Bethesda Handbook of Clinical Oncology, 2nd Edition

Digestive System

10

Anal Cancer

1. Wasif Saif

University of Alabama at Birmingham, Birmingham, Alabama

Anal cancer is an uncommon malignancy, accounting for only a small percentage (4%) of all cancers of the lower alimentary tract. Overall, the risk of anal cancer is rising, with data suggesting that individuals with human papillomavirus (HPV) and male homosexuals, in particular, are at increased risk for developing anal cancer. The three major prognostic factors are site (anal canal versus perianal skin), size (primary tumors <2 cm have a better prognosis), and differentiation (well-differentiated tumors are more favorable than poorly differentiated tumors). Concomitant radiotherapy [5-fluorouracil (5-FU) and mitomycin C] has proved to be useful in locally advanced anal canal carcinoma. Nevertheless, this conservative treatment has a failure rate of 30%. The tolerance and efficiency of a neoadjuvant chemotherapy [5-FU and cisplatin (CDDP)] have been validated by a phase II trial using 80 patients, which observed 73% colostomy-free survival and 70% relapse-free survival at 3-year follow-up in patients. Its usefulness is being studied in an ongoing phase III trial, as well as the dose escalation of the radiation boost, from 15 Gy to 25–25 Gy.

EPIDEMIOLOGY

In the United States, the annual incidence of anal cancer is 6 per 1,000,000 population in whites and is more frequent in female than in male subjects, showing an incidence of 9 of 1,000,000 in nonwhite women versus 5 per 1,000,000 in white and Hispanic men (F/M ratio is 2:1). However, cancer of the anal margin is more frequent in men. More than 80% of anal cancer develops in patients 50 to 60 years of age. Epidemiologic studies during the last decade suggest that the incidence of anal cancer has increased in men younger than 35 years, reversing the gender ratio in this age group; it also is related to receptive anal intercourse.

ETIOLOGY AND RISK FACTORS

No etiologic factor has been recognized in most cases of anal cancer. Environmental factors are predominantly implicated in the carcinogenesis of anal cancer. The most common risk factors can be classified as follows:

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Risk Factors with Strong Evidence:

1. HPV infection (anogenital warts)
2. History of receptive anal intercourse
3. History of sexually transmitted disease
4. More than 10 sexual partners
5. History of cervical, vulvar, or vaginal cancer
6. Immunosuppression after solid-organ transplantation.

Risk Factors with Moderately Strong Evidence:

1. Human immunodeficiency virus (HIV) infection
2. Long-term use of corticosteroids
3. Cigarette smoking.

PATHOLOGY

Anatomy

1. The anal canalextends from the anorectal ring to a zone approximately halfway between the pectinate (or dentate) line and the anal verge.
2. The anal marginconsists of the anal area distal to the anal canal, including perianal skin.

The World Health Organization (WHO) defines carcinoma of the anal canal as lesions arising from the anorectal ring proximally up to the dentate line distally, whereas carcinoma of the anal margin is defined as lesions arising distal to the dentate line to the junction between perineal skin and the hair-bearing skin of the buttocks (see Fig. 10.1).

FIG. 10.1. Anatomy of the anal canal. A tumor in location A is always considered anal canal cancer; in location C, it is anal margin cancer. A tumor in location B was called canal or margin cancer, depending on institutional preference, but now should be called anal canal cancer by the American Joint Committee on Cancer/Union Internationale Contre le Cance (AJCC/UICC) definition.

HISTOLOGY

The histologic types of carcinomas and the features of each type of carcinoma are given in Table 10.1.

TABLE 10.1. Features of Different Types of Anal Cancer

Histologic types Features •Squamous cell (epidermal) carcinoma Occurs in the lower anus, often ulcerating •Cloacogenic (also called basaloid, cuboidal, or transitional) carcinoma Develops high in the anal canal in the transitional zone between glandular mucosa of the rectum and the squamous epithelium of the distal anus •Intraepithelial squamous cell carcinoma (Bowen disease) Premalignant lesion of the perirectal skin •Intraepithelial mucous adenocarcinoma (Paget disease) Develops in apocrine or mucous glands

Frequency

The frequency of occurrence of each histologic type of carcinoma is given in Table 10.2. The table indicates that squamous cell carcinoma is the commonest form of anal cancer.

