Anal Cancer

Table of Contents

General Information
Cellular Classification
Stage Information
TNM definitions
Stage 0
Stage I
Stage II
Stage IIIA
Stage IIIB
Stage IV
Treatment Option Overview
HIV and anal cancer
Stage 0 Anal Cancer
Stage I Anal Cancer
Stage II Anal Cancer
Stage IIIA Anal Cancer
Stage IIIB Anal Cancer
Stage IV Anal Cancer
Recurrent Anal Cancer

General Information

Anal cancer is an often curable disease. The 3 major prognostic factors are site (anal canal versus perianal skin), size (primary tumors less than 2 centimeters in size have a better prognosis), and differentiation (well-differentiated tumors are more favorable than poorly differentiated tumors).

Anal cancer is an uncommon malignancy, accounting for only a small percentage (4%) of all cancers of the lower alimentary tract. Clinical trials have evaluated the roles of chemotherapy, radiation therapy, and surgery in the treatment of this disease.1,2
Overall, the risk of anal cancer is rising, with data suggesting that individuals with human papillomavirus and male homosexuals, in particular, are at increased risk of anal cancer.3-5

References:

1. Martenson JA, Lipsitz SR, Lefkopoulou M, et al.: Results of combined modality therapy for patients with anal cancer (E7283): an Eastern Cooperative Oncology Group study. Cancer 76(10): 1731-1736, 1995.

2. Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. Journal of the American College of Surgeons 185(5): 494-505, 1997.

3. Daling JR, Weiss NS, Hislop TG, et al.: Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. New England Journal of Medicine 317(16): 973-977, 1987.

4. Palefsky JM, Holly EA, Gonzales J, et al.: Detection of human papillomarvirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Research 51(3): 1014-1019, 1991.

5. Ryan DP, Compton CC, Mayer RJ: Carcinoma of the anal canal. New England Journal of Medicine 342(11): 792-800, 2000.

Cellular Classification

Squamous cell (epidermoid) carcinomas make up the majority of all primary cancers of the anus. The important subset of cloacogenic (basaloid transitional cell) tumors constitute the remainder. These two histologic variants are associated with human papillomavirus infection.1 Adenocarcinomas from anal glands or fistulae formation and melanomas are rare. Treatment of anal melanoma is not included in this summary.

References:

1. Palefsky JM, Holly EA, Gonzales J, et al.: Detection of human papillomarvirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Research 51(3): 1014-1019, 1991.

Stage Information

The anal canal extends from the rectum to the perianal skin and is lined by a mucous membrane that covers the internal sphincter. The following is a staging system for anal canal cancer that has been described by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer.1,2 Tumors of the anal margin (below the anal verge and involving the perianal hair-bearing skin) are classified with skin tumors.

TNM definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor 2 cm or less in greatest dimension T2: Tumor more than 2 cm but not more than 5 cm in greatest dimension T3: Tumor more than 5 cm in greatest dimension T4: Tumor of any size that invades adjacent organ(s), e.g., vagina, urethra, bladder (involvement of the 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 nodes 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

Stage 0

Stage 0 anal cancer is carcinoma in situ. Rarely diagnosed, it is a very early cancer that has not spread below the limiting membrane of the first layer of anal tissue. Stage 0 anal cancer corresponds to the following TNM grouping:

Tis, N0, M0

Stage I

Stage I anal cancer is cancer that is 2 centimeters or less in greatest dimension and that has not spread anywhere else. There is no sphincter involvement. Stage I anal cancer corresponds to the following TNM grouping:

T1, N0, M0

Stage II

Stage II anal cancer is cancer that is more than 2 centimeters and that does not involve adjacent organs or lymph nodes. Stage II anal cancer corresponds to the following TNM groupings:

T2, N0, M0 T3, N0, M0

Stage IIIA

Stage IIIA anal cancer is cancer that has spread to perirectal lymph nodes or to adjacent organs. Stage IIIA anal cancer corresponds to the following TNM groupings:

T1, N1, M0 T2, N1, M0 T3, N1, M0 T4, N0, M0

Stage IIIB

Stage IIIB anal cancer is cancer that has spread to internal iliac and/or inguinal nodes (unilateral or bilateral) or has spread to both adjacent organs and perirectal lymph nodes. Stage IIIB anal cancer corresponds to the following TNM groupings:

T4, N1, M0 Any T, N2, M0 Any T, N3, M0

Stage IV

Stage IV anal cancer is cancer that has spread to distant lymph nodes within the abdomen or to other organs in the body. Stage IV anal cancer corresponds to the following TNM groupings:

Any T, Any N, M1

References:

1. Anal canal. In: American Joint Committee on Cancer: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 91-95.

2. Anal canal. In: Sobin LH, Wittekind C, eds.: TNM: Classification of Malignant Tumours. New York, NY: Wiley-Liss, Inc., 5th ed., 1997, pp 70-73.

