Superficial thorax and abdomen

This video demonstration course by Madison Medical School, University of Wisconsin, includes dissections of thorax and abdomen, Back muscles and Spinal cord, Abdominal wall, Thorax, Posterior thorax, Peritoneal cavity, Gastrointestinal tract, Pelvic outlet, Superficial face, Infratemporal fossa, Superficial neck, Deep neck, Brain, Orbit, Ear, Pharynx, Nasal/paranasal, Superficial limbs, Axillary fossa, Shoulder and arm, Forearm and hand, Upper limb joints, Hip and thigh, Leg and foot and Lower limb joints.

Superficial thorax and abdomen

This video demonstration course by Madison Medical School, University of Wisconsin, includes dissections of thorax and abdomen, Back muscles and Spinal cord, Abdominal wall, Thorax, Posterior thorax, Peritoneal cavity, Gastrointestinal tract, Pelvic outlet, Superficial face, Infratemporal fossa, Superficial neck, Deep neck, Brain, Orbit, Ear, Pharynx, Nasal/paranasal, Superficial limbs, Axillary fossa, Shoulder and arm, Forearm and hand, Upper limb joints, Hip and thigh, Leg and foot and Lower limb joints.

Anal Cancer

Anal cancer is an uncommon malignancy, accounting for only a small percentage (4%) of all cancers of the lower alimentary tract. There are approximately 4,000 cases per year in the United States. Individuals with human papillomavirus (HPV) and homosexual men, in particular, are at increased risk of anal cancer. Most studies have included small numbers of patients accrued over several years, and in some situations, there is a lack of data from randomized trials on which to base treatment decisions. Small, early-stage carcinomas of the anal margin can be managed with local excision. Concurrent chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) is the standard of care for more advanced anal canal and anal margin cancers, although 30% of patients will fail after this organ-sparing approach. Patients who recur locally after definitive chemoradiation can undergo salvage with an abdominoperineal resection (APR) with a reasonable expectation of long-term survival.

EPIDEMIOLOGY
Anal cancer has an annual incidence of 0.6 per 100,000 in whites in the United States and is more frequent in women than in men by a ratio of 2:1. However, cancer of the anal margin is more frequent in men. More than 80% of anal cancers develop between the ages of 50 and 60 years. Epidemiologic studies during the last decade suggest that the incidence of anal cancer in men younger than 35 years has increased, and the gender ratio is reversed in this age group. The San Francisco study revealed an incidence of anal carcinoma in homosexual men of between 25 and 87 cases per 100,000. The incidence appears to be rising in this population, likely due to increased overall survival from the use of highly active antiretroviral medications.

ETIOLOGY AND RISK FACTORS
Environmental factors are predominantly implicated in the carcinogenesis of anal cancer. The most common risk factors can be classified as those with strong evidence and those with moderately strong evidence.
Risk factors with strong evidence include:

• HPV, particularly serotypes 16 and 18. HPV is associated with anal intraepithelial neoplasia (AIN), which is a precursor lesion. The same subtypes of HPV that cause malignant transformation in cervical cancer are also implicated in anal cancer. Patients may present with 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 include:

• Human immunodeficiency virus (HIV) infection. HIV-infected patients with severe immunosuppression, as evidenced by CD4 counts less than 50/mm3, may present with more aggressive and advanced disease.
• Long-term use of corticosteroids
  
• Cigarette smoking
  

PATHOLOGY Anatomy

• The anal canal extends from the anorectal ring (where the rectum enters the puborectalis sling at the apex of the sphincter complex) to the anal verge (where the anal squamous mucosa merges with the epidermis of the perianal skin). The length of the canal is approximately 3 to 4 cm.
  
• The anal margin consists of the anal area distal to the anal canal, including perianal skin. Some authors have suggested a radius of 5 cm from the anal verge as the distal boundary of the anal margin (Fig. 10.1).
  

HISTOLOGY The histology and features of the different types of anal carcinoma are described in Table 10.1. Frequency Table 10.2 shows the frequency of occurrence of each histologic type of anal cancer. Squamous cell carcinoma is the most common form of anal cancer. Presentation Symptoms The incidence of presenting symptoms for three types of anal carcinoma is shown in Table 10.3.

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 has been called canal or margin cancer, depending on institutional preference, but now should be called anal canal cancer by the AJCC/UICC definition.

TABLE 10.1. Characteristics of different types of anal cancer

Histologic types Features Squamous cell (epidermoid) carcinoma Occurs in the lower anus, often ulcerating Cloacogenic (also known as 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’s disease) Premalignant lesion of the perirectal skin Intraepithelial mucous adenocarcinoma (Paget’s disease) Develops in apocrine or mucous glands

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’s disease) 8 (4%) Melanoma 7 (3%) Basal cell carcinoma 6 (3%) Adenocarcinoma 6 (3%) Total 204

Signs

• Rectal bleeding or discharge
  
• Perianal mass
  
• Change in bowel habits or stool caliber
  

BIOPSY An incisional biopsy is preferred to confirm diagnosis. Clinically suspicious inguinal lymph nodes should be examined to rule out metastatic disease. STAGING AND PROGNOSTIC FACTORS Workup should include history, physical examination with special attention to digital rectal examination and palpation of the inguinal nodes, chest radiograph, pelvic CT or MRI, PET scan, liver function P.124
tests, and biopsy. Women should also undergo pelvic examination to rule out vaginal invasion by tumor and cervical cancer screening with a Pap smear. An endoscopic ultrasound of the anal canal may be helpful in assessing the perirectal lymph nodes. An HIV test and CD4 count should be considered.

TABLE 10.3. Frequency of occurrence of symptoms in different types of anal cancer
Presenting symptoms Squamous cell carcinoma Perianal Basaloid squamous carcinoma 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 a P = <0.001; differences not significant for other lesions. Source: From Beahrs OH, Wilson SM. Carcinoma of the anus. Ann Surg 1976;184(4):422-8, with permission.

The UICC (Union Internationale Contre le Cancer) and AJCC (American Joint Committee on Cancer) have proposed a practical staging system for anal cancers. The staging systems for both types of tumors are outlined in Tables 10.4 and 10.5. MAJOR PROGNOSTIC FACTORS There are four major prognostic factors:

• Site: Cancers of the anal margin have a more favorable prognosis than those of the anal canal.
  
• Size: Patients with primary tumors <5 cm have a more favorable prognosis than those with tumors >5 cm.
  
• Differentiation: Well-differentiated tumors are more favorable than poorly differentiated tumors.
  
• Lymph node involvement: Absence of nodal involvement or local extension indicates a better prognosis.
  

TABLE 10.4. 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, 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

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TABLE 10.5. TNM classification of anal margin tumors

Primary tumor (T)a T4 Tumor invades deep extradermal structures Regional lymph nodes (N) N1 Ipsilateral inguinal nodes Metastases (M) M1 Distant metastases Stage groupingsb Stage III T4 N0 M0 Any T N1 M0 aDesignation as for anal canal tumors, except T4. bStage groupings as for anal canal tumors, except stage III (no stage IIA or IIIB). Source: Adapted 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.