TABLE 10.2. Frequency of Occurrence of Different Types of Anal Cancer

Squamous cell carcinoma 113 (55%) Cloacogenic (basaloid) carcinoma 64 (31%) Intraepithelial adenocarcinoma (Paget disease) 8 (4%) Melanoma 7 (2%) Basal cell carcinoma 6 Adenocarcinoma 6 Total 204

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Presentation

Symptoms

The incidence of different presenting symptoms in three types of anal carcinoma is shown in Table 10.3. Bleeding seems to be the common symptom in squamous cell carcinoma and in basaloid squamous carcinoma, whereas pruritus is the most common presenting symptom in perianal carcinoma.

TABLE 10.3. Frequency of Occurrence of Symptoms in Different Types of Anal Cancer

Presenting symptoms Squamous cell carcinoma Perianal Basaloid squamous carcinoma a p <0.001. Differences not statistically significant for other lesions. From Beahrs OH, Wilson SM. Carcinoma of the anus. Ann Surg 1976;184(4):422–428, with permission. Bleeding 50    9 32 Pain 41    5 17 Mass 27    5 16 Constipation 11    1 10 Diarrhea    5    0    7 Pruritusa 22 17    1 Other 16    6 12 Asymptomatic 25    6 14

Signs

Physical examination should include digital anorectal examination, anoscopy, proctoscopy, and palpation of inguinal lymph nodes.

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BIOPSY

An incisional biopsy is preferred for confirming diagnosis. Suggestive inguinal lymph nodes should be examined to rule out metastatic disease.

STAGING AND PROGNOSTIC FACTORS

Staging work-up should include physical examination, with special attention to digital rectal and pelvic examination and inguinal nodes, chest radiograph, and liver function tests. Pelvic computerized tomography (CT) scan and endoscopic ultrasound (EUS) of the anal canal may be beneficial.

The UICC (Union Internationale Centre le Cancer) and AJCC (American Joint Committee on Cancer) have proposed a practical staging system for anal cancer. Cancer of the anal margin is staged identically to squamous cell cancer of skin. The staging system for both types of tumors is outlined in Tables 10.4 and 10.5.

TABLE 10.4. American Joint Committee on Cancer (AJCC) Classification of Anal Canal Tumors

Primary tumor (T)    TX    Primary tumor cannot be assessed      T0    No evidence of primary tumor      Tis    Carcinoma in situ      T1    Tumor ≤2 cm in greatest dimension      T2    Tumor >2 cm but <5 cm in greatest dimension      T3    Tumor >5 cm in greatest dimension      T4    Tumor of any size that invades adjacent organs (e.g., vagina, bladder, and urethra; involvement of sphincter muscle(s) alone is not classified as T4)   Regional lymph nodes (N)      NX    Regional lymph nodes cannot be assessed      N0    No regional lymph node metastasis      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 node(s) and/or bilateral internal iliac and/or inguinal lymph nodes   Distant metastasis (M)      MX    Distant metastasis cannot be assessed      M0    No distant metastasis      M1    Distant metastasis   Grade (G)      GX    Grade of differentiation cannot be assessed      G1    Well differentiated      G2    Moderately differentiated      G3    Poorly differentiated      G4    Undifferentiated   Stage groupings   Stage 0 Tis N0 M0   Stage I T1 N0 M0   Stage II T2 N0 M0   T3 N0 M0   Stage IIIA T1–3 N1 M0   T4 N0 M0   Stage IIIB T4 N1 M0   Any T N2–3 M0   Stage IV Any T Any N MI

TABLE 10.5. TNM Classification of Anal Margin Tumors

a Designation as for anal canal tumors, except T4. b Stage groupings as for anal canal tumors, except stage III (no stage IIA or IIIB). From Sobin LH, Wittekind C (eds). UICC International Union Against Cancer: TNM classification of malignant tumors. 5th ed. New York: John Wiley & Sons, 1997, with permission. Primary tumor (T)a    T4 Tumor invades deep extradermal structures Regional lymph nodes (N)    N1 Ipsilaterial inguinal nodes Metastases (M)    M1 Distant metastases Stage groupingsb    Stage III T4 N0 M0 Any T N1 M0

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MAJOR PROGNOSTIC FACTORS

There are four major prognostic factors:

• Site:anal canal versus perianal skin
• Size:<5 cm versus >5 cm
• Differentiation:well-differentiated tumors have more favorable outcomes than poorly differentiated tumors
• Lymph Node Involvement:absence of nodal involvement or local extension.

