Bethesda Handbook of Clinical Oncology, 2nd Edition
- 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.
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:
Risk Factors with Strong Evidence:
- HPV infection (anogenital warts)
- History of receptive anal intercourse
- History of sexually transmitted disease
- More than 10 sexual partners
- History of cervical, vulvar, or vaginal cancer
- Immunosuppression after solid-organ transplantation.
Risk Factors with Moderately Strong Evidence:
- Human immunodeficiency virus (HIV) infection
- Long-term use of corticosteroids
- Cigarette smoking.
- The anal canalextends from the anorectal ring to a zone approximately halfway between the pectinate (or dentate) line and the anal verge.
- 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.
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
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
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
Physical examination should include digital anorectal examination, anoscopy, proctoscopy, and palpation of inguinal lymph nodes.
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
TABLE 10.5. TNM Classification of Anal Margin Tumors
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.
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
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.
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)
- Potential advantages compared to radical surgery:
- no operative mortality
- no colostomy
iii. no sexual impotence.
- Disadvantages in comparison with surgery:
- 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.
- 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.
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
TABLE 10.9. Selected Results of Concurrent Radiation and Fluorouracil and Mitomycin C
TABLE 10.10. Dosage of Chemoradiation in Anal Cancer
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
FIG. 10.2. Management of anal cancer.
Surgical resection is the treatment of choice for the lesions of the perianal area that do not involve the anal sphincter.
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).
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 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.
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.
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.
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.
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.
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
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.
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).
- 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.
The clinical presentation of anal carcinoma in HIV-infected patients include:
- Rectal pain
- Rectal bleeding
- Rectal discharge
- Symptoms secondary to obstruction.
Diagnostic work-up is similar to the determination of the extent of local disease and staging for dissemination in immunocompetent patients.
- Squamous cell carcinoma
- Grading for AIN is similar to that for cervical intraepithelial neoplasia (CIN).
The staging of anal cancer in HIV-infected patients is similar to that in HIV-negative patients.
HIV-infected patients with severe immunosuppression, as evidenced by CD4 counts of < 50 per mm3, may experience more aggressive and advanced disease.
- 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.
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.
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