ANAL CARCINOMA

Dr. AADITYA PRAKASH

DNB Resident, Radiation Oncology

BMCHRC, Jaipur

ANATOMY• Anal canal extends from the

anorectal ring (dentate line) to the anal verge(3-4 cm).

• Regions:-

•Intraanal lesions:-Cannot be visualized or only slightly visualized with gentle traction on the buttocks

•Perianal lesions:-Completely visible

–Within a 5-cm radius of anal opening with gentle traction

•Skin lesions:-

–Outside of the 5-cm radius

INTRODUCTION

• Cancers of the anal region account for 1% to 2% of all large bowel cancers and 4% of all anorectal carcinomas.

I. squamous cell carcinomas:- 75% -80%

II. Adenocarcinomas:- 15%

• There is a slight female predominance with 1. 7 cases per 1 00,000 women compared with 1 .4 per 1 00,000 men per year

• Anal canal cancer most commonly develops in patients 50 to 60 years of age.

• The corresponding 5-year relative survival rates were :-

I. 80.1 % for localized disease,

II. 60.7% for regional lymph nodes, 29.4% for distant metastasis,

III.5 5 . 4 % for unstaged disease.

INTRODUCTION

• Risk Factors: >10 sexual partners, history of anal warts, history of anal intercourse < age 30 or with multiple partners, history of STD.

• HPV: strongly associated with SCC and may be requisite for disease formation. High-grade intraepithelial lesions are precursors.

• In particular HPV-16, 18 as in cervical cancer.

• The HPV viral proteins E6 and E7 inhibit tumor suppressor p53 and retinoblastoma proteins, respectively, and this disrupts normal cell-cycle regulation.

• AIDS is associated with anal cancer, likely through an association with immunodeficiency in the setting of HPV coinfection . Increased risk if CD4 < 200.

INTRODUCTION

• The incidence of anal cancer is also much higher (up to 35 per 1 00,000) in men who practice anal-receptive sexual intercourse(MSM), and those who are human immunodeficiency virus (HIV) -positive have twice the risk than those who are HIV-negative.

• Cigarette smoking has also been implicated as a risk factor for the development of anal cancer in a number of case-control studies. The risk is increased fivefold compared with controls.

• An association between anal cancer and benign anal conditions (e.g., hemorrhoids, anal fissure, or fistula) has been reported frequently and chronic irritation or inflammation of the anal tissue has been assumed to play a role in anal carcinogenesis.

• In a Danish population-based study, patients with anal fissure, fistula, perianal abscess, or haemorrhoids were found to be at increased risk for anal cancer.

PATHOLOGY

• Anal cancers occur between the anal verge and 2 cm beyond the dentate line; tumors occurring further from the dentate line are called rectal cancers.

• Adenocarcinomas can arise from anal crypts and should be treated as a rectal cancer though with a higher risk of inguinal node spread, given their location and lymphatic flow compared with rectal adenocarcinomas.

PATHOLOGY

• Primary anal melanoma is a rare tumor that accounts for only 1% of all anal cancers. Anal melanoma is similar to melanoma of the skin and is characterized by the distant spread of disease.

• Outcome is poor after wide local excision or abdominoperineal resection, with just a 10% survival in most series at 5-year follow-up.

• Perianal skin and anal margin tumors include squamous cell carcinoma, giant condyloma (verrucous carcinoma), basal cell carcinoma, Bowen disease, and Paget disease.

PATHOLOGY

• Classification of epidermoid anal cancers on the basis of morphologic :-

I. transitional cell carcinoma,

II. basaloid carcinoma, and

III. mucoepidermoid carcinoma.

• These tumors all arise from the anal transition zone and are often grouped together as cloacogenic carcinoma.

• The World Health Organization (WHO) (3rd & 4th edi.)classification of malignant epithelial tumors of the anal canal includes :-

• squamous cell carcinoma,

• adenocarcinoma,

• small cell carcinoma, and

• undifferentiated carcinoma.

PATHWAYS OF TUMOR SPREAD

• Anal cancer tumors spread by

I. direct extension to surrounding tissues,

II. lymphatic dissemination to pelvic and inguinal lymph nodes, or

III. hematogenous spread to distant viscera.

• At diagnosis, about half of all anal cancers have been found to invade the anal sphincter or surrounding soft tissue. Although Denonvilliers fascia is usually an effective barrier to prostatic invasion in men, direct extension to the rectovaginal septum is a common occurrence in women.

PATHWAYS OF TUMOR SPREAD

• The superficial inguinal nodes are the primary drainage basin for that part of the anal canal distal to the dentate line.