When balanced with other factors, the prognosis for patients with squamous cell carcinoma of the anus and for those with cloacogenic carcinoma is similar.

TREATMENT

Surgery

Anal Canal Lesions

Because anal cancer is a rare tumor, most studies have involved a small number of patients who have been included over several years. The absence of data from randomized trials makes treatment difficult in certain circumstances. The location of the primary tumor is a major determinant of appropriate treatment.

Traditionally, the standard (and sole) form of therapy for anal canal lesions has been surgical resection, often involving an anteroposterior (AP) resection with inguinal node dissection. Despite such radical procedures, the most common site of failure is the pelvis, with local recurrences occurring in 30% of patients (see Table 10.6). Although postoperative (adjuvant) radiation therapy has been used to reduce the local recurrence rate, the potential benefit of such a practice has not been documented through a controlled trial.

TABLE 10.6. Anal Canal Lesions

Surgical results 5-Yr survival (%) Nodes negative 54–70 Metachronous nodal spread 51 Synchronous nodal spread 16

Tumors that (a) involve the dentate line, (b) are larger than 2 cm, or (c) involve more than 50% of the bowel circumference are probably best managed with combined-modality treatment. This integrated approach improves overall survival and may allow avoidance of radical surgery. In the last several years, several studies have used combined-modality treatments with radiation and chemotherapy after local resection. Therefore, the primary therapeutic modalities for anal cancer are a combination of chemotherapy and radiation therapy. Combined chemoradiation is aimed at cure and preservation of anal function. AP resection is used as salvage therapy in patients with chemoradiation-resistant disease. Table 10.6 shows the results of a few of these trials.

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Anal Margin Lesions

For anal margin lesions, a wide local excision without the need for a colostomy seems to be adequate (see Table 10.7).

TABLE 10.7. Results: 5-year Survival After Local Excision in Anal Margin Cancer (31 Patients)

Tumor size (cm) 0–2 2–5 >5 NC Total NC, not classified. From Greenall MJ, Quan SH, Stearns MW, et al. Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results. Am J Surg 1985;149(1):95–101, with permission. Alive without recurrence    7    9 3 1 20 Alive with recurrence    0    1 0 0    1 Lost to follow-up    0    1 0 0    1 Died from recurrence    2    0 0 1    3 Died from unrelated causes    2    4 0 0    6 Total 11 15 3 2 31

Radiation Therapy

1. Potential advantages compared to radical surgery:
2. no operative mortality
3. no colostomy

iii.      no sexual impotence.

1. Disadvantages in comparison with surgery:
2. Although the abdominal–perineal resection (APR) has remained a standard procedure for the last 25 years, radiotherapeutic techniques and equipment have changed markedly, permitting, in recent years, the delivery of a far higher, precisely defined dose (approximately 6,000 cGy) with less toxicity; that is, as such, the substandard dosages of the past (3,500 to 4,000 cGy), which were occasionally accompanied by significant toxicity, do not reflect the present clinical situation.
3. The extent of local and nodal involvement among patients receiving primary irradiation is usually not determined.

iii.      The two techniques cannot be compared prospectively because the issue of a permanent colostomy is an unacceptable variable in a clinical trial.

Radiation therapy has been given using

• external beam treatment
• interstitial treatment
• external and interstitial treatment.

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The overall 45% to 50% rate of “cure” reported in the series of select patients who were treated primarily with radiation therapy is quite similar to that reported in surgically treated patients. Recent series utilizing external beam and interstitial treatment or very high dose external beam irradiation have shown encouraging responses, suggesting a local control rate of 70% to 80%, but will require further confirmation before receiving full acceptance.

Combined Radiation Therapy and Chemotherapy

In an attempt to enhance the efficacy of radical surgery in patients with anal cancer, in 1972, Nigro et al. (1) from Wayne State University began giving patients preoperative concomitant radiation (3,000 cGy external beam irradiation) and chemotherapy (by 5-FU continuous infusion and mitomycin C). When this attempt was last updated, 45 patients had been followed for a median period of 50 months; 38 of 45 patients (84%) achieved a complete biopsy-proven response after only radiation and chemotherapy, including all patients whose initial lesion was <5 cm; none of these 30 patients developed local or distant tumor recurrence, whereas all 7 of the patients who had recurrent disease after preoperative treatment developed distant spread of the tumor and subsequently died despite an APR.

