Anal Cancer

Four different types of epithelium :1.perianal skin anal verge2.(pale-colored zone) pectinate line3.mucosal folds of the anal valves, 4. transitional epithelium

Anatomy

The major lymphatic pathways flow to three lymph node systems.

1. The perianal skin, the anal verge, and the canal distal to the dentate line drain predominantly to the superficial inguinal nodes

2. Lymphatics from around and above the dentate line flow with those from the distal rectum to the internal pudendal, hypogastric, and obturator nodes of the internal iliac systems.

3. The proximal canal drains to the perirectal and superior hemorrhoidal nodes of the inferior mesenteric system.

SCC:(85% to 90% ) subtypes large-cell keratinizing and nonkeratinizing, and basaloid

or cloacogenic

Adenocarcinomas Adenocarcinomas from the rectal-type mucosa in the

upper canal are classified as primary rectal cancers.

SCC with mucous microcysts, small cell, and undifferentiated cancers.

perianal skin cancers Most are squamous cell cancers, with occasional basal

cell cancers and skin adnexal adenocarcinomas.

Pathologic Classification

one-tenth as common as cancers of the rectum

Cancers arise in the canal with three to four times the frequency of perianal cancers

more common in women The risk of anal cancer increases with age;

the median age at diagnosis is from 60 to 65 years.

Epidemiology

Sexual activity Sexually transmissible viruses Human papillomavirus infection(type 16 ) HIV infection  Chronic immunosuppression not due to HIV Cigarette smoking

Risk Factors

HPV infection is an initiating event in the majority of cases, but HPV DNA integration is necessary for the transition from low-grade to high-grade

Loss of heterozygosity at 11q23 In HIV-negative patients: allele losses as

17p, 18q, and 5q In HIV-positive patients: microsatellite

instability,

Natural History

direct extension lymphatic pathways Hematogenous metastases are less

common

Lymphatic invasion occurs relatively early.

Natural History

Extrapelvic metastases : fewer than 10% of patients.

most frequently in the liver and lungs Relapse after initial treatment is more common

in the area of the primary tumor and the pelvic lymph nodes than in extrapelvic organs.

Locoregional relapse rates of up to about 30% and extrapelvic failure rates up to about 20% are common

Overall 5-year survival rates = of 55% to 65%.

Natural History

grow locally and may extend into the anal canal. When the site of origin is in doubt, it is conventional to classify the cancer as arising in the anal canal

The ipsilateral inguinal nodes are the most common site of metastasis and are abnormal in from 5% to 20% of cases.

Overall 5-year cause-specific survival rates usually exceed 80%.

Perianal cancers

Nonspecific Bleeding 1/2 anal discomfort

awareness of an anal mass Pruritus anal discharge Pain alteration in bowel habits asymptomatic tumors (an inguinal node mass) Unsuspected microinvasive carcinoma is sometimes

found in mucosa removed at hemorrhoidectomy

Clinical Presentation

History and physical examination Biopsy anorectal examination Physical examination HIV clinically suspicious nodes should be biopsy Abdominal and pelvic CT or MRI CXR Transanorectal ultrasonography CBC, R and L FT and, +_ HIV antibody

Diagnostic Work-Up

Spread to pelvic node groups, including the external iliac, common iliac, and sigmoid nodes, is classified as metastasis (M1)

For perianal cancers, the regional nodes are the ipsilateral inguinal nodes.

Staging

Tumor 2 cm or less in greatest dimension T1

Tumor more than 2 cm but not more than 5 cm in greatest dimension

T2

Tumor more than 5 cm in greatest dimension T3

Tumor of any size invades adjacent organ(s) (e.g., vagina, urethra, bladder) (involvement of the sphincter muscle(s)

alone is not classified as T4)

T4

StagingAnal Canal TNM Classification

Metastasis in perirectal lymph nodes(s)

N1

Metastasis in unilateral iliac and/or inguinal lymph node(s)

N2

Metastasis in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal

lymph nodes

N3

Tumor 2 cm or less in greatest dimension T1

Tumor more than 2 cm but not more than 5 cm in greatest dimension

T2

Tumor more than 5 cm in greatest dimension T3

Tumor invades deep extradermal structures (i.e., cartilage, skeletal muscle, or bone) T4

Perianal Skin TNM Classification

M T N Age and performance status ? Women have a better prognosis Hemoglobin levels ≤10 g/L poor Px HIV-positive patients high viral load, low

lymphocyte CD4+ counts, and AIDS poor Px

Prognostic Factors

The combination of RT, (5-FU), and mitomycin is the standard

Radiation-based regimens produce survival rates at least equal to those of surgical series, while allowing preservation of anorectal function in the majority of patients.