When balanced for other factors, the prognosis for patients with squamous cell carcinoma of the anus and cloacogenic carcinoma is similar. TREATMENT Surgery Anal Canal Lesions Historically, the standard (and sole) form of therapy of the anal canal was surgical resection, often involving an APR with bilateral inguinal node dissection and formation of a colostomy. Despite such radical procedures, the most frequent site of failure is the pelvis, with local recurrences occurring in 30% of patients (Table 10.6). Although postoperative radiation therapy has been utilized in an effort to reduce the local recurrence rate, the benefit of this practice has not been documented through a controlled trial. Local excision may be sufficient to cure patients with small T1 N0 cancers of the anal canal, although patients treated in this manner need to be followed very closely. Local excision is not appropriate in cases where surgery would result in incontinence, or where the risk of involved lymph nodes exceeds 5%. Therefore, tumors that (a) involve the dentate line, or (b) are >2 cm (T2), or (c) involve greater than half the anal circumference, or (d) are moderately or poorly differentiated, are probably best managed with combined-modality treatment with chemotherapy and radiation. This integrated approach improves overall survival and may allow radical surgery to be avoided, preserving anal sphincter function. APR is used as salvage therapy in patients with chemoradiation-resistant disease, with a 50% 5-year survival rate. Anal Margin Lesions

• 
  For well-differentiated T1 N0 anal margin lesions, a wide local excision without the need for a colostomy seems to be adequate (Table 10.7).
  
• 
  Larger (T2-4N0) or node-positive anal margin cancers should be treated with chemoradiation with 5-FU and MMC, similar to anal canal carcinomas.
  

TABLE 10.6. Surgical results for anal canal lesions
Nodal status 5-year survival (%) Nodes negative 54-70 Metachronous nodal spread 51 Synchronous nodal spread 16

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TABLE 10.7. Five-year survival after local excision in anal margin cancer in 31 patients

Tumor size (cm) 0-2 2-5 >5 NC Total 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 Source: 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.

Radiation Therapy Radiation therapy has been given by external beam treatment, interstitial treatment. and combined external beam and interstitial treatment. The overall 45% to 50% rate of cure reported in the series of selected patients who were treated with primary radiation therapy is quite similar to that seen in patients treated with radical surgery. Definitive radiation and surgery cannot be prospectively compared since the issue of a permanent colostomy is an unacceptable variable in a clinical trial. While the APR has remained a standard procedure during the last 25 years, radiotherapy techniques and equipment have advanced markedly, permitting the delivery of a higher, more precisely defined dose (approaching 60 Gy) with less toxicity. Recent series utilizing external beam and interstitial treatment or high-dose external beam irradiation are encouraging, suggesting local control rates of 70% to 80%, but will require further confirmation before receiving full acceptance. Advantages of primary radiation-based treatment over surgery include avoidance of perioperative morbidity and mortality, avoidance of a colostomy, and a lower risk of impotence in men. Disadvantages include the inability to determine the pathological nodal stage. Combined Radiation Therapy and Chemotherapy In 1972, Nigro and colleagues at Wayne State University began treating patients with preoperative concomitant radiation (30 Gy external beam) and chemotherapy (continuous infusion 5-FU and MMC) in an attempt to enhance the efficacy of radical surgery in patients with anal canal cancer. When this experience was last updated, 45 patients had been followed for a median of 50 months; 38 of 45 (84%) achieved a complete biopsy-proven response after only radiation and chemotherapy including all patients whose initial lesion was <5 cm in size. None of the 38 patients developed local or distant tumor recurrence, but all seven of the patients who had recurrent disease after preoperative treatment developed distant spread and subsequently died despite salvage APR. While the original treatment plan called for an APR following the radiation and chemotherapy, this program was altered after it was found that five of the first six patients who had undergone the radical operation had no tumor in the operative specimen; subsequently, surgery has been performed only for those patients with residual tumor in the anal canal at the time of the posttreatment biopsy. The vast majority of patients have experienced cures of their anal cancers without the need for a colostomy and with manageable toxicity. These highly encouraging results from the Wayne State group have now been confirmed and extended by others in randomized trials. Tables 10.8 and 10.9 show results of some trials of chemoradiation for anal canal carcinoma. Radiation Therapy Alone Versus Combined-Modality Therapy The European Organization for Research and Treatment of Cancer (EORTC) randomized 110 patients with bulky tumors to receive 45 to 65 Gy of pelvic RT alone or in combination with 5-FU/ MMC. Statistically significant benefits for complete response rate, local regional control, and colostomy-free survival all favored the combined-modality approach. The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) randomized 585 patients to receive 45 Gy of pelvic RT alone or in combination with 5-FU/MMC (1). The local failure rate was reduced by 46% in patients P.127
given the combined-modality approach (Table 10.9). A planned subset analysis revealed a significant local control benefit even in T1-2N0 patients. P.128

TABLE 10.8. Selected results of concurrent radiation, 5-fluorouracil, and mitomycin C

Chemotherapy regimens Radiation (dose/fractions/time) Primary tumor control Regional nodal control 5-year survival Reference 5-FU 1,000mg/m2/d CIVI for 8 d, d 1-4, d 29-32 (total dose/course 8,000 mg/m2) 30 Gy/15/d -21 31/34 (91%) (≤5 cm) 7/10 (70%) (>5 cm) NS 80% crude 15 MMC, 15 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d CIVI d 2-5, d 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 actual 16 MMC, 10 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d, CIVI d 1-4, d 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 17 MMC 10 mg/m2 IV bolus, d 1 and 43 (total dose/course 20 mg/m2) 5-FU 1,000 mg/m2/d, CIVI d 1-4, d 29-32 (total dose/course 8,000 mg/m2) 50 Gy/25-28/d 1-35 ± boost 21/22 (95%) (≤5 cm) 14/19 (74%) (>5 cm or T4) 3/4 77%, actuarial 18 MMC 10 mg/m2 IV bolus, d 1 and 29 (total dose/course 20 mg/m2) 5-FU 600 mg/m2/d, CIVI d 1-5 (total dose/course 3,000 mg/m2) 42 Gy/10/d 1-19 plus interstitial iridium-192 boost No data in original publication 57/70 (81%) (≥4 cm) NS NS 8 MMC 12 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d CIVI d 1-4 (total dose/course 4,000 mg/m2) 50-54 Gy/25-27/d 1-35 28/30 (93%) (≥5 cm) 42/56 (75%) (>5 cm or T4) NS 72%, actuarial 19 MMC 10-15 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d CIVI d 1-4 (total dose/course, 4,000 mg/m2) 50 Gy/20/d 1-28 3/3 (100%) (≤5 cm) 11/13 (85%) (>5 cm or T4) 3/3 75%, actuarial 20 MMC 10 mg/m2 IV bolus d 1 5-FU 750 mg/m2/d CIVI d 1-5, d 43-7 (total dose/course, 4,000 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 21 MMC 15 mg/m2 IV bolus d 1, 43, 85 (total dose/course, 45 mg/m2) 5-FU 1,000 mg/m2/d, d 1-4, d 29-32 (total dose/course, 8,000 mg/m2) 40 Gy/20-24/d 1-24 then 10-13 Gy boost (split course) 13/17 (77%) (≤5 cm) 18/33 (55%) (>5 cm or T4) NS 74% 22 MMC 10 mg/m2 IV bolus d 2 5-FU 600-800 mg/m2/d d 1-5 (total dose/course 3,000-4,000 mg/m2) 38 Gy/19/d 1-21 then 18 Gy interstitial iridium-192 boost (split course) 23/33 (70%) (≤5 cm) 22/35 (63%) (>5 cm or T4) NS 65.5% 23 MMC 0.4 mg/kg IV bolus d 1 (maximum 20 mg) 5-FU, 5-fluorouracil; MMC, mitomycin C; CIVI, continuous intravenous infusion; NS, not stated; NA, not applicable; T, tumor invading adjacent organs; T4, tumor invading deep extradermal structures.