Although the original treatment plan called for an APR following the radiation and chemotherapy, this program was altered after five of the first six patients who underwent the radical operation were found to have no tumor in the operative specimen; subsequently, surgery has been performed only on those patients who have been found to have residual tumor in the anal canal during the posttreatment biopsy. Most patients have been cured of their anal cancers without the need for a colostomy and with relatively mild toxicity. These highly encouraging results from the group from Wayne State University have now been confirmed and extended by others in randomized trials.

Radiation Therapy alone versus Chemoradiation Therapy

European Organization for Research and Treatment of Cancer (EORTC) randomized 110 patients with bulky tumors to receive 4,500 to 6,500 cGy of pelvic radiotherapy (RT) alone or in combination with 5-FU and mitomycin C. Statistically significant benefits for complete response rate, local regional control, and colostomy-free survival favored the combined-modality approach.

United Kingdom Coordinating Committee on Cancer Research (UKCCCR) randomized 585 patients to receive 4,500 cGy of pelvic RT alone or in combination with 5-FU and mitomycin C. Local-failure rate was reduced by 46% in patients given the combined-modality approach.

Value of Mitomycin C in the Combined-modality Regimen

Radiation Therapy Oncology Group (RTOG) randomized 310 patients to receive 4,500 to 5,040 cGy of pelvic RT with 5-FU or the same and 5-FU with mitomycin C. A statistically significant benefit for disease-free survival was observed in the patient cohort who received mitomycin C. The substitution of cisplatin for mitomycin C (when combined with 5-FU and radiation therapy) has been explored in phase II trials (Doci et al.); the initial results are promising. Induction therapy with 5-FU and cisplatin followed by RT and 5-FU and cisplatin is presently being compared with “standard” RT and 5-FU and mitomycin C combination in an ongoing Intergroup protocol (see Tables 10.8, 10.9, and 10.10).

TABLE 10.8. Multimodality Studies

Group No. of patients Regimen XRT APR 5-Yr survival XRT, radiation therapy; APR, abdominal–perineal resection; 5-FU, 5-fluorouracil; Mito C, mitomycin C; RTOG/ECOG, Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group. Wayne State 104 5-FU 1 g/m2/24 h × 4 d Mito C 10–15 mg/m2 d 1 30 Gy 31 83% Memorial Sloan-Kettering    42 5-FU 750 mg/m2/24 h × 5 d Mito C 15 mg/m2 d 1 30 Gy 23 82% RTOG/ECOG    79 5-FU 1g/m2/24 h × 4 d Mito C 10 mg/m2 d 40 Gy    8 73% Fresno Community Hospital    30 5-FU 1 g/m2/ 24 h × 4 d Mito C 10–15 mg/m2 d 41–50 Gy    1 90% 255     63 (25%) 82%

TABLE 10.9. Selected Results of Concurrent Radiation and Fluorouracil and Mitomycin C