Treatment of Anal Canal Cancer

Primary Tumor Lymph Node Metastases Extrapelvic Metastases

Combined-Modality Therapy

5-FU (1,000 mg/m2/day for 4 days or 750 mg/m2/day for 5 days), by continuous peripheral intravenous infusion in the first and final weeks of radiation treatment

mitomycin (12 mg/m2) by bolus intravenous injection on day 1 of the first course of chemotherapy

The radiation dose was 45 Gy in 20 to 25 fractions in 4 to 5 weeks or 30 GY(2OOcGY)

Primary Tumor

The patients were reassessed clinically 6 weeks after treatment.

not regressed by at least 50%: 1. Surgery2. 15 Gy in six fractions by a perineal field or 25

Gy over 2 to 3 days by iridium-192 implant

Treatment-related morbidity requiring surgery After 6 weeks, boost irradiation of 15 Gy (if

complete clinical response) or 20 Gy (after partial response) was given by external-beam or interstitial irradiation.

CMT

Chemotherapy is not given during the boost radiation 5YS : 80% for cancers ≤2 cm (T1) 70% for tumors 2 to 5 cm (T2) 45% to 55% for (T3 or T4) 65% to 75% overall local control rates (excluding salvage treatment) are 90% to 100% (T1) 65% to 75% (T2) 40% to 55% (T3 or T4 60% overall Because of case mix and the preponderance of advanced cancers in

many series, generally only about two-thirds of all patients treated retain anorectal function. No more than about 5% of patients overall have lost anorectal function because of treatment-related complications

CMT

increases in total radiation dose shortening of overall treatment time exploration of combinations of radiation and

chemotherapy radiation, 5-FU, and cisplatin radiation, 5-FU, and mitomycin

to improve results

random biopsies from the site of the primary tumor, and/or abnormal nodes

Biopsies directed only to areas suspected clinically of harboring residual or recurrent cancer

A negative biopsy does not exclude the possibility of cancer regrowth .Residual masses at the site of the original anal cancer may take several months to resolve fully after chemoradiation or radiation therapy alone .Most authors now recommend biopsy only when persistent cancer is suspected clinically.

Treatment of local residual cancer or recurrence is planned according to the extent of disease, both locoregional and extrapelvic, and the potential for preserving anorectal function.

further radiation and chemotherapySurgery(APR) CT

Lymph node metastases can be eradicated by the same radiation and chemotherapy doses effective against the primary tumor.

first diagnosed, pelvic nodes are present in about 30% and inguinal node metastases are detectable clinically in 15% to 20%.

Approaches to the management of inguinal node metastases vary from radical dissection to excision or needle biopsy of enlarged nodes followed by radiation therapy or radiation and chemotherapy . Local control of the involved inguinal nodal areas is very good, usually ≥80% . However, 5-year survival rates are usually 10% to 20% lower than in those who do not have demonstrable node metastases

Lymph Node Metastases

Prophylactic or therapeutic radical dissection of the inguinofemoral nodes is not necessary and carries a high risk of late morbidity .

Elective irradiation of clinically normal inguinal node areas, with or without chemotherapy, reduces the risk of late node failure in that area to <5% .

Control of subclinical pelvic node metastases by irradiation and chemotherapy

اولیه : تومور مثل لنفاوی غدد درمان CMTنتیجه

Lymph Node Metastases

10% to 20% Deaths from extrapelvic metastases alone

are relatively infrequent.

rate of metastasis in CMT was 10%, compared to 17% in RT

Extrapelvic Metastases

The use of radiation therapy alone, either brachytherapy or external beam, has been greatly reduced since the confirmation of improved outcome of combined modality therapy. Radiation alone is now recommended mainly to patients who are unable to undergo radiation plus chemotherapy, especially elderly patients ,or for the treatment of smaller cancers up to about 3 to 4 cm in size

Radiation Therapy alone

Surgery is the principal treatment for anal intraepithelial neoplasia

extensive tumors that have destroyed the competence of the anal sphincters or fistulized into the vagina. These patients may be managed by APR with postoperative CRT, using drug schedules similar to those for primary treatment and radiation doses of about 45 Gy in 5 weeks.

S →CRT colostomy → CRT→immediate or delayed

resection Serious postradiation morbidity may require

surgical management,

Surgery

Local excision small well-differentiated squamous cell cancers

that have not invaded the sphincter muscles and are located distal to the dentate line

pararectal or superior hemorrhoidal system lymph node metastases were associated with <5% of well-differentiated squamous cell cancers <2 cm in size .

Excision of small cancers, especially of the distal canal and anal verge, is more expedient and generally associated with less morbidity than radiation-based treatments.

