Cancer of the anal canal

oncology

1. Cancer of the Anal Canal

2. INTRODUCTION C ancer of the anal canal is an uncommon malignancy, accounting for approximately 1.5% to 2% of all cancers of the lower alimentary tract in the United States. The risk of anal canal cancer has increased over the past 30 years with its association with HPV and HIV.

3. ANATOMY The anal canal is a 4-cm-long structure that passes downward and backward from the rectal ampulla (level of pelvic fl oor ) to the anus (anal verge). The proximal border of the anal canal clinically corresponds to the anal sphincter at the level of the puborectalis muscle (palpable as the anorectal ring on digital rectal examination). This is where the rectum enters the puborectalis sling, made by fibers from both sides. The distal end of the anal canal is at the level of the anal verge, where the groove between the internal sphincter and the subcutaneous part of the external sphincter is palpable. This also is the level of the squamous-mucocutaneous junction and the perianal skin.

4. At the dentate or pectinate line, which is a line that corresponds to the anal valves and anal sinuses, a zone of transitional mucosa is often present. This is defined as the zone interposed between uninterrupted colorectal-type mucosa above and uninterrupted squamous epithelium below. Distal to the dentate line, the anal canal is lined by nonkeratinizing squamous epithelium, which merges with perianal skin (true epidermis). This junction has historically been called anal verge or anal margin.

5. It follows that two distinct categories of tumors arise in the anal region. Tumors that develop from mucosa (columnar, transitional, or squamous ) are true anal canal cancers tumors that arise from skin at or distal to the squamous-mucocutaneous junction are termed anal margin tumors

6. ETIOLOGY AND RISK FACTORS HPV infection Immunosuppression Cigarrate smoking

7. NATURAL HISTORY Anal cancer is predominantly a locoregional disease, with possible direct extension to surrounding tissues and lymphatic dissemination to inguinal and pelvic nodes; hematogenous distant metastasis is a relatively rarer occurrence . Anal canal cancers constitute 75% of all lesions, and only 25% are anal margin tumors . Local spread may be present in approximately 50% of cancers at diagnosis with involvement of the anal sphincter or surrounding soft tissues . Extension to the rectum and perianal skin also may occur. Invasion of the vaginal septum is more common than invasion of the prostate gland because of the presence of Denonvillier’s fascia in men, which acts as a barrier

8. Lymphatic drainage is dependent on the anatomic location of the primary tumor . Tumors that arise distal to the dentate line drain to inguinal lymph nodes ( superficial and deep), and those above the dentate line spread primarily to the internal iliac system, and with more proximal lesions, spread occurs to the inferior mesenteric group. The regional nodes are considered to be inguinal ( superficial and deep femoral), internal iliac, and perirectal ( anorectal , perirectal , and lateral sacral). All other nodal groups represent sites of distant disease. The incidence of involvement of inguinal nodes is directly proportional to the size and extent of the primary tumor . Overall, this risk may be approximately 10% at diagnosis but may increase to 20% for tumors larger than 4 cm, and with T4 disease, this may be as high as 60%.

9. Distant metastasis may occur to any organ, but the liver and lungs are most frequently involved. Overall, distant metastases are relatively rare. At diagnosis, only 5% to 10% of patients will be found to have distant disease. After curative treatment, the risk of distant disease varies, ranging between 10% and 30%, and depends on the initial tumor (T) stage. The risk of distant metastasis also increases with the number of regional nodes involved

10. CLINICAL PRESENTATION AND DIAGNOSIS Most patients with anal cancer are first seen with rectal bleeding. This occurs in approximately 50% of patients; 30% experience pain or the sensation of a rectal mass. Pruritus in 30% Altered bowel habbits -rare A common concern with most anal neoplasms is the frequent delay in diagnosis resulting from confusion with more common, benign conditions. Thus, the clinician must maintain a high index of suspicion when evaluating lesions of the anal canal and margin. An interval of 4 to 6 months may ensue between onset of symptoms and diagnosis in up to 50% of patients.

11. WORK UP Physical examination Regional lymph nodes Adjacent organs for direct invasion Anogenital areas for concurrent malignancies Proctoscopy &Biopsy of primary tumor Fine-needle aspiration biopsy or simple excision of enlarged inguinal nodes Chest radiograph CT/MRI of abdomen and pelvis Liver and renal chemistry Complete blood cell count HIV antibody assay, if risk factors are present

12. STAGING 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 invades adjacent organ(s) (e.g., vagina, urethra, bladder) Direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or the sphincter muscle(s) is not classified as T4

13. 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 nodes and/or bilateral internal iliac and/or inguinal lymph node

14. HISTOPATHOLOGIC CLASSIFICATION The staging system applies to all carcinomas arising in the anal canal, including carcinomas that arise within anorectal fistulae . Melanomas, carcinoid tumors , and sarcomas are excluded from this staging system. Most carcinomas of the anal canal are squamous cell carcinomas. The terms “transitional cell carcinoma”and “ cloacogenic carcinoma” have been abandoned because these tumors are now recognized as nonkeratinizing types of squamous cell carcinoma.