Chemotherapy regimens Radiation (dose/fractions/time) Primary tumor control Regional node control 5-yr survival Reference CIVI, continuous intravenous infusion; NS, not stated; NA, not applicable; T, tumor invading adjacent organs; T4, tumor invading deep extradermal structures. From Cohen AM, Winawer SJ, eds. Cancer of the colon, rectum and anus. New York: McGraw Hill, 1995, with permission. Fluorouracil, 1,000 mg/m2/d, CIVI for 8 d, days 1–4, 29–32 (total dose/course, 8,000 mg/m2) 30 Gy/15/d 1–21 31/34 (91%) (≤5 cm) 7/10 (70%) (5 cm) NS 80% crude Leichman et al. (1985) (2) Mitomycin C, 15 mg/m2 i.v. bolus d 1 (total dose/course, 15 mg/m2) Fluorouracil, 1,000 mg/m2/d, CIVI for 8 d, days 2–5, on days 28–31 (total dose/course, 8,000 mg/m2) 40.8 Gy/24/d 1–35 22/26 (85%) (≥3 cm) 32/50 (64%) (≤3 cm) NA 73%, 3 yr actuarial Sischy et al. (1989) (3) Mitomycin C, 10 mg/m2 i.v. bolus d 1 (total dose/course, 10 mg/m2) Fluorouracil, 1,000 mg/m2/d, CIVI for 8 d, d 1–4, 43–46 (total dose/course, 8,000 mg/m2) 48–50 Gy/20–24/d 1–58 (split course) 25/27 (93%) (≤5 cm) 16/20 (80%) (≥5 cm or T) 4/5 65%, actuarial Cummings et al. (1982) (4) Mitomycin C, 10 mg/m2/dose i.v. bolus for 2 doses, d 1 and 43 (total dose/course, 20 mg/m2) Fluorouracil, 1,000 mg/m2/d, CIVI for 8 d, d 1–4, 29–32 (total dose/course, 8,000 mg/m2) 50 Gy/25–28/d 1–35 ± boost 21/22 (95%) (≤X cm) 14/19 (74%) (<5 cm or T4) 3/4 77%, actuarial Schneider et al. (1992) (5) Mitomycin C, 10 mg/m2/dose IV bolus for 2 doses, d 1 and 29 (total dose/course, 20 mg/m2) Fluorouracil, 600 mg/m2/d, CIVI for 5 d, d 1–5 (total dose/course, 3,000 mg/m2) 42 Gy/10/d 1–19 plus interstitial boost No data in original publication 57/70 (81%) (≥4 cm) NS NS Papillon and Montbarbon, (1987) (6) Mitomycin, 12 mg/m2 i.v. bolus day 1 (total dose/course, 12 mg/m2) Fluorouracil, 1,000 mg/m2/d, CIVI for 4 d, d 1–4 (total dose/course, 4,000 mg/m2) 50–54 Gy/25–27/d 1–35 (≤5 cm) 28/30 (93%) (≥5 cm or T4) 42/56 (75%) NS 72%, actuarial Tanum etal., (1991) (7) Mitomycin, 10–15 mg/m2 i.v. bolus d 1 (total dose/course, 10–15 mg/m2) Fluorouracil, 1,000 mg/m2/d, CIVI for 4 d, d 1–4 (total dose/course, 4,000 mg/m2) 50 Gy/20/d 1–28 (≤5 cm) 3/3 (≥5 cm or T4) 11/13 (85%) 3/3 75%, actuarial Cummings et al., (1984) (8) Mitomycin C, 10 mg/m2 i.v. bolus d 1 (total dose/course, 10 mg/m2) Fluorouracil, 750 mg/m2/d, CIVI for 8 d, d 1–5, 43–47 (total dose/course, 8,000 mg/m2) 54–60 Gy/30–33/d 1–53 (split course) 28/38 (74%) (≤5 cm) 9/17 (53%) (≥5 cm) 8/8 81%, actuarial Doci et al., (1992) (9) Mitomycin C, 15 mg/m2/dose i.v. bolus for 3 doses, d 1, 43, and 85 (total dose/course, 45 mg/m2)

TABLE 10.10. Dosage of Chemoradiation in Anal Cancer

RTOG, Radiation Therapy Oncology Group; i.v., intravenous. Treatment modalityDose External beam radiation 4,500–5,000 cGy    RTOG 170 cGy/d for 27 d, d 2–28 (total dose, 4,500–5,000 cGy)    Milan 180 cGy/d for 4 wk followed by a 2-wk rest (total dose, 5,400 cGy) Chemotherapy Mitomycin C       RTOG Mitomycin C, 10 mg/m2 i.v. bolus on d 2       Milan Mitomycin C, 15 mg/m2 i.v. bolus on d 1 Fluorouracil    RTOG Fluorouracil, 1,000 mg/m2/d CIVI for d 2–4 and 28–32 (total dose/course, 8,000 mg/m2)    Milan Fluorouracil, 750 mg/m2/d CIVI for 5 d, d 1–5 (total dose/course, 3,750 mg/m2)

Treatment options according to the stage are shown in Table 10.11. The overall management of anal cancer has been shown in Fig. 10.2.

TABLE 10.11. Treatment Options for Anal Cancer

Stage Treatment options 0 Surgery I Radiation Chemoradiation Surgery Interstitial iridium-192 after external beam radiation II Chemoradiation Surgery IIIa Treatment as for I and II IIIb Chemoradiation with surgical resection of residual disease IV Palliative surgery Palliative irradiation Palliative chemoradiation Clinical trials

FIG. 10.2. Management of anal cancer.

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Stage 0

Surgical resection is the treatment of choice for the lesions of the perianal area that do not involve the anal sphincter.