Local excision

The most common histologic type of invasive cancer of the perianal skin is SCC. BCC and adenocarcinomas

Wide local excision with a 1-cm margin for all histologic types.

Radiation alone or in combination with chemotherapy is also effective ,but may produce symptomatic long-term skin changes.

Radiation-based protocols identical to those for anal canal cancer are preferred when anal continence would be impaired by surgery.

Perianal Cancer

Perirectal and pelvic node metastases are uncommon unless the cancer involves the anal canal extensively

The risk of inguinal node metastases is about 10%, primarily with category T3 or T4 tumors or poorly differentiated cancers.

perianal cancer

Elective bilateral inguinal nodal irradiation 1. T3 or T4 tumors 2. poorly differentiated cancers

RT for abnormal inguinal nodes :similar to that for anal canal cancer

RT for pelvic nodes: if the anal canal is invaded.

Rt lymph node ( perianal cancer)

The principles of management for the uncommon basal cell and adenocarcinomas of the perianal skin are similar to those for these histological types elsewhere on the skin.

uncommon

The median age :the 40 decade increased risk of toxicity, particularly in the

perineal skin and anorectal mucosa ( modifications should be based on the severity of side effects in each individual patient )

Two factors may predict for heightened acute normal tissue toxicity and/or poor cancer control, namely, a CD4 count <200/µL at the start of treatment or the presence of AIDS

Patients with HIV/AIDS

Concurrent antiretroviral therapy does not reliably reduce the severity or incidence of toxicity of radiation and chemotherapy

Most arise from rectal-type mucosa Tx similarly to those that arise in the

rectum

The uncommon adenocarcinomas that develop from anal glands or in fistulae have also usually been managed by APR . (adjuvant CRT ? )

Adenocarcinomas

rare early metastases a poor prognosis Tx= surgery or radiation Systemic chemotherapy similar to that used

for small cell cancers that arise elsewhere may be combined with radiation for the primary tumor and used to treat metastases, but responses are generally limited.

Small Cell Carcinomas

Only well-differentiated squamous cell cancers ≤2 cm in size situated in the distal canal appear to have a risk of nodal metastases <5%

Metastases in the pararectal and internal iliac nodes in up to 30% and in inguinal nodes in up to 20% has encouraged most centers to irradiate these node groups electively

planning target volumes may be extensive Acute and late morbidity can be reduced by avoiding tangential

irradiation to the sensitive skin of the perineum and external genitalia or, if techniques that require tangential irradiation are elected, by the use of daily fractions ≤2 Gy. The irregularities and curvatures of the perineum and lower pelvis make homogenous radiation distributions difficult to achieve. Measurements with in vivo thermoluminescent dosimeters found dose variations of as much as 10% from predicted levels in the region of the anocutaneous junction .Computerized dose planning systems may not provide accurate values at skin–air interfaces. Care must be taken as far as possible to avoid regions of excessive dose.

Radiation Therapy TechniquesAnal Canal

Many radiation oncologists prefer to treat the primary tumor and the posterior pelvic and inguinal nodes in continuity.

An A-P–opposed pair of fields is the most common arrangement:

prone supine

Whole-Pelvis Techniques

upper border :lumbosacral junction if the intent is to include the common iliac, upper presacral, and rectosigmoid nodes in the treated volume.

This border is commonly moved down during treatment to the lower end of the sacroiliac joints, thus encompassing only the perirectal, lower presacral, and internal iliac nodes (and, if the volume is sufficiently wide, the lower external iliac nodes), in order to lessen the risk of radiation enteritis

Whole-Pelvis Techniques

upper : lumbosacral junction or lower end of the sacroiliac joints

inferior :3-cm distal to the lowermost extension of the primary tumor

lateral borders:asymmetric and/or matched fields

Whole-Pelvis Techniques

The location and depth of the inguinal

nodes should be obtained by axial imaging .When asymmetric and/or matched fields are used, there is potential for both over and under dosage .Considerable care is required in planning and in patient positioning.

If it is elected to irradiate the posterior pelvic tissues and inguinal nodes discontinuously for all or part of the prescription, or to treat the posterior pelvis only, the volume irradiated is reduced compared with that of whole-pelvis techniques.

The anal canal and posterior pelvic nodes may be treated by multiple beam techniques. These are commonly three- or four-field techniques, such as (AP/PA) fields, and opposed lateral beams, analogous to those used for rectal cancer.

Posterior Pelvis Techniques

multiple-field conformal techniques, including (IMRT), can re-duce the mean dose to the perineum and external genitalia by about 30%.