• Lymphatic drainage around the dentate line occurs to lymphatic plexuses of the rectal mucosa and along the pathway of the inferior and middle hemorrhoidal vessels to obturator and hypogastric lymph nodes.

• Lymphatic connections also join the anus to presacral , external iliac, and deep inguinal nodes.

PROGNOSTIC FACTORS • Mawdsley et al:-244 of 577 anal cancer

tissue samples were assessed from the

United Kingdom Coordinating Committee

on Cancer Research (UKCCCR) ACT I

study for the expression level of p53 , Bcl-

2, thymidylate synthase, thymidine

phosphorylase, and Ki-67. High

expressions of p53 were associated with

decreased DFS in the multivariate analysis.

However, Bcl-2, thymidylate synthase, Ki-

67, and thymidine phosphorylase

expressions had no prognostic value.

• Boman et al.:-reviewed 114 patients

treated with APR and demonstrated that

tumor size inversely related to survival and

was strongly associated with stage.

• Radiation Therapy Oncology Group (RTOG)

98 -11 trial:-tumor-related prognosticators for

poorer OS included node-positive cancer, large (

> 5 cm) tumor diameter, and male gender.

Tumors greater than 5 cm in diameter,

regardless of nodal status, had a higher

colostomy rate and inferior disease-free survival

(DFS ).

• Touboul et al.:- larger tumors yielded inferior

10-year OS (T1 86 % ; T2, 82.5 % ; T3, 56. 8 % ;

and T4, 45 %). In addition, survival was

significantly better in patients with tumors 4 cm

or less in diameter as compared to tumors

greater than 4 cm.

CLINICAL PRESENTATION

• The most common presenting symptoms are bleeding (45%) and anal pain(30%). Other less common symptoms include pruritus , palpable mass ,anal swelling and changes in bowel habits are the main symptoms.

• It is common for patients and their physicians to attribute such symptoms to hemorrhoids for many months preceding the diagnosis, underscoring the importance of performing a simple anorectalexamination for patients with such symptoms.

Workup for Anal Canal Cancer

• PET imaging is useful in further evaluating the extent of the primary tumor and the presence of regional lymph node metastases, and distant metastases, as well as in evaluating the response to therapy.

• For patients with HIV risk factors, a determination of HIV status should be made before the initiation of therapy.

• Female patients should be subjected to a gynecologic examination to exclude other HPV-associated cancers.

• Counselling for loss of fertility for men and women.

Workup for Anal Canal Cancer

• Surgery for the initial diagnosis and staging of anal canal tumors should be limited to a biopsy of the primary tumorand evaluation of the inguinal lymph nodes.

• Clinically enlarged inguinal lymph nodes should be aspirated. If the cytology is nondiagnostic or demonstrates only benign disease, an open excisional biopsy of 1 or 2 lymph nodes is recommended.

• Under no circumstances should a formal lymph node dissection be performed for the initial evaluation of suspicious nodes, as it can increase the morbidity of radiation and has no therapeutic value.

AJCC TNM STAGING ,7TH

AJCC TNM STAGING ,7TH

• Note: Direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or the sphincter muscle(s) is not classified as T4.

• Until the late 1970s, the conventional treatment for anal canal cancer was an APR. Nigro et al. challenged this practice with a report of patients with squamous cell cancer of the anal cancer who following preoperative treatment with 30 Gy plus concurrent fluorouracil (5-FU) and mitomycin-C were found to have a pathologic complete response at the time of surgery.

TREATMENT OF LOCALIZEDSQUAMOUS CELL CARCINOMA

OF THE ANAL CANAL

• Combined Modality Therapy has been the standard of care since the 1980s, a review of 38,882 patients with anal cancer registered in the National Cancer Data Base from 1985 to 2005 revealed that only 75% received that treatment.:-

• Those treated with CMT (plus surgery) had higher 5-year survival rates compared to those who did not receive CMT (65% versus 58%, P < .0001).

ROLE OF INDUCTION CHEMOTHERAPY

• NCCN:-

• “…Induction chemotherapy preceding chemoradiation may be beneficial in subset of patients with T4 cancer. 5-year colostomy free survival rate was significantly better in T4 patients who received induction 5-FU/ cisplatin compared to those did not.(100% vs. 38+/-16.4%.P=.0006)”

NOVEL BIOLOGICAL RADIOSENSITIZING AGENTS

• Cetuximab , a monoclonal chimeric antibody against EGFR, is effective in combination with radiotherapy in treating squamous cell carcinoma of the head and neck.