Stage I

Stage I involves

• Tumors of the perianal skin or anal margin not involving the anal sphincter: wide local excision (for small tumors)
• Anal canal cancer.

Stage I involving tumors of the anal sphincter and those that are too large for complete local resection are treated with external beam radiation therapy with or without chemotherapy. Results from the UKCCCR randomized trial of RT alone versus RT, 5-FU, and mitomycin C revealed that combined chemoradiation is more effective than radiation therapy alone (Table 10.11).

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Radical resection is reserved for residual cancer in the anal canal after chemoradiation therapy.

Interstitial iridium-192 implantation after external beam RT may aid some patients with residual disease to have complete response.

The optimal dose of external beam radiation with concurrent chemotherapy still must be determined.

Stage II

Stage II involves

• Tumors of the perianal skin or anal margin not i nvolving the anal sphincter: wide local resection (of small tumors)
• Cancers of the anal canal (involving the anal sphincter and those that are too large to be completely excised locally)
• Chemoradiation therapy:(Table 10.8, 10.9, and 10.10). Salvage chemotherapy with fluorouracil and cisplatin, combined with a radiation boost may avoid a permanent colostomy in patients with residual tumor after initial nonoperative therapy, as suggested by a phase III randomized intergroup study (Flam et al.)
• Resection:Radical resection for residual disease in the anal canal after the initial nonoperative treatment is also an option.

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Stage IIIA

Stage IIIA anal cancer presents clinically as stage II anal cancer in most patients but is upstaged to IIIA by the presence of perirectal nodal disease or adjacent organ involvement. EUS (endoanal or endorectal) may help in staging.

• Treatment is similar to that for stage I and II disease involving chemoradiation.
• Salvage chemotherapy combined with a radiation boost is an option, as shown by Flam et al.
• Postoperative radiation therapy is also used.

Stage IIIB

Although curing stage IIIB disease is possible, the presence of metastatic disease secondary to the involvement of inguinal lymph nodes (unilateral or bilateral) constitutes a poor prognostic sign.

• Chemoradiation (as described for stage II) with surgical resection of residual disease at the primary site plus unilateral or bilateral superficial and deep inguinal lymph node dissection is a mode of treatment.
• Because of the poor prognosis of these patients, they should be recruited for clinical trials whenever possible.

Stage IV

There is no standard chemotherapy for stage IV disease. Palliation of symptoms constitutes the backbone of management. Patients with stage IV anal cancer should be included in clinical trials.

Various treatment modalities for stage IV disease are as follows:

• Palliative surgery
• Palliative radiation therapy
• Palliative combined chemotherapy and radiation therapy
• Clinical trials.

RECURRENT ANAL CANCER

Local recurrences after initial treatment with either chemoradiation or surgical resection can be effectively controlled by alternate treatment options (Table 10.8) including

• surgical resection after radiation (salvage APR)
• postoperative radiation.

FOLLOW-UP

Patients with anal cancer should be monitored

• every 3 months for the first 3 years
• every 6 months for an additional 2 years
• and then annually.

The following specific recommendations should be undertaken:

• Medical history
• Physical examination
• Complete blood counts
• Liver function tests
• Chest radiograph
• CT scan every 6 to 12 months for the first 3 years.

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Prognosis: 5-year disease-free survival for primary and persistent disease is given in Table 10.12. (See Fig.10.2).

TABLE 10.12. 5-year Disease-free Survival Rates

Stage % Primary disease 65–80 Persistent or recurrent disease 40–50

Prevention

The physician can create an awareness and a high-risk group (homosexual men, patients with cervical or vulvar cancer) can be recognised to aid patients by early detection of the disease. Yearly anoscopy may be indicated in such a group. Role of the Papanicolaou smear still must be studied.

ANAL CARCINOMA IN HUMAN IMMUNODEFICIENCY VIRUS–INFECTED PATIENTS

The incidence of anal cancer is increasing in patients with HIV infection, especially with the advent of new antiretroviral medications.

Epidemiology

The San Francisco Study revealed that the incidence of anal carcinoma in homosexual men was between 25 and 87 cases per 100,000 population, as compared with 0.7 cases per 100,000 in the entire male population (10).

Etiology

• HPV, especially oncogenetic serotypes 16 and 18, which are found to be associated with anal intraepithelial neoplasia (AIN), which designates a precursor lesion. The same subtypes of HPV that are implicated in malignant transformation in cervical cancer are implicated in malignant transformation in anal cancer.
• Perianal herpes simplex
• Anal condylomas
• Anal-receptive behavior in homosexual or bisexual men, especially with multiple sexual partners.