Although these techniques generally include beams tangential to the perineum, doses of at least 54 Gy in 1.8-Gy fractions can be delivered with only occasional need for treatment breaks due to skin or gastrointestinal toxicity .

IMRT techniques have described the use of patient immobilization devices, but have not discussed the possible effects on dose distribution of internal organ motion.

IMRT :Posterior Pelvis Techniques

megavoltage equipment. without concurrent chemotherapy. primary tumor of 60 to 65 Gy, in 1.8- to 2-Gy fractions, after 40 to 45 Gy the volume is reduced. the primary tumor with a margin of 2 to 3 cm(by interstitial

therapy, by external-beam therapy with a perineal field, or by multifield techniques )

A dose of 15 to 20 Gy in 2 weeks is given to the reduced volume. If low–dose-rate interstitial radiation is used, a dose of 15 to 20 Gy at 0.5 cm from the plane of the implant over 24 hours (Paris system) is recommended

Proven or suspected metastases in the inguinal nodes and abnormal perirectal or pelvic nodes should be treated to the same total dose as the primary tumor.

Dose–Time Factors

FIGURE 59.3. Transverse axial computed tomography of pelvis showing conformal intensity-modulated radiation therapy plan designed to include anorectum, posterior pelvic, internal iliac, and inguinal lymph nodes.

Delivery of the final reduced volume treatment phase by brachytherapy is more common in Europe than in North America, where external beam treatment is favored.

effective brachytherapy, including low–dose-rate (LDR) ,pulsed–dose-rate (PDR) ,and high–dose-rate (HDR) techniques .

Brachytherapy has usually been given 2 to 8 weeks after external-beam therapy.

There is no agreement on whether the treatment volume should include the full extent of the initial primary cancer or only the tumor remaining at the time of implant .

The brachytherapy dose depends on the composite dose of the total radiation prescription. Occasionally, significant toxicity has been encountered

Techniques to reduce the risk of serious toxicity by minimizing the volume irradiated , avoiding fully circumferential implants ,and reducing the dose to the uninvolved anal circumference ,have been described.

The merits of adjuvants to brachytherapy such as intracavitary or interstitial hyperthermia or concurrent chemotherapy are unproven.

When radiation is given with concurrent 5-FU and mitomycin, or 5-FU and cisplatin, some modification of these dose–time guidelines is usual.

Increases in total radiation doses and shortening of overall time of treatment by eliminating elective interruptions in radiation (split course therapy) have been advocated.

Dose-time

elective breaks after about 3 weeks' treatment

as required by individual patients

Interruption

Overall treatment time

A dose–control relationship ? The need to continue to review dose–time

factors and techniques carefully is reflected by the finding of excessive acute and late toxicity when 5-FU and mitomycin were given concurrently with high-dose radiation

Escalating the total radiation dose

When clinically normal lymph nodes are irradiated electively, doses of about 36 Gy in 18 fractions in 3.5 weeks in combination with chemotherapy appear adequate ,and doses as low as 24 Gy in 12 fractions in 2.5 weeks have been used successfully .

Nodal metastases should be treated to the same dose as the primary cancer.

Lymph nodes

If small (<4 cm) perianal cancers with low risk of regional node metastases are treated by radiation, a dose of 60 to 66 Gy in 2-Gy fractions over 6 weeks may be used.

A direct perineal field is preferred

Orthovoltage equipment may suffice, although electrons or low energy megavoltage photons (with bolus) are used more commonly.

Flattening the perineum

Perianal

Usually treated by the techniques and schedules of radiation and chemotherapy used for anal canal cancers

The upper border : at the lower end of the sacroiliac joints.

The final phase of radiation may be given by direct perineal photon or electron therapy.

Although brachytherapy may be used for the final phase, full treatment of perianal cancers by brachytherapy has been associated with high rates of necrosis in some series.

Larger perianal cancers, or cancers invading the anal canal

Some nonrandomized series have described higher acute and late toxicity rates from combined modality therapy than those reported in the multicenter randomized trials. This probably results from use of different criteria for recording and reporting toxicity.

Sequelae of Therapy

CMT : moderate leukopenia, thrombocytopenia, anoproctitis, and perineal dermatitis

Cisplatin :marrow toxicity may be less, but at radiation doses of 59.4 Gy in 6.5 weeks, acute soft tissue toxicity rates are similar

incidence (<2% overall) of mortality associated with acute toxicity, usually as a result of neutropenia with sepsis.

after doses of 30 Gy :NO 5% to 15% of those receiving higher

radiation doses Risk of pelvic fracture ?

late toxicity

changes in anorectal function such as urgency anorectal telangiectasia perineal dermatitis dyspareunia, and impotence These lower-grade side effects are usually

managed medically with varying success.

Less serious side effects