 4 cm in
size where the physician does not wish to add
chemotherapy.
• Knowledge of patterns of failure is vital to accurately
delineate treatment volumes and avoid marginal
misses about 3 to 4 cm in size where the physician
does not wish to add chemotherapy.
• As with combined RT and chemotherapy, primary
tumor control is better with small tumors
38.
39. The need for elective nodal irradiation
Radiotherapy field design should be based on better understanding
of the natural history of anal cancer and correlation of sites of
treatment failure with the treatment plan
The finding in surgical series of histopathologically verified
metastases in
- the pararectal and internal iliac nodes is up to 30%,
- the inguinal nodes in up to 20%,
This has encouraged most radiation oncologists to irradiate these
node groups electively.
Retrospective and prospective studies have shown the advantages
of elective nodal irradiation (ENI).
A report from France: Following ENI to a total dose of 40 to 50 Gy
(1.8 to 2 Gy fractions),
- the 5-year cumulative rates of inguinal recurrence was
2% in those who received ENI (n = 75) versus
16% in those who did not (n = 106).
In the no-ENI group, recurrence rates were 12% from T1 to T2 and
30% from T3 to T4 tumors
40. Patient positioning and simulation
Patients should be scanned from 2cm superior to the top of L5 to 7cm
below the anal marker with 3mm slices.
Can be simulated in the supine or prone position and there are benefits to
each approach in the appropriate clinical setting.
Prone setup with a false tabletop allows for improved small bowel
avoidance and may be useful in individuals with a large pannus and pelvic
node involvement.
Supine(arms across the chest) setup is usually more reproducible,
potentially allowing for reduced PTV margins and smaller treatment fields.
If prone positioning is used for primary fields, better to consider supine
positioning for the boost phase as it is typically away from small bowel so
that desquamated patients may be positioned more comfortably.
41. Cont’d
Bladder Preparation: full bladder for simulation and treatment to
decrease the amount of small bowel within the pelvis
Oral contrast should be used to delineate the small bowel.
Barium enema to delineate the tumor.
IV contrast to delineate the tumor and LN.
Anal marker to delineate the anus.
Any visible or palpable perianal tumor should be demarcated with
radiopaque material as it may not be apparent on simulation imaging.
Wire to involved inguinal LN.
For tumors involving the perianal skin or superficial inguinal nodes,
bolus should be placed as necessary for adequate dosing of gross
disease and avoid dose inhomgenity in these areas
42. Treatment volumes
GTV: - Primary tumor and clinically positive LN seen on planning CT
- PET or MRI fusion typically aides in GTV delineation. - -
Colonoscopy/anoscopy reports may help determine tumor location.
CTV: 2.5 cm expansion on primary tumor and 1 cm expansion on
involved nodes
LN at risk include common iliac, external iliac, internal iliac, presacral
mesorectal, perianal, and inguinal.
PTV = CTV + 1 cm
43. Conventional(2D)Treatment panning
Phase I filed borders ( AP/PA)
Superior border: L5/S1 vertebral body interspace.
Inferior border: 2.5 to 3 cm below the anal marker (or 3 cm margin on
extent of disease if extending into the anal margin/perianal skin).
Lateral border
● PA: 1.5 cm on pelvic brim.
● AP: include inguinal nodes with 2 cm lateral to greater sciatic notch.
Phase II/ cone down 1
Superior border is lowered down to the bottom of SI joints.
Inferior and lateral borders remain the same.
44. Boost Phase : Indicated for T3, T4, N1, or T2 lesions with
residual disease after 45 Gy.
2 cm margin on GTV via
AP/PA,
3-field (opposed laterals and PA lowest anterior skin dose),
4-field (AP/PA/laterals) approach.
Alternatively, may use en face perineal electron or photon field
with the patient in a frog-leg position depending on the depth of
the primary tumor.
45. Dose and fractionation
CTV to 45 Gy/1.8 Gy/fraction
Field reduction to cone down no. 1 after 30.6 Gy.
T3, T4, or T2 lesions with residual disease after 45 Gy should receive an additional
9 to 14.4 Gy to the GTV via boost field.
T2 dose goal, 45 to 50.4 Gy
T3 dose goal, 54 Gy
T4 dose goal, 54 to 59.4 Gy
Clinically negative inguinal LN should receive a minimum of 36 Gy, measuring
prescription depth on CT classically, 3 cm has been used (this may underdose
thicker patients).
Clinically positive inguinal LN should receive a minimum of 45 Gy.