Treatment Option Overview

Abdominoperineal resection leading to permanent colostomy was previously thought to be required for all but small anal cancers below the dentate line, with approximately 70% of patients surviving 5 or more years in single institutions,1 but such surgery is no longer the treatment of choice.2,3 Radiation therapy alone may lead to a 5-year survival rate in excess of 70%, although high doses (6,000 cGy or greater) may yield necrosis or fibrosis.4 Chemotherapy concurrent with lower-dose radiation therapy has a 5-year survival rate in excess of 70% with low levels of acute and chronic morbidity, and few patients require surgery for dermal or sphincter toxic effects.5-10 The optimal dose of radiation with concurrent chemotherapy to optimize local control and minimize sphincter toxic effects is under evaluation but appears to be in the 45 Gy to 60 Gy range.11,12 Analysis of an intergroup trial that compared radiation therapy plus fluorouracil/mitomycin with radiation therapy plus fluorouracil alone in patients with anal cancer has shown improved results (lower colostomy rates and higher colostomy-free and disease-free survival) with the addition of mitomycin.13 Radiation with continuous infusion of fluorouracil plus cisplatin is also under evaluation.14,15 Standard salvage therapy for those patients with either gross or microscopic residual disease following chemoradiotherapy has been abdominoperineal resection. Alternately, patients may be treated with additional salvage chemoradiotherapy in the form of fluorouracil, cisplatin, and a radiation boost to potentially avoid permanent colostomy.13

Because of the small number of cases, information that can only come from patient participation in well-designed clinical trials is needed to improve the management of anal cancer. Patients with stages II, III, and IV disease should be considered candidates for clinical trials.

HIV and anal cancer

The tolerance of patients with human immunodeficiency virus (HIV) and anal carcinoma to standard fluorouracil/mitomycin chemoradiation is not well defined.16,17 Patients with pretreatment CD4 counts of less than 200 may have increased acute and late toxic effects;18 chemoradiation doses may require modification in this subset of patients.

References:

1. Boman BM, Moertel CG, O'Connell MJ, et al.: Carcinoma of the anal canal: a clinical and pathologic study of 188 cases. Cancer 54(1): 114-125, 1984.

2. Stearns MW, Quan SH: Epidermoid carcinoma of the anorectum. Surgery, Gynecology and Obstetrics 131(5): 953-957, 1970.

3. Cummings BJ: The role of radiation therapy with 5-fluorouracil in anal canal cancer. Seminars in Radiation Oncology 7(4): 306-312, 1997.

4. Cantril ST, Green JP, Schall GL, et al.: Primary radiation therapy in the treatment of anal carcinoma. International Journal of Radiation Oncology, Biology, Physics 9(9): 1271-1278, 1983.

5. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal: model for preoperative adjuvant combined modality therapy. American Journal of Medicine 78(2): 211-215, 1985.

6. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. International Journal of Radiation Oncology, Biology, Physics 11(9): 1587-1593, 1985.

7. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

8. Cummings BJ: Anal cancer. International Journal of Radiation Oncology, Biology, Physics 19(5): 1309-1315, 1990.

9. Zucali R, Doci R, Bombelli L: Combined chemotherapy-radiotherapy of anal cancer. International Journal of Radiation Oncology, Biology, Physics 19(5): 1221-1223, 1990.

10. Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. Journal of the American College of Surgeons 185(5): 494-505, 1997.

11. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiation Oncology Investigations 2(3): 152-156, 1994.

12. John M, Pajak T, Flam M, et al.: Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer Journal from Scientific American 2(4): 205-211, 1996.

13. Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 14(9): 2527-2539, 1996.

14. Rich TA, Ajani JA, Morrison WH, et al.: Chemoradiation therapy for anal cancer: radiation plus continuous infusion of 5-fluorouracil with or without cisplatin. Radiotherapy and Oncology 27(3): 209-215, 1993.