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TABLE 10.9. Randomized trials comparing radiation alone and chemoradiation

Group Arm N Complete responsesa (%) 3-year local controlb (%) Crude metastasis rate (%) 3-year survival (%) EORTC RT 52 54 55 21 64 RT/5-FU/MMC 51 80 69c 18 69 UKCCCR RT 285 30 39 17 58 RT/5-FU/MMC 292 39 61c 10 65 EORTC, European Organization for Research and Treatment of Cancer; UKCCCR, United Kingdom Coordinating Committee on Cancer Research; RT, radiation therapy; 5-FU, 5-fluorouracil; MMC, mitomycin C. aLocal control was assessed 6 weeks after completion of 45 Gy in EORTC trial (before boost) and 6 weeks after completion of 60 to 65 Gy radiation in the UKCCCR trial. bPatients requiring surgery to achieve local control after radiation were considered locally controlled in the EORTC trial. Patients who had surgery after completion of radiation or for treatment-related morbidity were counted as local failures in the UKCCCR trial. cDifference statistically significant at P <0.05.

Value of MMC in the Combined-Modality Regimen The RTOG/Intergroup study randomized 310 patients to receive 45 to 50.4 Gy of pelvic RT with 5-FU or the same radiation and 5-FU/MMC (2). A statistically significant increase in 4-year disease-free survival was observed in the patient cohort that received MMC, although toxicity was significantly greater. Substitution of cisplatin for MMC in combination with 5-FU and radiation therapy has been explored in phase 2 trials (3) with promising initial results. Induction therapy with 5-FU/cisplatin followed by RT/5-FU/cisplatin was compared with “standard” RT/5-FU/MMC in RTOG 98-11 (Table 10.10). The results showed equal overall survival of 69% at 5 years and equivalent 5-year disease-free survival (48% in the experimental arm and 56% in the standard arm). Hematologic toxicity was worse in the MMC-containing arm, although nonhematologic toxicities were similar. However, the colostomy rate was higher in the experimental arm (19% vs. 10%). The authors concluded that the experimental regimen was not superior to standard chemoradiation with 5-FU/MMC (4). Toxicity of Combined-Modality Therapy The acute toxicities of chemoradiation for anal cancer can be severe and include anemia, thrombocytopenia, desquamation and skin breakdown, diarrhea, infection, fluid and electrolyte derangements, pain, and fatigue. The RTOG/ECOG trial (2) reported a 3% rate of treatment-related death in the 5-FU/MMC arm. Aggressive use of barrier creams and emollients on the inguinal and perianal regions and antidiarrheal medications such as loperamide and diphenoxylate/atropine can be helpful in reducing the risk of infection and trauma to the perianal region. Opioid analgesics are often necessary for pain control and help decrease the frequency of stools. Blood counts should be monitored closely, particularly if MMC is used. Fecal contamination of areas of compromised perianal skin in the setting of neutropenia can pose a high-risk of sepsis. Overall, however, treatment breaks should be avoided if possible. A protocol of split-course chemoradiation with a planned 2-week treatment break produced a significantly higher local failure and colostomy rate (5). Late complications of chemoradiation for anal cancer can include painful fibrosis, lymphedema, anal stenosis and sphincter dysfunction, fistula formation, rectal bleeding, impotence, infertility, femoral neck fractures, and small-bowel injury.

TABLE 10.10. Randomized trials comparing radiation with 5-fluorouracil and mitomycin C to other chemoradiation regimens

Trial Arm N Disease-free survival (%) Colostomy rate (%) Toxicity Overall survival (%) RTOG/ECOG RT/5-FU 145 51 22 8% 67 Grade 4-5 RT/5-FU/MMC 146 73* 9* 26%* Grade 4-5 76 RTOG 98-11 Induction 5-FU/CDDP then 598 analyzable 56 19 75% non-heme 47% heme 69 RT/5-FU/CDDP 324 Grade 3-4 RT/5-FU/MMC 320 48 10* 76% non-heme 69 67% heme* Grade 3-4 RTOG, Radiation Therapy Oncology Group; ECOG, Eastern Cooperative Oncology Group; RT, radiation therapy; 5-FU, 5-fluorouracil; MMC, mitomycin C; CDDP, cisplatin; heme, hematologic toxicity; nonheme, nonhematologic toxicity. * Statistically significant at P <0.05.

