Nora A Janjan John M Skibber Miguel A Rodriguez Bigas Christopher Crane Marc E Delclos Edward H Lin and Jaffer A Ajani

Dorn Spinal Therapy

Spine Healing Therapy

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Chapter Overview 246

Epidemiology 247

Anatomy and Patterns of Disease Spread 247

Pathology 248

Clinical Presentation 250

Staging 250

Prognostic Factors 252

Combined-Modality Therapy 253

Regimens with Radiation plus 5-Fluorouracil and

Mitomycin C 254

Regimens with Radiation plus 5-Fluorouracil and

Cisplatin 257

Other Issues 257

Special Treatment Issues 257

Posttreatment Biopsy 257

Treatment of the Elderly and Patients with Comorbid

Conditions 258

Treatment of HIV-Positive Patients 258

Anal Margin 258

Definitive Chemoradiation 259

The M. D. Anderson Technique 260

Treatment Interruptions and Management of

Treatment-Related Side Effects 264

Follow-up Evaluations 266

Surgical Salvage 267

Key Practice Points 267

Suggested Readings 268

Chapter Overview

Anal cancer is a relatively rare tumor. Despite this, anal cancer has provided a model for organ preservation and combined-modality therapy. Previously, an abdominoperineal resection was the only therapeutic option for anal cancer. Advances in radiation techniques and clinical studies of combined chemotherapy and radiation therapy led to the estab lishment of chemoradiation as definitive treatment for anal cancer. Surgery is now reserved for recurrent or persistent disease. Functional outcome and quality of life are key issues in anal cancer treatment. Although the total number of patients with anal cancer is small, innovations in the treatment of this disease established therapeutic principles that have been applied in the treatment of nearly every type of cancer.

Epidemiology

Anal cancer is a rare neoplasm, accounting for less than 2% of all cancers of the digestive tract. Despite its rarity, specific risk factors for anal cancer development have been identified. High rates of human papillomavirus (HPV) infection have been observed in anal cancer, and an increased risk of anal HPV infection has been demonstrated in HIV-seropositive patients. An inverse relationship has been shown between the CD4 count and HPV infection. Immunosuppression from other causes, like organ transplantation, increases the risk of anal cancer by a factor of 100. Smoking increases the risk of anal cancer by a factor of 2 to 5; conversely, a prior diagnosis of anal cancer increases the risk of lung cancer by a factor of 2.5.

Anatomy and Patterns of Disease Spread

Anal cancers may arise around the anus or in the anal canal. The anal canal is about 3 to 4 cm long. The anatomy of the anal region is shown in Figure 16-1. A conventional definition classifies cancers that arise above the

Internal sphincter

Figure 16-1. Anatomic diagram of the sphincter muscles of the anus.

Internal sphincter

Figure 16-1. Anatomic diagram of the sphincter muscles of the anus.

dentate (pectinate) line as anal canal tumors and tumors that arise below the dentate line as cancers of the anal margin. The dentate line is a histologic transition zone between squamous and columnar epithelium and designates the location of the anal valves. The anorectal ring is the palpable muscle bundle formed by the upper portion of the internal sphincter, the deep or subcutaneous part of the external sphincter, the puborectalis muscle, and the distal longitudinal muscle from the large bowel. Perianal cancers (cancers of the anal margin) are located within a 5-cm radius around the anal verge in the buttock and the perineal region.

Direct invasion into the sphincteric muscles and perianal connective tissue occurs early. About half of patients will have tumor invasion of the rectum or perianal region. Extensive tumors may infiltrate the sacrum or pelvic sidewalls. Extension to the vagina is common, but invasion of the prostate gland is uncommon.

Both the vascular and lymphatic drainage of the anus is extensive. The arterial supply above the dentate line is from the superior and middle rectal arteries, which are branches of the inferior mesenteric and hypogas-tric arteries, respectively. Venous drainage is to the portal system. Below the dentate line, the arterial supply is to the middle and inferior rectal arteries, and venous drainage is to the inferior rectal vein.