- Boost additional 5.4 to 9 Gy depending on LN size and clinical response.
Clinically positive pelvic LN may be boosted along with primary boost field for an
additional 5.4 to 9 Gy above 45 Gy CTV dose depending on LN size and clinical
response.
46.
47.
48. IMRT
• Offers the possibility of further reducing the dose to normal
tissues, mainly due to improvements in radiation dose
distributions
• Recommended for anal carcinoma cases as it should be of
benefit to patients of all age groups and genders to help
lessen acute side effects and potential long-term toxicities
by reducing dose to bowel, bone marrow, femoral heads,
genitalia, and skin
• Require considerable attention to identifying gross target
volumes (GTV) and relevant elective clinical target volumes
(CTV).
• Particular attention to patient positioning and
immobilization is necessary
50. Prognostic factors
Tumor factors
• Features related to the anatomic extent of disease
generally provide the most prognostic value.
• Tumor size (T stage) and nodal status (N stage) are the
most significant prognostic factors
• The most adverse factor for survival is the presence of
extrapelvic metastasis.
• When anal cancer is confined to the pelvis, the size of
the primary tumor is the most useful predictor for local
control and preservation of anorectal function and
survival.
51. 5 year survival ( N= 19,199)
Five-year survival rates
by T category
• T1 = 68.5%;
• T2 = 58.9%;
• T3 = 43.1%;
• T4 = 34.3%.
The survival rates by AJCC
stage
52. Patient Factors
Patient-related factors are not consistent between series.
Age, ( above 65 years)
Performance status,
Gender ( male, worse prognosis)
Baseline hemoglobin level
Patients who continue to smoke tobacco may be at greater
risk of local relapse.
In some series of HIV-positive patients, high viral load, low
lymphocyte CD4-positive counts, and AIDS have been
prognostic of poor local tumor control and survival and, in
some series, of impaired tolerance of RT and chemotherapy
53. Molecular prognosticators
• Provide information on patient outcomes regardless of therapy
• Predictive biomarkers provide information about the effect of specific
therapeutic intervention.
• Wong et al. described that increased p53 expression was associated
with worse local–regional control (P = .02) and DFS (P = .01)
• Some studies have indicated that the lack of p21 expression is
associated with poor prognosis
• Elevated pretreatment neutrophil-lymphocyte ratio (NLR) in blood
samples and p16 expression in tumor tissue, both of which are found
to be associated with higher risk of recurrence.
54. Followup
• In a post hoc analysis of the ACT II trial, at 11 weeks
following treatment initiation, 64% of patients were
found to be in clinical complete response; by week 26,
85% demonstrated such.
• Of patients who did not experience complete response
at 11 weeks, 72% went on to achieve such by week 26
• Posttreatment evaluation is critical to assess the
effectiveness of therapy and to detect a persistent or
recurrent tumor
• The first evaluation typically is between 8 to 12 weeks
after the completion of chemoradiation.
55. Ongoing clinical evaluation typically occurs every 3 to 6 months for
the first 2 years and then every 6 to 12 months until 5 years
following completion of chemoradiation.
Approximately 20% to 25% of patients with SCC treated by
chemoradiation will either fail to completely respond or relapse
within the first 3 years after treatment
Given that SCC of the anus can regress slowly following treatment
completion (up to 12 months), it is generally recommended that
patients who have regressive disease do not undergo repeat
biopsies
It may be appropriate to conduct less intense follow-ups following
3 years, given that only 7% of relapses occur beyond this time point.
Lesions persisting beyond 3 months following treatment are more
concerning for residual disease; however, as stated previously, it is
important to assess changes over time.
Notas del editor
Of all patients presenting with palpable inguinal lymph nodes, only approximately 50% are malignant ( other 50 % are of reactive hyperplasia); therefore, fine-needle aspiration is often recommended in suspected cases, and a positive result may guide radiation field design and dose prescription.
It may be necessary to examine patients under anesthesia secondary to pain and sphincter muscle spasms
PET scans may also alter treatment planning volumes, including the gross tumor volume (GTV) in 56% of cases and clinical target volume (CTV) in 37% of cases, especially with a fusion of both PET and CT, which increased the size of GTV and CTV, but these results have not been validated pathologically
In the past patients with invasive anal carcinoma were routinely treated with an APR.
However, LRR was high, and the morbidity with a permanent colostomy was compromising the quality of life of patients
A pivotal approach led to the anecdotal finding that surgery may not be necessary for curative intent in the treatment of SCC of the anal canal
Patients received concomitant 5-fluorouracil (5-FU) and mitomycin C, which was administered along with external beam radiation therapy (EBRT) (30 Gy).