Chemoradiation in HIV-Positive Patients HIV-positive patients are more likely to require treatment breaks and hospitalization during treatment. Dose reduction of chemotherapy and radiation or alterations of the treatment plan (such as omission of MMC) may be necessary for HIV-positive patients with a history of HIV/AIDS-related complications. However, sequential chemoradiation in anal cancer is markedly inferior to concurrent treatment and should not be used. Combined External Beam and Interstitial Radiation Therapy Lower-dose external beam radiation has been combined with chemotherapy and an interstitial iridium-192 implant in an effort to improve the therapeutic radio. Several European investigators have reported series showing average local control rates of 81% (range 73-89%), with 5-year survival of 70% (range 60-84%) (6,7,8,9,10,11). The rate of anal necrosis ranged from 2% to 76%, and many of these patients required salvage with APR, even if they were free of disease. Interstitial implantation after external beam radiotherapy may help some patients with residual disease to have a complete response. Dose of Radiation Although series have been published suggesting that highly selected early-stage patients can be cured with only 30 Gy with concurrent 5-FU/MMC after a local excision, several reports have suggested that radiation doses above 54 Gy are associated with improved local control and survival (12). Recently, attempts have been made to escalate the radiation dose used in combined-modality therapy, including the recent RTOG 98-11 randomized protocol. However, local control and survival for the best arm of this trial, which used doses up to 59.4 Gy with 5-FU/MMC, were not substantially better than the results obtained in the RTOG/ECOG study with 45 to 50.4 Gy and 5-FU/MMC. Increases in dose have
also been associated with greater toxicity. Daily fraction sizes should not exceed 2 Gy with concurrent chemotherapy due to enhanced acute and late toxicity. In select cases, radiation alone in doses of 60 to 70 Gy has been used to safely and successfully treat small, early-stage tumors. Intensity-Modulated Radiation Therapy (IMRT) IMRT can achieve tight conformality of the prescribed radiation dose to the target volume while increasingly sparing normal tissues, and is particularly useful in situations where the target is complex or concave in shape. In anal cancer, IMRT has been investigated as a means of decreasing dose to the skin, bone marrow, and bowel while maintaining or escalating the tumor dose. Salama et al. reported preliminary results from a series of 53 anal cancer patients treated with IMRT and concurrent chemotherapy (13). The median dose to the pelvic and inguinal lymph nodes was 45 Gy; the primary site and involved nodes were boosted to a median dose of 51.5 Gy; 48 of the patients received 5-FU/MMC and 15% of patients developed acute grade 3 gastrointestinal toxicity and 34% had grade 3 dermatologic toxicity, significantly better than the results from RTOG 98-11 (34% and 48%, respectively). There were no nonhematologic toxicities of grade 4 or higher. Local control was excellent with a 93% complete response rate and 84% colostomy-free survival at 18 months. These encouraging results are being confirmed in RTOG 0529, a phase 2 protocol. Tumor Regression After Chemoradiation The median time to complete tumor regression after combined-modality treatment is 12 weeks, and most local recurrences manifest within 2 years. Regression after treatment with radiation alone may be even more prolonged, and up to a year may need to elapse before a complete response is evident. Biopsy should only be performed if tumor persists on serial exams. Results from a phase 3 study suggested benefit to adding a radiation boost with cisplatin for patients with persistent disease after chemoradiation (2), but this was more likely due to continued prolonged tumor regression from the initial therapy TREATMENT OPTIONS ACCORDING TO STAGE Treatment options according to stage for anal cancer are contained in Table 10.11. Stage 0

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

TABLE 10.11. Treatment options for anal cancer
Stage Treatment options 0 Surgery I Radiation Chemoradiation Surgery II Chemoradiation Surgery III Chemoradiation Surgery IV Palliative surgery Palliative irradiation Palliative chemoradiation Clinical trial

Stage I

• 
  Small, well-differentiated tumors of the anal margin not involving the anal sphincter can be treated with wide local excision.
  
• 
  All other stage I tumors of the anal margin and anal canal are treated with chemoradiation with 5-FU/MMC.
  
• 
  Patients who cannot tolerate chemotherapy may be treated with radiation alone.
  
• 
  Surgical salvage with APR is reserved for residual cancer in the anal canal after chemoradiation.
  

Stage II

• 
  Chemoradiation with 5-FU/MMC is the recommended initial approach.
  
• 
  Patients who cannot tolerate chemotherapy may be treated with radiation alone.
  
• 
  Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
  

Stage IIIA Stage IIIA anal cancer presents clinically as stage II anal cancer in most patients but is upstaged to IIIA by presence of perirectal nodal disease or adjacent organ involvement. Endoscopic ultrasound (endoanal or endorectal) may aid in assessing perirectal lymph nodes.

• 
  Chemoradiation with 5-FU/MMC is the recommended initial approach.
  
• 
  Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
  

Stage IIIB Though the cure of this stage is possible, the involvement of inguinal lymph nodes (unilateral or bilateral) constitutes a poor prognostic sign.

• 
  Chemoradiation with 5-FU/MMC is the recommended initial approach.
  
• 
  Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
  
• 
  Because of the poor prognosis of these patients, they should be recruited for clinical trials whenever possible.
  

Stage IV There is no standard chemotherapy regimen for stage IV disease. Chemotherapy with 5-FU/MMC or cisplatin has been reported to give a 50% response rate, with a median survival of 12 months (14). Palliation of symptoms constitutes the backbone of management. Patients with stage IV anal cancer should be enrolled in clinical trials.

• 
  Palliative chemotherapy
  
• 
  Palliative radiation therapy to localized symptomatic metastases
  
• 
  Palliative surgery
  
• 
  Palliative combined chemotherapy and radiation therapy
  
• 
  Clinical trials
  

PERSISTENT OR RECURRENT ANAL CANCER Persistent anal cancer can be managed according to Fig. 10.2. Local recurrences after initial treatment with either chemoradiation or surgical resection can be effectively controlled by alternate treatment options, including:

• 
  Surgical resection after chemoradiation (salvage APR)
  
• 
  Salvage radiation with or without chemotherapy if normal tissue tolerances permit
  
• 
  Isolated recurrence in the inguinal area may be managed with inguinal node dissection or, if possible, with local radiation with or without chemotherapy
  

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Fig. 10.2. Management of anal cancer after definitive chemoradiation. (PR, partial response; CR, complete response; APR, abdominoperineal resection; XRT, radiation therapy.)

Follow-up Patients with anal cancer should be monitored as follows:

• 
  Every 3 months for the first 3 years
  
• 
  Every 6 months for an additional 2 years
  
• 
  Annually thereafter
  

The following specific recommendations should be undertaken:

• 
  Medical history
  
• 
  Physical examination, including digital rectal exam and palpation of inguinal nodes
  
• 
  Complete blood counts
  
• 
  Liver function tests
  
• 
  Chest radiograph yearly
  
• 
  CT scan of the pelvis every 6 to 12 months for the first 3 years
  

Prognosis Frequency and 5-year survival of anal canal carcinoma patients by stage is shown in Table 10.12. Prevention Awareness of the disease by the physician and the recognition of a high-risk group (homosexual men, women with cervical or vulvar cancer) may aid patients by early detection. There are currently no standard recommendations for screening for anal cancer in high-risk populations. Anoscopy with anal cytology should be undertaken in patients with abnormal discharge, bleeding, pruritis, bowel irregularity, rectal or pelvic pain, and those with a history of previous preinvasive lesions or abnormal Pap smears. Other patients who should be screened include HIV-negative men with a history of analreceptive intercourse, HIV-positive men and women with CD4 cell counts less than 500/mm3, and HIV-positive and -negative women with a history of high-grade cervical intraepithelial neoplasia (CIN).

TABLE 10.12. Frequency and 5-year survival of anal canal carcinoma patients by stage in a series of 270 patients
Stage Frequency at presentation (%) 5-year survival (%) T1 9 86 T2 51 86 T3 30 60 T4 10 45 Node-negative 87 76 Node-positive 13 54 Source: Data from Touboul E, Schlienger M, Buffat L et al. Epidermoid carcinoma of the anal canal. Results of curative-intent radiation in 270 patients. Cancer 1994;73(6):1569-79.