Clinical Presentation

The clinical presentation of anal carcinoma in HIV-infected patients include:

• Rectal pain
• Rectal bleeding
• Rectal discharge
• Symptoms secondary to obstruction.

Diagnosis

Diagnostic work-up is similar to the determination of the extent of local disease and staging for dissemination in immunocompetent patients.

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Pathology

• Squamous cell carcinoma
• Grading for AIN is similar to that for cervical intraepithelial neoplasia (CIN).

Staging

The staging of anal cancer in HIV-infected patients is similar to that in HIV-negative patients.

Prognosis

HIV-infected patients with severe immunosuppression, as evidenced by CD4 counts of < 50 per mm³, may experience more aggressive and advanced disease.

Treatment

• The treatment of choice for squamous cell carcinoma of the anus is combined-modality therapy with
• – mitomycin C, 10 mg per m², day 1 (total dose per course, 10 mg per m²) intravenous bolus
• – 5-FU, 1,000 mg/m²/day continuous intravenous infusion (CIVI) for 4 days, days 1 to 4 (total dose/course, 4,000 mg per m²) PLUS
• – external beam radiation therapy.
• Appropriate radiation dosage still must be investigated in HIV infection. Anecdotal experience indicates that HIV-infected patients have a decreased tolerance to full pelvic RT, resulting in myelotoxicity and mucositis, thereby limiting the size of treatment fields. Surgical excision with or without local RT may be considered for small localized cancer with minimal depth of invasion.
• Treatment of AIN:Treatment of AIN in HIV-infected patients is similar to the treatment of CIN in women and may include electrocautery, cryoablation, or laser ablation.

Screening

Anal Papanicolaou smears have a reported sensitivity of approximately 70% (equal to that associated with uterine cervix Papanicolaou testing). There are currently no standard recommendations for screening of anal cancer in this population. Anoscopy with anal cytologic evaluation should be undertaken in patients with abnormal discharge, bleeding, pruritus, bowel irregularity, rectal, or pelvic pain, and in those with a history of previous preinvasive lesions or abnormal Papanicolaou smears. Other patients who should be screened include HIV-negative men with a history of anal-receptive intercourse, HIV-positive men and women with CD4 cell counts <500 per mm³, and HIV-positive and HIV-negative women with a history of high-grade CIN.

References

1. Nigro ND, Seydel HG, Considine B, et al. Combined preoperative radiation and chemotherapy for squarnous cell carcnoma of the anal canal cancer. Cancer 1983;51:1826–1829.
2. Leichman L, Nigro N, Vatikevicius VK, et al. Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med1985;72(2):211–5.
3. Sischy B, Doggett RL, Krall JM, et al. Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on radiation therapy oncology group study no. 8314. J Natl Cancer Inst1989;81(11):850–6.
4. Cummings BJ, Rider WD, Harwood AR, et al. Combined radical radiation therapy and chemotherapy for primary squamous cell carcinoma of the anal canal. Cancer Treat Rep1982;66(3):489–92.
5. Schneider IH, Grabenbauer GG, Reck T, et al. Combined radiation and chemotherapy for epidermiod carcinoma of the anal canal. Int J Colorectal Dis1992;7(4):192–6.

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6. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal. A series of 276 cases. Dis Colon Rectum1987;30(5):324–33.
7. Tanum G, Tveit K, Karlsen KO, et al. Chemotherapy and radiation therapy for anal carcinoma. Survival and late morbidity. Cancer1991;67(10):2462–6.
8. Cummings B, Keane T, Thomas G, et al. Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer1984;54(10):2062–8.
9. Doci R, Zucali R, Bombelli L, et al. Combined chemoradiation therapy for anal cancer. A report of 56 cases. Ann Surg1992;215(2):150–6.
10. Palef sky JM, Holly EA, Ralston ML, et al. High incidence of anal high grade squarnous intraepithelial lesions among HIV- positive and HIV- negative homosexual and bisexual men. AIDS1998;12:495–503.

Suggested Readings

Allal AS, Laurencet FM, Raymond MA, et al. Effectiveness of surgical salvage therapy for patients with locally uncontrolled anal carcinoma after sphincter conserving treatment. Cancer 1999;86:405–409.

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