• A small phase 1 study of anal cancer patients showed that the addition of cetuximab to cisplatin and 5-FU chemoradiation is safe and feasible . This phase 1 study had patients with T2N2 - 3 ,T3N0-3, and T4NO. A 78 % pathologic complete response rate was reported. KRAS and BRAF mutation appear to be infrequent, reinforcing the potential benefit of EGFR inhibitors.

SURGERY• Surgery is the principal treatment for anal

intraepithelial neoplasia but retains only a limited place in the initial management of primary invasive anal cancer.

• Local excision, preserving anorectalfunction, is possible in some patients, although this is now 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.

• The combination of local surgery and RT and chemotherapy has resulted in regional control rates in the groin of 80% or better. However, 5-year survival rates are usually 20% less than in those who do not present with inguinal node metastases.

• Surgery is reserved for failure to achieve complete response or for local failures.

RADIATION THERAPY • Localization, Immobilization, and

Simulation

• Immobilization and patient position

• Supine with arms across the chest or prone in a belly board in an alpha-cradle or other immobilization device, arms extended. If using the prone setup for primary fields, may consider supine positioning for the boost (which is typically away from small bowel) so that desquamated patients may be positioned more comfortably.

• Contrast agents and markers

I. Oral contrast to delineate the small bowel.

II. Barium enema to delineate the tumor.

III. IV contrast to delineate the tumor and LN.

IV. Anal marker to delineate the anus.

V. Wire to involved inguinal LN.

VI. Bladder should be moderately filled.

• Target Volume Definitions

• GTV:- Primary tumor clinically positive LN seen on planning CT (>1 cm short axis diameter).

I. PET or MRI fusion typically aides in GTV delineation.

II. Colonoscopy/anoscopy reports may help determine tumor location.

• CTV:- LN at risk include common iliac, external iliac, internal iliac, presacral, mesorectal, perianal, and inguinal.

I. CTV = 2.5 cm expansion on primary tumor and 1 cm expansion on involved nodes

• PTV

• PTV = CTV + 1cm

RADIATION THERAPY • GUIDELINES:-

• Whole Pelvic Field

• Posterior-anterior:-

• Superior border:- L5/S1 junction for the first 30.6 Gy. This is then decreased to the inlet of the true pelvis (bottom of the sacroiliac joints) for the remaining 14.4 Gy.

• Lateral borders:- 1.5 cm lateral to the widest bony margin of the true pelvic side walls. The lateral border is then extended to include the lateral inguinal nodes. These nodes should be outlined with wire in order to help identify them.

• Inferior border:-minimum 2.5 cm below the anal verge or the inferior extent of the primary tumor—whichever is most inferior.

GUIDELINES

• Laterals:-

• Superior border:- Same as posterior-anterior field.

• Inferior border:- Same as posterior-anterior field.

• Posterior border:- 1-1.5 cm behind the anterior body sacral margin.

• Anterior border:- Posterior margin of the symphysis pubis (to treat only the internal iliac nodes).

• Blocking:-

• Blocks are used to spare the posterior muscle and soft tissues behind the sacrum, to reduce the amount of dose inferior to the symphysis pubis, and to decrease the amount of small bowel treated both superiorly and anteriorly

GUIDELINES

• Perineum:-

• Never use an electron or photon boost for the perineum—there will be overlap between the electron and photon fields. The perineum should be treated in the photon fields.

• Inguinal Nodes Boost Field:-While the patient is in the supine position, the medial and lateral inguinal nodes are outlined with a 2-cm margin in all directions.

• Primary Tumor Boost for Combined-Modality Therapy Salvage:- If the Radiation Therapy Oncology Group recommendations for combined-modality therapy salvage are followed, then an additional 9 Gy (concurrent with 5-fluorouracil-cisplatin) are delivered. With a multiple-field technique, the field includes the primary tumor plus a 3-cm margin in all directions.

GUIDELINES

LOWER BORDER

UPPER BORDER

MINI. 2.5 CM MARGIN AROUND ANUS & TUMOR

CONE DOWN FIELD BORDERS

• Lower superior border to the bottom of SI joints.

• Inferior and lateral borders remain the same.

• Boost field

Indicated for T3, T4, N1, or T2 lesions with residual disease after 45 Gy.

Use 2 cm margin on GTV via AP/PA, 3-field (opposed laterals and PA –lowest anterior skin dose), or 4-field (AP/PA/laterals) approach.

• 4-field technique: This usually requires higher electron supplement to the inguinal nodes, which can result in greater inguinal desquamation.

Volumetric Planning Goals

• 95% of the PTV should receive at least 95% of the prescription dose.