15. Ajani JA, Radiation Therapy Oncology Group: Phase III Randomized Study of Fluorouracil and Mitomycin With Concurrent Radiotherapy Versus Fluorouracil and Cisplatin With Concurrent Radiotherapy in Patients With Anal Canal Carcinoma (Summary Last Modified 09/2001), RTOG-9811, clinical trial, active, 10/31/1998.

16. Holland JM, Swift PS: Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy. Radiology 193(1): 251-254, 1994.

17. Peddada AV, Smith DE, Rao AR, et al.: Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. International Journal of Radiation Oncology, Biology, Physics 37(5):1101-1105, 1997.

18. Hoffman R, Krieg R, Klencke B: Outcome and treatment tolerance for HIV-positive patients with anal cancer based on pretreatment CD4 count. International Journal of Radiation Oncology, Biology, Physics 42(1 suppl): A-80, 164, 1998.

Stage 0 Anal Cancer

Treatment options:

Surgical resection is used for treatment of lesions of the perianal area not involving the anal sphincter (approach depends on the location of the lesion in the anal canal).

Stage I Anal Cancer

Stage I anal cancer was formerly treated with abdominoperineal resection. Current sphincter-sparing therapies include wide local excision for small tumors of the perianal skin or anal margin, or definitive chemoradiation (fluorouracil and mitomycin) for cancers of the anal canal. Salvage chemoradiotherapy (fluorouracil and cisplatin plus a radiation boost) may avoid permanent colostomy in patients with residual tumor following initial nonoperative therapy.1 Radical resection is reserved for patients with incomplete responses or recurrent disease. Therefore, continued surveillance with rectal examination every 3 months for the first 2 years and endoscopy/biopsy when indicated after completion of sphincter-preserving therapy is important.

Treatment options:

1. Small tumors of the perianal skin or anal margin not involving the anal sphincter may be adequately treated with local resection.2
2. All other stage I cancers of the anal canal that involve the anal sphincter or are too large for complete local excision are treated with external beam radiation therapy with or without chemotherapy.1,3-8 Chemotherapy with fluorouracil and mitomycin combined with primary radiation therapy appears to be more effective than radiation therapy alone.9 The optimal dose of radiation with concurrent chemotherapy is under evaluation.10-12 Selected tumors are also suitable for interstitial irradiation.4
3. Radical resection is reserved for residual or recurrent cancer in the anal canal after nonoperative therapy.
4. Alternately, salvage chemotherapy with fluorouracil and cisplatin combined with a radiation boost may avoid a permanent colostomy in selected patients with small amounts of residual tumor following initial nonoperative therapy.1
5. Interstitial iridium-192 after external-beam radiation may convert some patients with residual disease into complete responders.13

References:

1. Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 14(9): 2527-2539, 1996.

2. Enker WE, Heilwell M, Janov AJ, et al.: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Archives of Surgery 121(12): 1386-1390, 1986.

3. Papillon J, Mayer M, Montbarbon JF, et al.: A new approach to the management of epidermoid carcinoma of the anal canal. Cancer 51(10): 1830-1837, 1983.

4. Cummings B, Keane T, Thomas G, et al.: Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 54(10): 2062-2068, 1984.

5. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal: model for preoperative adjuvant combined modality therapy. American Journal of Medicine 78(2): 211-215, 1985.

6. James RD, Pointon RS, Martin S: Local radiotherapy in the management of squamous carcinoma of the anus. British Journal of Surgery 72(4): 282-285, 1985.

7. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. International Journal of Radiation Oncology, Biology, Physics 11(9): 1587-1593, 1985.

8. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

9. UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348(9034): 1049-1054, 1996.

10. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiation Oncology Investigations 2(3): 152-156, 1994.

11. John M, Pajak T, Flam M, et al.: Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer Journal from Scientific American 2(4): 205-211, 1996.

12. Ajani JA, Radiation Therapy Oncology Group: Phase III Randomized Study of Fluorouracil and Mitomycin With Concurrent Radiotherapy Versus Fluorouracil and Cisplatin With Concurrent Radiotherapy in Patients With Anal Canal Carcinoma (Summary Last Modified 09/2001), RTOG-9811, clinical trial, active, 10/31/1998.

13. Sandhu AP, Symonds RP, Robertson AG, et al.: Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. International Journal of Radiation Oncology, Biology, Physics 40(3): 575-581, 1998.