Anal Pap smears have a reported sensitivity of approximately 70% (equal to that associated with uterine cervix Pap testing). AIN is graded like CIN and the treatment of AIN is similar to the treatment for CIN in women. It may include electrocautery, cryoablation, or laser ablation.
A vaccine against the transmission of high-risk HPV serotypes has recently been approved for use in the prevention of cervical cancer in women, and this represents a promising strategy for prevention of anal cancer. A trial of HPV prevention in men is ongoing.

Anal Cancer

Anal cancer is an uncommon malignancy, accounting for only a small percentage (4%) of all cancers of the lower alimentary tract. There are approximately 4,000 cases per year in the United States. Individuals with human papillomavirus (HPV) and homosexual men, in particular, are at increased risk of anal cancer. Most studies have included small numbers of patients accrued over several years, and in some situations, there is a lack of data from randomized trials on which to base treatment decisions. Small, early-stage carcinomas of the anal margin can be managed with local excision. Concurrent chemoradiation with 5-fluorouracil (5-FU) and mitomycin C (MMC) is the standard of care for more advanced anal canal and anal margin cancers, although 30% of patients will fail after this organ-sparing approach. Patients who recur locally after definitive chemoradiation can undergo salvage with an abdominoperineal resection (APR) with a reasonable expectation of long-term survival.

EPIDEMIOLOGY
Anal cancer has an annual incidence of 0.6 per 100,000 in whites in the United States and is more frequent in women than in men by a ratio of 2:1. However, cancer of the anal margin is more frequent in men. More than 80% of anal cancers develop between the ages of 50 and 60 years. Epidemiologic studies during the last decade suggest that the incidence of anal cancer in men younger than 35 years has increased, and the gender ratio is reversed in this age group. The San Francisco study revealed an incidence of anal carcinoma in homosexual men of between 25 and 87 cases per 100,000. The incidence appears to be rising in this population, likely due to increased overall survival from the use of highly active antiretroviral medications.

ETIOLOGY AND RISK FACTORS
Environmental factors are predominantly implicated in the carcinogenesis of anal cancer. The most common risk factors can be classified as those with strong evidence and those with moderately strong evidence.
Risk factors with strong evidence include:

• HPV, particularly serotypes 16 and 18. HPV is associated with anal intraepithelial neoplasia (AIN), which is a precursor lesion. The same subtypes of HPV that cause malignant transformation in cervical cancer are also implicated in anal cancer. Patients may present with 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 include:

• Human immunodeficiency virus (HIV) infection. HIV-infected patients with severe immunosuppression, as evidenced by CD4 counts less than 50/mm3, may present with more aggressive and advanced disease.
• Long-term use of corticosteroids
  
• Cigarette smoking
  

PATHOLOGY Anatomy

• The anal canal extends from the anorectal ring (where the rectum enters the puborectalis sling at the apex of the sphincter complex) to the anal verge (where the anal squamous mucosa merges with the epidermis of the perianal skin). The length of the canal is approximately 3 to 4 cm.
  
• The anal margin consists of the anal area distal to the anal canal, including perianal skin. Some authors have suggested a radius of 5 cm from the anal verge as the distal boundary of the anal margin (Fig. 10.1).
  

HISTOLOGY The histology and features of the different types of anal carcinoma are described in Table 10.1. Frequency Table 10.2 shows the frequency of occurrence of each histologic type of anal cancer. Squamous cell carcinoma is the most common form of anal cancer. Presentation Symptoms The incidence of presenting symptoms for three types of anal carcinoma is shown in Table 10.3.

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 has been called canal or margin cancer, depending on institutional preference, but now should be called anal canal cancer by the AJCC/UICC definition.

TABLE 10.1. Characteristics of different types of anal cancer

Histologic types Features Squamous cell (epidermoid) carcinoma Occurs in the lower anus, often ulcerating Cloacogenic (also known as 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’s disease) Premalignant lesion of the perirectal skin Intraepithelial mucous adenocarcinoma (Paget’s disease) Develops in apocrine or mucous glands

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’s disease) 8 (4%) Melanoma 7 (3%) Basal cell carcinoma 6 (3%) Adenocarcinoma 6 (3%) Total 204

Signs

• Rectal bleeding or discharge
  
• Perianal mass
  
• Change in bowel habits or stool caliber
  

BIOPSY An incisional biopsy is preferred to confirm diagnosis. Clinically suspicious inguinal lymph nodes should be examined to rule out metastatic disease. STAGING AND PROGNOSTIC FACTORS Workup should include history, physical examination with special attention to digital rectal examination and palpation of the inguinal nodes, chest radiograph, pelvic CT or MRI, PET scan, liver function P.124
tests, and biopsy. Women should also undergo pelvic examination to rule out vaginal invasion by tumor and cervical cancer screening with a Pap smear. An endoscopic ultrasound of the anal canal may be helpful in assessing the perirectal lymph nodes. An HIV test and CD4 count should be considered.

TABLE 10.3. Frequency of occurrence of symptoms in different types of anal cancer
Presenting symptoms Squamous cell carcinoma Perianal Basaloid squamous carcinoma 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 a P = <0.001; differences not significant for other lesions. Source: From Beahrs OH, Wilson SM. Carcinoma of the anus. Ann Surg 1976;184(4):422-8, with permission.

The UICC (Union Internationale Contre le Cancer) and AJCC (American Joint Committee on Cancer) have proposed a practical staging system for anal cancers. The staging systems for both types of tumors are outlined in Tables 10.4 and 10.5. MAJOR PROGNOSTIC FACTORS There are four major prognostic factors:

• Site: Cancers of the anal margin have a more favorable prognosis than those of the anal canal.
  
• Size: Patients with primary tumors <5 cm have a more favorable prognosis than those with tumors >5 cm.
  
• Differentiation: Well-differentiated tumors are more favorable than poorly differentiated tumors.
  
• Lymph node involvement: Absence of nodal involvement or local extension indicates a better prognosis.
  

TABLE 10.4. 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, 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

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TABLE 10.5. TNM classification of anal margin tumors

Primary tumor (T)a T4 Tumor invades deep extradermal structures Regional lymph nodes (N) N1 Ipsilateral inguinal nodes Metastases (M) M1 Distant metastases Stage groupingsb Stage III T4 N0 M0 Any T N1 M0 aDesignation as for anal canal tumors, except T4. bStage groupings as for anal canal tumors, except stage III (no stage IIA or IIIB). Source: Adapted 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.

