Anal Cancer

1. Anal Cancer

4. Anatomy • Four different types of epithelium : 1.perianal skin anal verge 2.(pale-colored zone) pectinate line 3.mucosal folds of the anal valves, 4. transitional epithelium

5. The major lymphatic pathways flow to three lymph node systems. • The perianal skin, the anal verge, and the canal distal to the dentate line drain predominantly to the superficial inguinal nodes • Lymphatics from around and above the dentate line flow with those from the distal rectum to the internal pudendal, hypogastric, and obturator nodes of the internal iliac systems. • The proximal canal drains to the perirectal and superior hemorrhoidal nodes of the inferior mesenteric system.

6. Pathologic Classification • SCC:(85% to 90% ) subtypes large-cell keratinizing and nonkeratinizing, and basaloid or cloacogenic • Adenocarcinomas Adenocarcinomas from the rectal-type mucosa in the upper canal are classified as primary rectal cancers. • SCC with mucous microcysts, small cell, and undifferentiated cancers. • perianal skin cancers Most are squamous cell cancers, with occasional basal cell cancers and skin adnexal adenocarcinomas.

7. Epidemiology • one-tenth as common as cancers of the rectum • Cancers arise in the canal with three to four times the frequency of perianal cancers • more common in women • The risk of anal cancer increases with age; the median age at diagnosis is from 60 to 65 years.

8. Risk Factors • Sexual activity • Sexually transmissible viruses • Human papillomavirus infection(type 16 ) • HIV infection  • Chronic immunosuppression not due to HIV • Cigarette smoking

9. Natural History • HPV infection is an initiating event in the majority of cases, but HPV DNA integration is necessary for the transition from low-grade to high-grade • Loss of heterozygosity at 11q23 • In HIV-negative patients: allele losses as 17p, 18q, and 5q • In HIV-positive patients: microsatellite instability,

10. Natural History • direct extension • lymphatic pathways • Hematogenous metastases are less common Lymphatic invasion occurs relatively early.

11. Natural History • Extrapelvic metastases : fewer than 10% of patients. most frequently in the liver and lungs • Relapse after initial treatment is more common in the area of the primary tumor and the pelvic lymph nodes than in extrapelvic organs. • Locoregional relapse rates of up to about 30% and extrapelvic failure rates up to about 20% are common • Overall 5-year survival rates = of 55% to 65%.

12. Perianal cancers • grow locally and may extend into the anal canal. When the site of origin is in doubt, it is conventional to classify the cancer as arising in the anal canal • The ipsilateral inguinal nodes are the most common site of metastasis and are abnormal in from 5% to 20% of cases. • Overall 5-year cause-specific survival rates usually exceed 80%.

13. Clinical Presentation • Nonspecific • Bleeding 1/2 • anal discomfort • awareness of an anal mass • Pruritus • anal discharge • Pain • alteration in bowel habits • asymptomatic tumors (an inguinal node mass) • Unsuspected microinvasive carcinoma is sometimes found in mucosa removed at hemorrhoidectomy

14. Diagnostic Work-Up • History and physical examination • Biopsy • anorectal examination • Physical examination • HIV • clinically suspicious nodes should be biopsy • Abdominal and pelvic CT or MRI • CXR • Transanorectal ultrasonography • CBC, R and L FT and, +_ HIV antibody

15. Staging • Spread to pelvic node groups, including the external iliac, common iliac, and sigmoid nodes, is classified as metastasis (M1) • For perianal cancers, the regional nodes are the ipsilateral inguinal nodes.

16. StagingAnal Canal TNM Classification

18. Perianal Skin TNM Classification

19. Prognostic Factors • M • T • N • Age and performance status ? • Women have a better prognosis • Hemoglobin levels ≤10 g/L poor Px • HIV-positive patients high viral load, low lymphocyte CD4+ counts, and AIDS poor Px

20. Treatment of Anal Canal Cancer • The combination of RT, (5-FU), and mitomycin is the standard • Radiation-based regimens produce survival rates at least equal to those of surgical series, while allowing preservation of anorectal function in the majority of patients.

21. Combined-Modality Therapy • Primary Tumor • Lymph Node Metastases • Extrapelvic Metastases

22. Primary Tumor • 5-FU (1,000 mg/m2/day for 4 days or 750 mg/m2/day for 5 days), by continuous peripheral intravenous infusion in the first and final weeks of radiation treatment • mitomycin (12 mg/m2) by bolus intravenous injection on day 1 of the first course of chemotherapy • The radiation dose was 45 Gy in 20 to 25 fractions in 4 to 5 weeks or 30 GY(2OOcGY)

23. CMT • The patients were reassessed clinically 6 weeks after treatment. • not regressed by at least 50%: • Surgery • 15 Gy in six fractions by a perineal field or 25 Gy over 2 to 3 days by iridium-192 implant • Treatment-related morbidity requiring surgery • After 6 weeks, boost irradiation of 15 Gy (if complete clinical response) or 20 Gy (after partial response) was given by external-beam or interstitial irradiation.