15. WHO Classification Squamous cell carcinoma ( basaloid,cloacogenic,transitional,mucoepidermoid,verrucous mucoepidermoid ) Adenocarcinoma (Rectal type, of anal glands ,within anorectal fistula ) Mucinous adenocarcinoma Small cell carcinoma/ Neuroendocrine tumors Undifferentiated carcinoma

16. WHO Classification Squamous cell carcinoma ( basaloid,cloacogenic,transitional,mucoepidermoid,verrucous mucoepidermoid ) Adenocarcinoma (Rectal type, of anal glands ,within anorectal fistula ) Mucinous adenocarcinoma Small cell carcinoma/ Neuroendocrine tumors Undifferentiated carcinoma

17. TREATMENT Carcinoma of the anal canal is a chemoradiotherapy -sensitive tumor and therefore is often a curable cancer The treatment of anal canal cancer has changed from radical surgery to a combined approach of organ-sparing chemotherapy and radiotherapy and constitutes one of the success stories in recent oncologic management

18. Surgery Surgical treatment was the primary therapy 20 to 35 years ago, but it has been replaced by sphincter-sparing therapy with combination chemoradiotherapy . Surgical therapy is now used most often as a method of salvage. Surgical treatment, when it was used as a primary therapy, required an abdominoperineal resection (APR). This consisted of wide local excision of the anus, to include the levator ani muscles and contents of the ischiorectal fossa . The operation results in a permanent colostomy, as well as loss of sexual function, in most patients. Overall, 5-year survival rates were approximately 50-70% in different serieses .

19. Tumor size, depth of invasion, and presence of inguinal or pelvic lymph nodes have been shown to have prognostic significance in terms of higher risk of local recurrence and worse survival.

20. Radiotherapy Radiotherapy has been used for treatment of anal cancers since the early 1900s, especially in Europe, whereas surgery was the treatment of choice in the United States. Most series have demonstrated survival rates on the order of 45% to 65%.

21. As with surgery, better outcomes have been seen with smaller tumors and in patients with disease negative inguinal lymph nodes. Likelihood of survival and local recurrence also depended on the extent of the tumor’s circumferential involvement of the anal canal. For tumors with a circumferential involvement of 25% and 50%, survival rates of 71% and 61%, respectively, were demonstrated. Survival decreased to 19%, however, with 75% or more circumferential involvement. Local recurrence rates were 16%, 28%, and 100%, respectively.

22. Complications of radiotherapy may result in the need for colostomy in 2% to 10% of patients. Overall, results with a definitive course of radiotherapy are similar to if not better than results with surgery, especially for tumors smaller than 4 cm in diameter. Radiotherapy allows sphincter preservation, thus making it a more preferred option compared with surgery.

23. Combined-Modality Treatment Combined-modality therapy was described initially by Nigro and coworkers . This was a preoperative regimen inspired by reports that 5-fl uorouracil (5-FU) potentiated the effects of radiotherapy on gastrointestinal tumors. This regimen consisted of delivering 30 Gy in 15 fractions to the primary tumor and pelvic lymph nodes with concurrent 5-FU (1000 mg/m2 as a 4-day continuous infusion) and mitomycin C (MTC) (15 mg/m2 bolus injection) chemotherapy, and APR 6 weeks after completion of the protocol.

24. Promising early results, however, suggested that surgery may not be necessary. The series of Nigro and colleagues included 31 patients who underwent surgery and 73 who received chemoradiotherapy alone. Twenty-two of the 31 surgical specimens had no evidence of disease (NED) on histopathologic examination, and on long-term follow-up evaluation, an NED rate of 79% was found for the surgical patients, compared with 82% NED for patients receiving combined-modality treatment. Overall death rates were 6% in patients with tumors smaller than 4 cm and 26% for those larger than 4 cm

25. Most of the series show good survival and local control rates in the range of 60% to 90%.

26. Following up a trial from Princess Margaret Hospital,EORTC (European Organization for Research and Treatment of Cancer) and the UKCCR (United Kingdom Coordinating Committee for Cancer Research) have done two randomized studies comparing radiation alone with combined radiation therapy and 5-FU–MTC chemotherapy.

27. The EORTC trial a locally advanced primary tumor (T3 or T4) or regional lymph node involvement was required for eligibility. Initial radiotherapy consisted of 45 Gy to the pelvis in both trials but the boost was different. a 20-Gy boost was delivered to partial responders 6 weeks after completion of therapy and complete responders received 15 Gy . The chemotherapy regimen consisted of 5-FU, 750 mg/m2 per 24 hours on days 1 to 5 and 29 to 33, with a single 15-mg/m2 dose of MTC on day 1.

28. UKCCR trial Any stage of disease was eligible for the UKCCR trial. a 15- to 25-Gy boost was given to patients who had a more than 50% response, and those who had a less than 50% response underwent surgery. 5-FU was given at a dosage of 1000 mg/m2 per 24 hours on days 1 to 4 and on days 29 to 32 or 750 mg/m2 per 24 hours on days 1 to 5 and 29 to 33, with a single dose 12 mg/m2 MMC on day 1.