When balanced for other factors, the prognosis for patients with squamous cell carcinoma of the anus and cloacogenic carcinoma is similar. TREATMENT Surgery Anal Canal Lesions Historically, the standard (and sole) form of therapy of the anal canal was surgical resection, often involving an APR with bilateral inguinal node dissection and formation of a colostomy. Despite such radical procedures, the most frequent site of failure is the pelvis, with local recurrences occurring in 30% of patients (Table 10.6). Although postoperative radiation therapy has been utilized in an effort to reduce the local recurrence rate, the benefit of this practice has not been documented through a controlled trial. Local excision may be sufficient to cure patients with small T1 N0 cancers of the anal canal, although patients treated in this manner need to be followed very closely. Local excision is not appropriate in cases where surgery would result in incontinence, or where the risk of involved lymph nodes exceeds 5%. Therefore, tumors that (a) involve the dentate line, or (b) are >2 cm (T2), or (c) involve greater than half the anal circumference, or (d) are moderately or poorly differentiated, are probably best managed with combined-modality treatment with chemotherapy and radiation. This integrated approach improves overall survival and may allow radical surgery to be avoided, preserving anal sphincter function. APR is used as salvage therapy in patients with chemoradiation-resistant disease, with a 50% 5-year survival rate. Anal Margin Lesions

• 
  For well-differentiated T1 N0 anal margin lesions, a wide local excision without the need for a colostomy seems to be adequate (Table 10.7).
  
• 
  Larger (T2-4N0) or node-positive anal margin cancers should be treated with chemoradiation with 5-FU and MMC, similar to anal canal carcinomas.
  

TABLE 10.6. Surgical results for anal canal lesions
Nodal status 5-year survival (%) Nodes negative 54-70 Metachronous nodal spread 51 Synchronous nodal spread 16

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TABLE 10.7. Five-year survival after local excision in anal margin cancer in 31 patients

Tumor size (cm) 0-2 2-5 >5 NC Total 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 Source: 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.

Radiation Therapy Radiation therapy has been given by external beam treatment, interstitial treatment. and combined external beam and interstitial treatment. The overall 45% to 50% rate of cure reported in the series of selected patients who were treated with primary radiation therapy is quite similar to that seen in patients treated with radical surgery. Definitive radiation and surgery cannot be prospectively compared since the issue of a permanent colostomy is an unacceptable variable in a clinical trial. While the APR has remained a standard procedure during the last 25 years, radiotherapy techniques and equipment have advanced markedly, permitting the delivery of a higher, more precisely defined dose (approaching 60 Gy) with less toxicity. Recent series utilizing external beam and interstitial treatment or high-dose external beam irradiation are encouraging, suggesting local control rates of 70% to 80%, but will require further confirmation before receiving full acceptance. Advantages of primary radiation-based treatment over surgery include avoidance of perioperative morbidity and mortality, avoidance of a colostomy, and a lower risk of impotence in men. Disadvantages include the inability to determine the pathological nodal stage. Combined Radiation Therapy and Chemotherapy In 1972, Nigro and colleagues at Wayne State University began treating patients with preoperative concomitant radiation (30 Gy external beam) and chemotherapy (continuous infusion 5-FU and MMC) in an attempt to enhance the efficacy of radical surgery in patients with anal canal cancer. When this experience was last updated, 45 patients had been followed for a median of 50 months; 38 of 45 (84%) achieved a complete biopsy-proven response after only radiation and chemotherapy including all patients whose initial lesion was <5 cm in size. None of the 38 patients developed local or distant tumor recurrence, but all seven of the patients who had recurrent disease after preoperative treatment developed distant spread and subsequently died despite salvage APR. While the original treatment plan called for an APR following the radiation and chemotherapy, this program was altered after it was found that five of the first six patients who had undergone the radical operation had no tumor in the operative specimen; subsequently, surgery has been performed only for those patients with residual tumor in the anal canal at the time of the posttreatment biopsy. The vast majority of patients have experienced cures of their anal cancers without the need for a colostomy and with manageable toxicity. These highly encouraging results from the Wayne State group have now been confirmed and extended by others in randomized trials. Tables 10.8 and 10.9 show results of some trials of chemoradiation for anal canal carcinoma. Radiation Therapy Alone Versus Combined-Modality Therapy The European Organization for Research and Treatment of Cancer (EORTC) randomized 110 patients with bulky tumors to receive 45 to 65 Gy of pelvic RT alone or in combination with 5-FU/ MMC. Statistically significant benefits for complete response rate, local regional control, and colostomy-free survival all favored the combined-modality approach. The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) randomized 585 patients to receive 45 Gy of pelvic RT alone or in combination with 5-FU/MMC (1). The local failure rate was reduced by 46% in patients P.127
given the combined-modality approach (Table 10.9). A planned subset analysis revealed a significant local control benefit even in T1-2N0 patients. P.128

TABLE 10.8. Selected results of concurrent radiation, 5-fluorouracil, and mitomycin C

Chemotherapy regimens Radiation (dose/fractions/time) Primary tumor control Regional nodal control 5-year survival Reference 5-FU 1,000mg/m2/d CIVI for 8 d, d 1-4, d 29-32 (total dose/course 8,000 mg/m2) 30 Gy/15/d -21 31/34 (91%) (≤5 cm) 7/10 (70%) (>5 cm) NS 80% crude 15 MMC, 15 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d CIVI d 2-5, d 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 actual 16 MMC, 10 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d, CIVI d 1-4, d 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 17 MMC 10 mg/m2 IV bolus, d 1 and 43 (total dose/course 20 mg/m2) 5-FU 1,000 mg/m2/d, CIVI d 1-4, d 29-32 (total dose/course 8,000 mg/m2) 50 Gy/25-28/d 1-35 ± boost 21/22 (95%) (≤5 cm) 14/19 (74%) (>5 cm or T4) 3/4 77%, actuarial 18 MMC 10 mg/m2 IV bolus, d 1 and 29 (total dose/course 20 mg/m2) 5-FU 600 mg/m2/d, CIVI d 1-5 (total dose/course 3,000 mg/m2) 42 Gy/10/d 1-19 plus interstitial iridium-192 boost No data in original publication 57/70 (81%) (≥4 cm) NS NS 8 MMC 12 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d CIVI d 1-4 (total dose/course 4,000 mg/m2) 50-54 Gy/25-27/d 1-35 28/30 (93%) (≥5 cm) 42/56 (75%) (>5 cm or T4) NS 72%, actuarial 19 MMC 10-15 mg/m2 IV bolus d 1 5-FU 1,000 mg/m2/d CIVI d 1-4 (total dose/course, 4,000 mg/m2) 50 Gy/20/d 1-28 3/3 (100%) (≤5 cm) 11/13 (85%) (>5 cm or T4) 3/3 75%, actuarial 20 MMC 10 mg/m2 IV bolus d 1 5-FU 750 mg/m2/d CIVI d 1-5, d 43-7 (total dose/course, 4,000 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 21 MMC 15 mg/m2 IV bolus d 1, 43, 85 (total dose/course, 45 mg/m2) 5-FU 1,000 mg/m2/d, d 1-4, d 29-32 (total dose/course, 8,000 mg/m2) 40 Gy/20-24/d 1-24 then 10-13 Gy boost (split course) 13/17 (77%) (≤5 cm) 18/33 (55%) (>5 cm or T4) NS 74% 22 MMC 10 mg/m2 IV bolus d 2 5-FU 600-800 mg/m2/d d 1-5 (total dose/course 3,000-4,000 mg/m2) 38 Gy/19/d 1-21 then 18 Gy interstitial iridium-192 boost (split course) 23/33 (70%) (≤5 cm) 22/35 (63%) (>5 cm or T4) NS 65.5% 23 MMC 0.4 mg/kg IV bolus d 1 (maximum 20 mg) 5-FU, 5-fluorouracil; MMC, mitomycin C; CIVI, continuous intravenous infusion; NS, not stated; NA, not applicable; T, tumor invading adjacent organs; T4, tumor invading deep extradermal structures.