24. CMT • Chemotherapy is not given during the boost radiation • 5YS : 80% for cancers ≤2 cm (T1) 70% for tumors 2 to 5 cm (T2) 45% to 55% for (T3 or T4) 65% to 75% overall • local control rates (excluding salvage treatment) are 90% to 100% (T1) 65% to 75% (T2) 40% to 55% (T3 or T4 60% overall • Because of case mix and the preponderance of advanced cancers in many series, generally only about two-thirds of all patients treated retain anorectal function. No more than about 5% of patients overall have lost anorectal function because of treatment-related complications

25. to improve results • increases in total radiation dose • shortening of overall treatment time • exploration of combinations of radiation and chemotherapy radiation, 5-FU, and cisplatin radiation, 5-FU, and mitomycin

26. random biopsies from the site of the primary tumor, and/or abnormal nodes Biopsies directed only to areas suspected clinically of harboring residual or recurrent cancer • A negative biopsy does not exclude the possibility of cancer regrowth .Residual masses at the site of the original anal cancer may take several months to resolve fully after chemoradiation or radiation therapy alone .Most authors now recommend biopsy only when persistent cancer is suspected clinically.

27. Treatment of local residual cancer or recurrence is planned according to the extent of disease, both locoregional and extrapelvic, and the potential for preserving anorectal function. further radiation and chemotherapy Surgery(APR) CT

28. Lymph Node Metastases • Lymph node metastases can be eradicated by the same radiation and chemotherapy doses effective against the primary tumor. • first diagnosed, pelvic nodes are present in about 30% and inguinal node metastases are detectable clinically in 15% to 20%. • Approaches to the management of inguinal node metastases vary from radical dissection to excision or needle biopsy of enlarged nodes followed by radiation therapy or radiation and chemotherapy . Local control of the involved inguinal nodal areas is very good, usually ≥80% . However, 5-year survival rates are usually 10% to 20% lower than in those who do not have demonstrable node metastases

29. Lymph Node Metastases • Prophylactic or therapeutic radical dissection of the inguinofemoral nodes is not necessary and carries a high risk of late morbidity . • Elective irradiation of clinically normal inguinal node areas, with or without chemotherapy, reduces the risk of late node failure in that area to <5% . • Control of subclinical pelvic node metastases by irradiation and chemotherapy نتیجه :درمان غدد لنفاوی مثل تومور اولیه CMT

30. Extrapelvic Metastases • 10% to 20% • Deaths from extrapelvic metastases alone are relatively infrequent. • rate of metastasis in CMT was 10%, compared to 17% in RT

31. Radiation Therapy alone • The use of radiation therapy alone, either brachytherapy or external beam, has been greatly reduced since the confirmation of improved outcome of combined modality therapy. Radiation alone is now recommended mainly to patients who are unable to undergo radiation plus chemotherapy, especially elderly patients ,or for the treatment of smaller cancers up to about 3 to 4 cm in size

32. Surgery • Surgery is the principal treatment for anal intraepithelial neoplasia • extensive tumors that have destroyed the competence of the anal sphincters or fistulized into the vagina. These patients may be managed by APR with postoperative CRT, using drug schedules similar to those for primary treatment and radiation doses of about 45 Gy in 5 weeks. S →CRT colostomy → CRT→immediate or delayed resection • Serious postradiation morbidity may require surgical management,

33. Local excision • Local excision small well-differentiated squamous cell cancers that have not invaded the sphincter muscles and are located distal to the dentate line • pararectal or superior hemorrhoidal system lymph node metastases were associated with <5% of well-differentiated squamous cell cancers <2 cm in size . • Excision of small cancers, especially of the distal canal and anal verge, is more expedient and generally associated with less morbidity than radiation-based treatments.

34. Perianal Cancer • The most common histologic type of invasive cancer of the perianal skin is SCC. BCC and adenocarcinomas • Wide local excision with a 1-cm margin for all histologic types. • Radiation alone or in combination with chemotherapy is also effective ,but may produce symptomatic long-term skin changes. • Radiation-based protocols identical to those for anal canal cancer are preferred when anal continence would be impaired by surgery.

35. perianal cancer • Perirectal and pelvic node metastases are uncommon unless the cancer involves the anal canal extensively • The risk of inguinal node metastases is about 10%, primarily with category T3 or T4 tumors or poorly differentiated cancers.

36. Rt lymph node ( perianal cancer) • Elective bilateral inguinal nodal irradiation • T3 or T4 tumors • poorly differentiated cancers • RT for abnormal inguinal nodes :similar to that for anal canal cancer • RT for pelvic nodes: if the anal canal is invaded.