• No portion of the PTV should receive less than 85% of the prescription dose.

• 99% of the CTV should receive at least 95% of the prescription dose.

• 0.1 cc of tissue is limited to 115% of the prescription dose.

• 1.0 cc of tissue (or 5% of the PTV) is limited to 110% of the prescription dose.

• 5 cc of tissue (or 10% of the PTV) is ideally limited to 105% of the prescription dose.

• For external genitalia, attempt to limit

50% to less than 20 Gy

95% to less than 40 Gy

• For iliac crest, may attempt to limit

50% to less than 30 Gy

95% to less than 50 Gy

DOSE / FRACTIONATION (NCCN)

• CTV to 45 Gy/1.8 Gy/fx

• Field reduction to cone down 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 underdosethicker patients).

DOSE / FRACTIONATION (NCCN)

• 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.

• RTOG 0529 (employs IMRT using dose-painting technique):

• For T2N0:

• PTVA (primary tumor): 50.4 Gy in 28 fx (1.8 Gy/fx)

• Nodal PTV: 42 Gy in 28 fx (1.5 Gy/fx)

• For T3/4 N0:

• PTVA (primary tumor): 54 Gy in 30 fx (1.8 Gy/fx)

• Nodal PTV: 45 Gy in 30 fx (1.5 Gy/fx)

• For N+:

• PTVA (primary tumor): 54 Gy in 30 fx (1.8 Gy/fx)

• Nodal PTV (uninvolved nodes): 45 Gy in 30 fx (1.5 Gy/fx)

• Nodal PTV (≤3 cm): 50.4 Gy in 30 fx (1.68 Gy/fx)

• Nodal PTV (>3 cm): 54 Gy in 30 fx (1.8 Gy/fx)

RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Carcinoma of the Anal Canal

DP-IMRT was associated with significant sparing of acute grade 2+ hematologic and grade 3+ dermatologic and gastrointestinal toxicity.IJROBP 2013;86:27

Anus cancer

Nodes

High Risk Node

RTOG 0529 (IMRT with 5-FU and MMC)VS. RTOG 98 - 11

• 77% of patients experienced grade 2 or higher gastrointestinal/ genitourinary ( GVGU) acute adverse events (AEs) that were equal to that noted in the MMC arm of RTOG 9 8 - 1 1 ( 76 % ).

• There was a statistically significant reduction in grade 3 or higher GVGU AEs with IMRT, 2 1 % versus 3 6 % RTOG 9 8 - 1 1 (P < .00 8 ) , and grade 3 or higher dermatologic AEs, 2 1 % versus 47% RTOG 9 8 - 1 1 (P < .000 1 ) .

• The use of IMRT with 5-FU and MMC resulted in significant reduction in grade 3 + dermatologic and GVGU acute toxicity.

BRACHYTHERAPY

• Brachytherapy is an ideal method by which to deliver conformal radiation for anal cancer while sparing the surrounding normal structures such as small intestine and bladder. In most series, patients received 30 to 55 Gy of pelvic radiation with or without 5-FU/mitomycin-C or cisplatin followed by a 15 to 25 Gy boost with Ir192 afterloadingcatheters.

• In a retrospective review from Bruna et al, 71 patients with a variety of T and N classifications were treated with a median of 45 Gy external beam to the pelvis with or without cisplatin-based chemotherapy, followed by a median of 17.8 Gy pulsed dose rate brachytherapy.

• The 2-year actuarial local control was 90%; however, 17% had grade 3+ complications.

Side Effects of Pelvic Radiation

Radiation fields

Radiation may hit the small bowel causing some cramps, diarrhea and fatigue

High dose area

Side Effects of Pelvic Radiation

Radiation fields

Radiation may hit the bladder and rectum causing urinary burning or frequency and ano-rectal irritation and skin burning

High dose area

In pre-menopausal women, radiation is likely to effect ovarian function and should not be used if the woman is pregnant.

TREATMENT OF THE HIV-POSITIVE PATIENT

• HIV-positive patients should receive lowerdoses of radiation and chemotherapy because of a concern that standard therapy may not be tolerated (Melbye M, Cote T, Kessler L, et al: AIDS/Cancer Working Group. High incidence of anal cancer among AIDS patients. Lancet 1994; 343:636-639)

• Although it is not necessary to alter standard management recommendations, HIV-infected patients, especially those with a CD4 count less than 200/mcL, should be monitored for an increased risk of toxicity when treated with chemoradiation. (NCCN)

TREATMENT OF THE HIV-POSITIVE PATIENT

• George Washington University Medical Centerand the affiliated Veterans Administration hospital revealed an 80% grade 3 or 4 major acute toxicity rate for patients with HIV treated with 5 -FU, MMC, and radiation compared to 30 % in patients without HIV. Late complications were higher patients with HIV compared to patients without HIV (40% vs. 1 6 % ; NS ) .