Subsequent nonrandomized studies using similar regimens and varied doses of chemotherapy and RT provided support for this conclusion.
And later randomized trials were developed.
Late toxicity events (severity was not graded) after a median of 13 years’ follow-up were similar in each treatment group
These two above mentioned trials established RT, 5-FU, and MMC as the standard first-line treatment
One patient group received 59 Gy in 6.5 weeks (45 Gy in 1.8-Gy fractions, followed without interruption by 14 Gy in 2-Gy fractions), together with concurrent 5-FU (1,000 mg/m2/d) by continuous infusion on days 1 - 4 and 29 - 32 plus MMC 10 mg/m2 intravenous bolus on days 1 and 29;
The other group received 5-FU (1,000 mg/m2/d) days 1 - 4, 29 - 32, 57 - 60, and 85 - 88 plus cisplatin (75 mg/m2 bolus injection on days 1, 29, 57, and 85) with the same 59-Gy radiation schedule ( but it started on day 57)
There was a greater incidence of acute grade 3 or 4 hematologic toxicity on the mitomycin C arm (26% vs 16%, P = .001) but no statistical differences in grade 3 or 4 nonhematologic toxicities.
Following a median 50- month follow-up, there was no significant difference in 5-year colostomy-free survival rates (70% ( G1) - 82% (G2)).
Similarly, no significant differences were seen between the arms in terms of LRF, cause-specific survival, and (OS : 71 – 75 %).
Grade 3 & 4 hematologic toxicities G1+ G2 = 19, G3+G4 = 12 %
Grade 3 & 4 non hematologic toxicities ( diarrhea) G1+G2 = 9 %, G3+G4= 12 %
Grade 4 late toxicity ( colostomy) = 3 %
The overall response rates at 8 weeks were 92% (34 of 37)to RT, MMC, and Cisplatin versus 80% (31 of 39) to RT, 5-FU, and MMC, although greater compliance to the full regimen was seen with RT, 5-FU, and MMC
Hesitancy to administer CRT in patients who are HIV positive stems from toxicity, particularly lowered blood counts, or possible opportunistic infections during treatment, and a poorer ability to recover from treatment toxicity in the face of chronic immunosuppression
It is favored that patients with HIV be managed with CRT incorporating IMRT, MMC, and 5-FU, if possible, on the basis of CD4 counts and performance status. HAART should also be initiated.
IMRT may be well suited to this population of patients with the potential to reduce acute morbidities making CRT more tolerable.
In a study by Oehler-Janne et al. comparing patients who are HIV negative to those who are HIV positive, patients who are HIV positive were able to receive standard CRT with good CR rates and similar 5-year OS rates as patients who are HIV negative, but the major cause of death in patients who are HIV positive was anal cancer
It appears that outcomes should be comparable in patients who are HIV positive to those who are HIV negative, but there is a chance of greater toxicity and relapse
The most important prognostic factor of survival after resection is margin status, and patients with negative margins (R0) have up to a 75% 5 year OS.
Further predictors of a poor OS outcome following surgery include inguinal lymph node involvement, tumor size >5 cm, adjacent organ involvement, male gender, and comorbidities
Current radiation treatment strategies have been developed through better understanding of the natural history of anal cancer and correlation of sites of treatment failure with the treatment plan. Most failures were at the site of the primary tumor, followed by the regional and other pelvic node groups.
In a prospective study in Australasia in which patients with T1 or T2 tumors up to 4 cm in diameter did not receive inguinal ENI, inguinal node failure occurred in 9 of 40 (23%), in 5 as first site of failure.
Another study from Germany reported that treatment of larger cancers by interstitial brachytherapy alone resulted in failure in pelvic nodes above the treated volume in 16% (14 of 88)
In patients with adequate renal function, IV contrast facilitates identification of the pelvic and groin vasculature (which approximates at-risk nodal regions).
prone in a belly board in an alpha-cradle or other immobilization device, arms extended
When IMRT techniques are to be used, particular attention to patient positioning and immobilization is necessary. If possible, the accuracy of setup should be verified frequently, for example, by image-guided radiation treatment.
When all other factors are equal, male gender, advanced age (65 years or above), and poor performance status before treatment are associated with poor outcome after definitive treatment
The physical examination should include a visual inspection, a digital rectal exam, an anoscopy, and a palpation of the inguinal nodal regions