29. The rate of sphincter preservation also appears to be higher in patients who receive combined-modality therapy; rates of 85% to 100% were reported by several studies.

30. U.S. RTOG–ECOG trial (RTOG 87–04/ ECOG 1289) The need for MTC in combined-modality therapy of anal cancers was evaluated This was the first study comparing two methods of chemoradiotherapy in patients with anal cancer. One study arm used 5-FU alone with radiotherapy, and the other arm used 5-FU and MTC with radiotherapy.

31. CONCLUSION Two of the four treatment-related deaths in the MTC regimen group were believed to be due to failure to follow protocol dosage-reduction guidelines for the second MTC dose. The investigators concluded that despite the greater toxicity, the use of MTC in a definitive complete response regimen for anal cancer was justified .

32. The RTOG study 98–11 compared external beam radiotherapy (EBRT) with 5-FU plus MTC, given during weeks 1 and 5, and two courses of induction 5-FU and cisplatin , followed by concurrent EBRT plus 5-FU and cisplatin , with radiotherapy beginning on day 57. The study hypothesis was that induction chemotherapy may reduce tumor bulk before combined chemoradiation therapy and thereby provide better local control and colostomy-free survival; an additional two cycles of chemotherapy may positively affect the distant metastatic rate.

33. The trial enrolled 644 non–HIV-infected patients with squamous cell cancer of the anal canal. A preliminary report found no significant difference in rates of 5-year disease-free survival (48% and 56% for the experimental and control arms, respectively) or overall survival (69% in both groups), but the colostomy rate was significantly higher in the cisplatin treatment group. Although hematologic toxicity was worse in the MTC group, nonhematologic toxicity and late radiotherapy-related toxicity rates were similar in the two groups. The investigators concluded that a 5-FU–cisplatin combination was not superior to the standard regimen of 5-FU plus MTC.

34. ACT II trial randomized trial of 950 non-HIV infected patients with anal SCC (30 percent node-positive, 43 percent T3/4) . Treatment consisted of RT in both arms (50.4 Gy in 28 fractions) with concurrent infusional 5-FU (1000 mg/m2 per day on days 1 to 4 and 29 to 32) and either cisplatin (60 mg/m2 on days 1 and 29) or mitomycin (12 mg/m2 day 1 only). There was a second randomization to receive or not receive maintenance chemotherapy starting four weeks after chemoradiotherapy (two courses of cisplatin plus 5-FU, administered four weeks apart).

35. RESULTS patients receiving mitomycin had more acute grade 3 or 4 hematologic toxicity (25 versus 13 percent), but no higher rates of febrile neutropenia (3.1 versus 3.2 percent) during chemoradiotherapy . Rates of grade 3 or 4 nonhematologic toxicity were similar (61 versus 65 percent). The complete response rate at six months (the primary endpoint) was 95 percent with both cisplatin and mitomycin , and the three-year colostomy rate was not significantly different (13.7 versus 11.3 percent). Three year RFS was similar with or without the use of maintenance therapy (75 percent for both arms) as was overall survival (84 versus 85 percent).

36. Mx Algorithm

37. Anal margin Cancer Tumors of the anal margin or perianal region are treated much as for skin cancers. treatment recommendation is local excision. If the tumor is large enough such that it requires an APR, treatment as for an anal canal cancer with combination chemoradiotherapy

38. Adenocarcinoma of the anal canal Adenocarcinoma of the anal canal also can occur, arising from anal ducts. This is a fairly uncommon entity. In general, such tumors are treated with preoperative chemoradiotherapy , followed by an APR. The chemotherapy used in these instances is 5-FU, in a regimen appropriate for adenocarcinoma , with radiotherapy fields appropriate for anal canal cancer.

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40. Radiotherapy Techniques Photon energy of 6 MV or greater is indicated for irradiation of pelvic fields . In the past, large anteroposterior (AP) and posteroanterior (PA) fields were used for comprehensive coverage of the area of primary disease and inguinal nodes. Although this still is an appropriate technique, alternate- field arrangements also have been used. One such technique suggests that supplementary inguinal node radiation be given, preferably with electrons. In this alternate technique, initial pelvic fields include AP and PA fields to include the pelvis, anus, perineum, and inguinal lymph nodes. The lateral inguinal nodes should be irradiated using the AP field , but not the PA field , to minimize radiation dose to the femoral head and neck. The PA field should extend 2 cm lateral to the sciatic notch and should be designed to include the primary tumor and pelvic nodes.

41. designed to incorporate the lateral inguinal nodes not included in the posterior field . The superior border of the initial pelvic fields starts at L5-S1 and is dropped to the level of the inferior border of the sacroiliac joints at 36 Gy . The inferior border includes the anus, with at least a 2.5-cm margin. The initial dose is 36 Gy given at 1.8 Gy per fraction.

42. Another method of treatment uses a three- field technique as for rectal cancer, with one posterior and two lateral fields . The PA field is large enough to include the lateral inguinal nodes. The dose to the inguinal nodes is calculated and typically is approximately one third of the contribution from the PA field . The remaining dose is supplemented with inguinal electron fields .