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TABLE 10.9. Randomized trials comparing radiation alone and chemoradiation

Group Arm N Complete responsesa (%) 3-year local controlb (%) Crude metastasis rate (%) 3-year survival (%) EORTC RT 52 54 55 21 64 RT/5-FU/MMC 51 80 69c 18 69 UKCCCR RT 285 30 39 17 58 RT/5-FU/MMC 292 39 61c 10 65 EORTC, European Organization for Research and Treatment of Cancer; UKCCCR, United Kingdom Coordinating Committee on Cancer Research; RT, radiation therapy; 5-FU, 5-fluorouracil; MMC, mitomycin C. aLocal control was assessed 6 weeks after completion of 45 Gy in EORTC trial (before boost) and 6 weeks after completion of 60 to 65 Gy radiation in the UKCCCR trial. bPatients requiring surgery to achieve local control after radiation were considered locally controlled in the EORTC trial. Patients who had surgery after completion of radiation or for treatment-related morbidity were counted as local failures in the UKCCCR trial. cDifference statistically significant at P <0.05.

Value of MMC in the Combined-Modality Regimen The RTOG/Intergroup study randomized 310 patients to receive 45 to 50.4 Gy of pelvic RT with 5-FU or the same radiation and 5-FU/MMC (2). A statistically significant increase in 4-year disease-free survival was observed in the patient cohort that received MMC, although toxicity was significantly greater. Substitution of cisplatin for MMC in combination with 5-FU and radiation therapy has been explored in phase 2 trials (3) with promising initial results. Induction therapy with 5-FU/cisplatin followed by RT/5-FU/cisplatin was compared with “standard” RT/5-FU/MMC in RTOG 98-11 (Table 10.10). The results showed equal overall survival of 69% at 5 years and equivalent 5-year disease-free survival (48% in the experimental arm and 56% in the standard arm). Hematologic toxicity was worse in the MMC-containing arm, although nonhematologic toxicities were similar. However, the colostomy rate was higher in the experimental arm (19% vs. 10%). The authors concluded that the experimental regimen was not superior to standard chemoradiation with 5-FU/MMC (4). Toxicity of Combined-Modality Therapy The acute toxicities of chemoradiation for anal cancer can be severe and include anemia, thrombocytopenia, desquamation and skin breakdown, diarrhea, infection, fluid and electrolyte derangements, pain, and fatigue. The RTOG/ECOG trial (2) reported a 3% rate of treatment-related death in the 5-FU/MMC arm. Aggressive use of barrier creams and emollients on the inguinal and perianal regions and antidiarrheal medications such as loperamide and diphenoxylate/atropine can be helpful in reducing the risk of infection and trauma to the perianal region. Opioid analgesics are often necessary for pain control and help decrease the frequency of stools. Blood counts should be monitored closely, particularly if MMC is used. Fecal contamination of areas of compromised perianal skin in the setting of neutropenia can pose a high-risk of sepsis. Overall, however, treatment breaks should be avoided if possible. A protocol of split-course chemoradiation with a planned 2-week treatment break produced a significantly higher local failure and colostomy rate (5). Late complications of chemoradiation for anal cancer can include painful fibrosis, lymphedema, anal stenosis and sphincter dysfunction, fistula formation, rectal bleeding, impotence, infertility, femoral neck fractures, and small-bowel injury.

TABLE 10.10. Randomized trials comparing radiation with 5-fluorouracil and mitomycin C to other chemoradiation regimens

Trial Arm N Disease-free survival (%) Colostomy rate (%) Toxicity Overall survival (%) RTOG/ECOG RT/5-FU 145 51 22 8% 67 Grade 4-5 RT/5-FU/MMC 146 73* 9* 26%* Grade 4-5 76 RTOG 98-11 Induction 5-FU/CDDP then 598 analyzable 56 19 75% non-heme 47% heme 69 RT/5-FU/CDDP 324 Grade 3-4 RT/5-FU/MMC 320 48 10* 76% non-heme 69 67% heme* Grade 3-4 RTOG, Radiation Therapy Oncology Group; ECOG, Eastern Cooperative Oncology Group; RT, radiation therapy; 5-FU, 5-fluorouracil; MMC, mitomycin C; CDDP, cisplatin; heme, hematologic toxicity; nonheme, nonhematologic toxicity. * Statistically significant at P <0.05.

Chemoradiation in HIV-Positive Patients HIV-positive patients are more likely to require treatment breaks and hospitalization during treatment. Dose reduction of chemotherapy and radiation or alterations of the treatment plan (such as omission of MMC) may be necessary for HIV-positive patients with a history of HIV/AIDS-related complications. However, sequential chemoradiation in anal cancer is markedly inferior to concurrent treatment and should not be used. Combined External Beam and Interstitial Radiation Therapy Lower-dose external beam radiation has been combined with chemotherapy and an interstitial iridium-192 implant in an effort to improve the therapeutic radio. Several European investigators have reported series showing average local control rates of 81% (range 73-89%), with 5-year survival of 70% (range 60-84%) (6,7,8,9,10,11). The rate of anal necrosis ranged from 2% to 76%, and many of these patients required salvage with APR, even if they were free of disease. Interstitial implantation after external beam radiotherapy may help some patients with residual disease to have a complete response. Dose of Radiation Although series have been published suggesting that highly selected early-stage patients can be cured with only 30 Gy with concurrent 5-FU/MMC after a local excision, several reports have suggested that radiation doses above 54 Gy are associated with improved local control and survival (12). Recently, attempts have been made to escalate the radiation dose used in combined-modality therapy, including the recent RTOG 98-11 randomized protocol. However, local control and survival for the best arm of this trial, which used doses up to 59.4 Gy with 5-FU/MMC, were not substantially better than the results obtained in the RTOG/ECOG study with 45 to 50.4 Gy and 5-FU/MMC. Increases in dose have
also been associated with greater toxicity. Daily fraction sizes should not exceed 2 Gy with concurrent chemotherapy due to enhanced acute and late toxicity. In select cases, radiation alone in doses of 60 to 70 Gy has been used to safely and successfully treat small, early-stage tumors. Intensity-Modulated Radiation Therapy (IMRT) IMRT can achieve tight conformality of the prescribed radiation dose to the target volume while increasingly sparing normal tissues, and is particularly useful in situations where the target is complex or concave in shape. In anal cancer, IMRT has been investigated as a means of decreasing dose to the skin, bone marrow, and bowel while maintaining or escalating the tumor dose. Salama et al. reported preliminary results from a series of 53 anal cancer patients treated with IMRT and concurrent chemotherapy (13). The median dose to the pelvic and inguinal lymph nodes was 45 Gy; the primary site and involved nodes were boosted to a median dose of 51.5 Gy; 48 of the patients received 5-FU/MMC and 15% of patients developed acute grade 3 gastrointestinal toxicity and 34% had grade 3 dermatologic toxicity, significantly better than the results from RTOG 98-11 (34% and 48%, respectively). There were no nonhematologic toxicities of grade 4 or higher. Local control was excellent with a 93% complete response rate and 84% colostomy-free survival at 18 months. These encouraging results are being confirmed in RTOG 0529, a phase 2 protocol. Tumor Regression After Chemoradiation The median time to complete tumor regression after combined-modality treatment is 12 weeks, and most local recurrences manifest within 2 years. Regression after treatment with radiation alone may be even more prolonged, and up to a year may need to elapse before a complete response is evident. Biopsy should only be performed if tumor persists on serial exams. Results from a phase 3 study suggested benefit to adding a radiation boost with cisplatin for patients with persistent disease after chemoradiation (2), but this was more likely due to continued prolonged tumor regression from the initial therapy TREATMENT OPTIONS ACCORDING TO STAGE Treatment options according to stage for anal cancer are contained in Table 10.11. Stage 0