• Other retrospective analyses show similar findings, most notably in patients with low pretreatment CD4 counts.

• One multicenter retrospective study evaluating treatment outcomes in HIV-positive patients treated consecutively between 1997 and 2006, demonstrated a trend toward decreased cancer-specific survival at 5 years (HIVpositive,68 % ; HIV-negative, 79 % ; P = .09).

• Long-term LC was also worse in the HIV-positive group, with a 5-year LC rate of 38 % in patients with HIV versus 87 % in those who were HIV-negative.

SALVAGE THERAPY FOR LOCAL RECURRENCE

• Most patients undergo an APR and a permanent colostomy is established with creation of a large pelvic floor defect.

• Tumors that invade local structures such as the vagina or prostate should be resected with negative margins and this often involves multivisceral resection.

• The OS at 5 years following resection is in the range of 30 % to 64 % , with DFS rates i n the range o f 30 % t o 40 % .

• The most important prognostic factor of survival after resection is the status of the margin, and patients with negative margins (R0) have up to 75 % 5-year OS.

• Predictors of a poor OS outcome following surgery are inguinal lymph node status, tumorsize greater than 5 cm, adjacent organ involvement male gender, and more numerous comorbidities.

Diagnostic and treatment algorithm for newly diagnosed anal cancer

MANAGEMENT OF METASTATIC DISEASE

• Systemic chemotherapy for metastatic squamous cell carcinoma of the anus is generally similar to other metastatic squamous histology, such as lung or head and neck cancers.

• Cisplatin and 5-FU have been reported to achieve an 11 % complete response and 61 % partial response rate.

• Hainsworth et al:- treated 60 patients with the combination of carboplatin, paclitaxel, and 5 -FU in a phase 2 study with an overall response rate of 90 % .

SQUAMOUS CELL CANCER OF THE ANAL MARGIN

• Anal margin is usually defined as the area extending from the anal verge to 5 cm out.Theonset of the disease is usually in the seventh and eighth decade with a slight female predominance. In most cases, these tumorsare well differentiated and slow growing and distant metastases are rare.

• Inguinal lymph nodes are the primarily nodal drainage for anal margin cancers, and regional nodal metastasis is directly related to the size of the tumor.

• The treatment of anal margin cancer needs to be individualized based on the size and location. Wide local excision with a 1 -cm margin is often sufficient for small and superficial tumors. When the tumor is advanced, or located close to the anal canal and sufficient surgical margin cannot be achieved, combined modality treatment or APR may have to be considered.

SQUAMOUS CELL CANCER OF THE ANAL MARGIN

• Papillon and Chassard reported on 8 patients with T1 or T2 lesions that were treated with either radium implant brachytherapy alone (six patients) or in combination with external-beam radiation (two patients ) .

• The local control rate was 100 % . In this study, an additional 36 patients were treated with external radiation with 5-FU and MMC. The cure rate for T 1 , T2, and T3 lesions were 100 % , 84 % , and 50 % , respectively.

• Cummings compared radiation alone versus chemoradiation retrospectively in 29 patients; 1 1 patients were treated with radiotherapy alone and 1 8 patients received 5-FU, MMC, and radiotherapy.

• After a median of 7 years of 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 ->1 0 cm, 40 % ) .

ADENOCARCINOMA OF THE ANAL CANAL

• Adenocarcinoma arises from the columnar epithelium of the anal canal and its incidence is low accounting for less than 5 % of all anal malignancies.

• Extension of rectal cancer into the anal canal is the more common presentation. Occasionally, adenocarcinoma may occur in patients with ulcerative colitis or Crohn disease who have ileal pouch-anal anastomosis.

• APR should be offered for early-stage disease.

• For locally advanced disease (T3 or any T with N + ), a multimodality approach should be considered. Patients treated with APR had significantly improved 5-year OS than those treated with radiation alone.

MELANOMA OF THE ANORECTAL REGION

• Anorectal melanoma is rare and accounts for less than 3 % of all malignant melanomas and less than 1 % of all anal canal tumors.

• 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 % for APR; 5 8 % for local excision) . However, there was no difference in OS between the two groups ( 19 . 5 months for APR; 18 .9 months for local resection ) .

• Most authors recommend local excision of anorectal melanoma if adequate margins could be achieved.

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