Although hematogenous dissemination of anal cancer occurs, local and lymphatic extension of disease is more common. Tumors proximal to the dentate line drain to the perirectal, external iliac, obturator, hypogastric, and para-aortic nodal regions. At abdominoperineal resection, about 30% of patients with tumors in the anal canal have pelvic lymph node metastases and 16% have inguinal node metastases. Tumors in the distal anal canal drain to the inguinal-femoral and external and common iliac nodal regions. About 15% to 20% of patients have clinical evidence of inguinal lymph node involvement at presentation, and it is usually unilateral. Inguinal node metastases are evident in 30% of superficial and 63% of deeply infiltrating or poorly differentiated tumors. The inguinal nodes are located within an anatomic region bounded by defined anatomic landmarks (Figure 16-2). The most medial location for the inguinal lymph nodes is 3 cm from the pubic symphysis or midline. From there, they extend to the lateral aspect of the femoral head. The most inferior location is 2.5 cm caudal to the inferior pubic ramus, and the most superior extent is the superior aspect of the femoral head.

Pathology

Two epithelial transition zones occur at the anal region. The first area of transitional epithelium exists between the glandular mucosa of the rectum and the squamous mucosa of the anal region. This transitional epithelium

Figure 16-2. X-ray image indicating the anatomic location of the inguinal lymph nodes. Eighty-six percent of the nodes lie within the defined rectangle. PT, pubic tubercle; ASIS, anterior superior iliac spine. Reprinted with permission from Janjan NA, Ballo MT, Delclos ME, Crane CH. The anal region. In: Cox JD, Ang KK, eds. Radiation Oncology: Rationale, Technique, Results. 8th ed. St. Louis, MO: Mosby; 2003:537-556.

Figure 16-2. X-ray image indicating the anatomic location of the inguinal lymph nodes. Eighty-six percent of the nodes lie within the defined rectangle. PT, pubic tubercle; ASIS, anterior superior iliac spine. Reprinted with permission from Janjan NA, Ballo MT, Delclos ME, Crane CH. The anal region. In: Cox JD, Ang KK, eds. Radiation Oncology: Rationale, Technique, Results. 8th ed. St. Louis, MO: Mosby; 2003:537-556.

extends for about 6 to 20 mm and incorporates rectal, urothelial, and squamous elements. The second area of transitional epithelium exists between the squamous epithelium in the anal canal and the skin around the anus; this is a region of modified squamous epithelium, called the pecten. The pectinate (dentate) line is the superior aspect of the pecten. The skin of the perianal region is similar to skin located elsewhere and contains apocrine glands.

Keratinizing squamous cell carcinoma is the most common type of anal cancer in the region distal to the pectinate line. Cancers that develop in the transition zone between squamous and columnar epithelium around the dentate line are usually nonkeratinizing squamous cell carcinomas, and these are often referred to as basaloid or cloacogenic cancers. Both squamous cell carcinomas and cloacogenic tumors should be treated with definitive chemoradiation.

Other histologic subtypes include adenocarcinoma of the anus, small cell carcinoma, and melanoma. All of these histologic subtypes are associated with high rates of local recurrence and disseminated disease. A 1997 National Cancer Data Base report (Myerson et al, 1997) described the differences in anal cancer recurrence rates by histologic subtype and disease stage. Over one fourth of patients with adenocarcinoma develop distant metastases. The risk of local or distant recurrence was twice as high for squamous cell cancers as for adenocarcinomas, but the risk of distant metastasis was more than twice as high for adenocarcinomas as for squa-mous cell carcinomas (Table 16-1).

Clinical Presentation

Bleeding and anal discomfort are the most common symptoms of anal cancer, and they occur in about half of patients. Other complaints include the sensation of a mass in the anus, pruritis, and anal discharge. Although obstructive symptoms can occur with proximal tumors, such symptoms are unusual when the tumor involves the distal anus. Fewer than 5% of patients have sphincteric destruction resulting in fecal incontinence. Vaginal or other fistulas are uncommon. Only 10% of patients are found to have distant metastases at the time of diagnosis. Local relapse is more common than the development of extrapelvic disease. When distant metastases occur, they most commonly are found in the liver and the lungs.

Staging

The American Joint Committee on Cancer clinical staging system (Table 16-2) is the system most commonly used for carcinomas of the anal canal. Cancers that arise in the anal margin are staged according to the system used for skin cancers.

Table 16-1. Recurrence by Site and "Combined"

Stage for 1988 Anal Carcinoma Cases

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