37. uncommon • The principles of management for the uncommon basal cell and adenocarcinomas of the perianal skin are similar to those for these histological types elsewhere on the skin.

38. Patients with HIV/AIDS • The median age :the 40 decade • increased risk of toxicity, particularly in the perineal skin and anorectal mucosa ( modifications should be based on the severity of side effects in each individual patient ) • Two factors may predict for heightened acute normal tissue toxicity and/or poor cancer control, namely, a CD4 count <200/µL at the start of treatment or the presence of AIDS

39. Concurrent antiretroviral therapy does not reliably reduce the severity or incidence of toxicity of radiation and chemotherapy

40. Adenocarcinomas • Most arise from rectal-type mucosa • Tx similarly to those that arise in the rectum • The uncommon adenocarcinomas that develop from anal glands or in fistulae have also usually been managed by APR . (adjuvant CRT ? )

41. Small Cell Carcinomas • rare • early metastases • a poor prognosis • Tx= surgery or radiation • Systemic chemotherapy similar to that used for small cell cancers that arise elsewhere may be combined with radiation for the primary tumor and used to treat metastases, but responses are generally limited.

42. Radiation Therapy TechniquesAnal Canal • Only well-differentiated squamous cell cancers ≤2 cm in size situated in the distal canal appear to have a risk of nodal metastases <5% • Metastases in the pararectal and internal iliac nodes in up to 30% and in inguinal nodes in up to 20% has encouraged most centers to irradiate these node groups electively • planning target volumes may be extensive • Acute and late morbidity can be reduced by avoiding tangential irradiation to the sensitive skin of the perineum and external genitalia or, if techniques that require tangential irradiation are elected, by the use of daily fractions ≤2 Gy. The irregularities and curvatures of the perineum and lower pelvis make homogenous radiation distributions difficult to achieve. Measurements with in vivo thermoluminescent dosimeters found dose variations of as much as 10% from predicted levels in the region of the anocutaneous junction .Computerized dose planning systems may not provide accurate values at skin–air interfaces. Care must be taken as far as possible to avoid regions of excessive dose.

43. Whole-Pelvis Techniques • Many radiation oncologists prefer to treat the primary tumor and the posterior pelvic and inguinal nodes in continuity. • An A-P–opposed pair of fields is the most common arrangement: prone supine

44. Whole-Pelvis Techniques • upper border :lumbosacral junction if the intent is to include the common iliac, upper presacral, and rectosigmoid nodes in the treated volume. • This border is commonly moved down during treatment to the lower end of the sacroiliac joints, thus encompassing only the perirectal, lower presacral, and internal iliac nodes (and, if the volume is sufficiently wide, the lower external iliac nodes), in order to lessen the risk of radiation enteritis

45. Whole-Pelvis Techniques • upper : lumbosacral junction or lower end of the sacroiliac joints • inferior :3-cm distal to the lowermost extension of the primary tumor • lateral borders: • asymmetric and/or matched fields

46. The location and depth of the inguinal nodes should be obtained by axial imaging .When asymmetric and/or matched fields are used, there is potential for both over and under dosage .Considerable care is required in planning and in patient positioning.

47. Posterior Pelvis Techniques • If it is elected to irradiate the posterior pelvic tissues and inguinal nodes discontinuously for all or part of the prescription, or to treat the posterior pelvis only, the volume irradiated is reduced compared with that of whole-pelvis techniques. • The anal canal and posterior pelvic nodes may be treated by multiple beam techniques. These are commonly three- or four-field techniques, such as (AP/PA) fields, and opposed lateral beams, analogous to those used for rectal cancer.

48. IMRT :Posterior Pelvis Techniques • multiple-field conformal techniques, including (IMRT), can re-duce the mean dose to the perineum and external genitalia by about 30%. • Although these techniques generally include beams tangential to the perineum, doses of at least 54 Gy in 1.8-Gy fractions can be delivered with only occasional need for treatment breaks due to skin or gastrointestinal toxicity . • IMRT techniques have described the use of patient immobilization devices, but have not discussed the possible effects on dose distribution of internal organ motion.

49. Dose–Time Factors • megavoltage equipment. • without concurrent chemotherapy. primary tumor of 60 to 65 Gy, in 1.8- to 2-Gy fractions, after 40 to 45 Gy the volume is reduced. the primary tumor with a margin of 2 to 3 cm(by interstitial therapy, by external-beam therapy with a perineal field, or by multifield techniques ) A dose of 15 to 20 Gy in 2 weeks is given to the reduced volume. If low–dose-rate interstitial radiation is used, a dose of 15 to 20 Gy at 0.5 cm from the plane of the implant over 24 hours (Paris system) is recommended Proven or suspected metastases in the inguinal nodes and abnormal perirectal or pelvic nodes should be treated to the same total dose as the primary tumor.