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

TABLE 10.11. Treatment options for anal cancer
Stage Treatment options 0 Surgery I Radiation Chemoradiation Surgery II Chemoradiation Surgery III Chemoradiation Surgery IV Palliative surgery Palliative irradiation Palliative chemoradiation Clinical trial

Stage I

• 
  Small, well-differentiated tumors of the anal margin not involving the anal sphincter can be treated with wide local excision.
  
• 
  All other stage I tumors of the anal margin and anal canal are treated with chemoradiation with 5-FU/MMC.
  
• 
  Patients who cannot tolerate chemotherapy may be treated with radiation alone.
  
• 
  Surgical salvage with APR is reserved for residual cancer in the anal canal after chemoradiation.
  

Stage II

• 
  Chemoradiation with 5-FU/MMC is the recommended initial approach.
  
• 
  Patients who cannot tolerate chemotherapy may be treated with radiation alone.
  
• 
  Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
  

Stage IIIA Stage IIIA anal cancer presents clinically as stage II anal cancer in most patients but is upstaged to IIIA by presence of perirectal nodal disease or adjacent organ involvement. Endoscopic ultrasound (endoanal or endorectal) may aid in assessing perirectal lymph nodes.

• 
  Chemoradiation with 5-FU/MMC is the recommended initial approach.
  
• 
  Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
  

Stage IIIB Though the cure of this stage is possible, the involvement of inguinal lymph nodes (unilateral or bilateral) constitutes a poor prognostic sign.

• 
  Chemoradiation with 5-FU/MMC is the recommended initial approach.
  
• 
  Surgical salvage with APR is reserved for residual disease in the anal canal after chemoradiation.
  
• 
  Because of the poor prognosis of these patients, they should be recruited for clinical trials whenever possible.
  

Stage IV There is no standard chemotherapy regimen for stage IV disease. Chemotherapy with 5-FU/MMC or cisplatin has been reported to give a 50% response rate, with a median survival of 12 months (14). Palliation of symptoms constitutes the backbone of management. Patients with stage IV anal cancer should be enrolled in clinical trials.

• 
  Palliative chemotherapy
  
• 
  Palliative radiation therapy to localized symptomatic metastases
  
• 
  Palliative surgery
  
• 
  Palliative combined chemotherapy and radiation therapy
  
• 
  Clinical trials
  

PERSISTENT OR RECURRENT ANAL CANCER Persistent anal cancer can be managed according to Fig. 10.2. Local recurrences after initial treatment with either chemoradiation or surgical resection can be effectively controlled by alternate treatment options, including:

• 
  Surgical resection after chemoradiation (salvage APR)
  
• 
  Salvage radiation with or without chemotherapy if normal tissue tolerances permit
  
• 
  Isolated recurrence in the inguinal area may be managed with inguinal node dissection or, if possible, with local radiation with or without chemotherapy
  

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Fig. 10.2. Management of anal cancer after definitive chemoradiation. (PR, partial response; CR, complete response; APR, abdominoperineal resection; XRT, radiation therapy.)

Follow-up Patients with anal cancer should be monitored as follows:

• 
  Every 3 months for the first 3 years
  
• 
  Every 6 months for an additional 2 years
  
• 
  Annually thereafter
  

The following specific recommendations should be undertaken:

• 
  Medical history
  
• 
  Physical examination, including digital rectal exam and palpation of inguinal nodes
  
• 
  Complete blood counts
  
• 
  Liver function tests
  
• 
  Chest radiograph yearly
  
• 
  CT scan of the pelvis every 6 to 12 months for the first 3 years
  

Prognosis Frequency and 5-year survival of anal canal carcinoma patients by stage is shown in Table 10.12. Prevention Awareness of the disease by the physician and the recognition of a high-risk group (homosexual men, women with cervical or vulvar cancer) may aid patients by early detection. There are currently no standard recommendations for screening for anal cancer in high-risk populations. Anoscopy with anal cytology should be undertaken in patients with abnormal discharge, bleeding, pruritis, bowel irregularity, rectal or pelvic pain, and those with a history of previous preinvasive lesions or abnormal Pap smears. Other patients who should be screened include HIV-negative men with a history of analreceptive intercourse, HIV-positive men and women with CD4 cell counts less than 500/mm3, and HIV-positive and -negative women with a history of high-grade cervical intraepithelial neoplasia (CIN).

TABLE 10.12. Frequency and 5-year survival of anal canal carcinoma patients by stage in a series of 270 patients
Stage Frequency at presentation (%) 5-year survival (%) T1 9 86 T2 51 86 T3 30 60 T4 10 45 Node-negative 87 76 Node-positive 13 54 Source: Data from Touboul E, Schlienger M, Buffat L et al. Epidermoid carcinoma of the anal canal. Results of curative-intent radiation in 270 patients. Cancer 1994;73(6):1569-79.

Anal Pap smears have a reported sensitivity of approximately 70% (equal to that associated with uterine cervix Pap testing). AIN is graded like CIN and the treatment of AIN is similar to the treatment for CIN in women. It may include electrocautery, cryoablation, or laser ablation.
A vaccine against the transmission of high-risk HPV serotypes has recently been approved for use in the prevention of cervical cancer in women, and this represents a promising strategy for prevention of anal cancer. A trial of HPV prevention in men is ongoing.