Stage II Anal Cancer

Stage II anal cancer was formerly treated with abdominoperineal resection. Current sphincter-sparing therapies include wide local excision for small tumors of the perianal skin or anal margin, or definitive chemoradiation (fluorouracil and mitomycin) for cancers of the anal canal. Salvage chemotherapy (fluorouracil with cisplatin plus a radiation boost) may avoid permanent colostomy in patients with residual tumor following initial nonoperative therapy. Radical resection is reserved for patients with incomplete responses or recurrent disease. Therefore, continued surveillance with rectal examination every 3 months for the first 2 years and endoscopy/biopsy when indicated after completion of sphincter-preserving therapy is important.

Treatment options:

1. Small tumors of the perianal skin or anal margin not involving the anal sphincter may be adequately treated with local resection.1
2. All other stage II cancers of the anal canal that involve the anal sphincter or are too large for complete local excision are treated with external beam radiation therapy plus chemotherapy.2-8 Chemotherapy with fluorouracil and mitomycin combined with primary radiation therapy appears to be more effective than radiation therapy alone.9 The optimal dose of radiation with concurrent chemotherapy is under evaluation.10-12 Selected tumors are also suitable for interstitial irradiation.3,13
3. Radical resection is reserved for continued residual or recurrent cancer in the anal canal after nonoperative therapy.
4. Alternately, salvage chemotherapy with fluorouracil and cisplatin combined with a radiation boost may avoid a permanent colostomy in selected patients with small amounts of residual tumor following initial nonoperative therapy.8

References:

1. Enker WE, Heilwell M, Janov AJ, et al.: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Archives of Surgery 121(12): 1386-1390, 1986.

2. Papillon J, Mayer M, Montbarbon JF, et al.: A new approach to the management of epidermoid carcinoma of the anal canal. Cancer 51(10): 1830-1837, 1983.

3. Cummings B, Keane T, Thomas G, et al.: Results and toxicity of the treatment of anal canal carcinoma by radiation therapy or radiation therapy and chemotherapy. Cancer 54(10): 2062-2068, 1984.

4. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal: model for preoperative adjuvant combined modality therapy. American Journal of Medicine 78(2): 211-215, 1985.

5. James RD, Pointon RS, Martin S: Local radiotherapy in the management of squamous carcinoma of the anus. British Journal of Surgery 72(4): 282-285, 1985.

6. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally resectable adenocarcinoma of the rectum. International Journal of Radiation Oncology, Biology, Physics 11(9): 1587-1593, 1985.

7. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

8. Flam M, John M, Pajak TF, et al.: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. Journal of Clinical Oncology 14(9): 2527-2539, 1996.

9. UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348(9034): 1049-1054, 1996.

10. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiation Oncology Investigations 2(3): 152-156, 1994.

11. John M, Pajak T, Flam M, et al.: Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer Journal from Scientific American 2(4): 205-211, 1996.

12. Ajani JA, Radiation Therapy Oncology Group: Phase III Randomized Study of Fluorouracil and Mitomycin With Concurrent Radiotherapy Versus Fluorouracil and Cisplatin With Concurrent Radiotherapy in Patients With Anal Canal Carcinoma (Summary Last Modified 09/2001), RTOG-9811, clinical trial, active, 10/31/1998.

13. Sandhu AP, Symonds RP, Robertson AG, et al.: Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. International Journal of Radiation Oncology, Biology, Physics 40(3): 575-581, 1998.

Stage IIIA Anal Cancer

Stage IIIA anal cancer presents clinically as stage II in most instances and is determined to be IIIA by clinically evident perirectal nodal disease or adjacent organ involvement. Endorectal or endoanal ultrasound may aid in pretreatment staging.

Treatment options:

1. Treatment as for stage I and II disease, using radiation therapy plus chemotherapy.1
2. Abdominoperitoneal resection combined with resection of femoral, inguinal, abductor, and iliac lymph nodes, followed by postoperative radiation therapy.

References:

1. Sischy B, Doggett RL, Krall JM, et al.: Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. Journal of the National Cancer Institute 81(11): 850-856, 1989.

Stage IIIB Anal Cancer

The presence of inguinal nodes that are involved with metastatic disease (unilateral or bilateral) is a poor prognostic sign, although cure of this stage of disease is possible. Because of the poor prognosis associated with this stage, patients should be included in clinical trials whenever possible.

Treatment options:

Radiation therapy plus chemotherapy (as described for stage II) with surgical resection of residual disease at the primary site (local resection or abdominoperineal resection) and unilateral or bilateral superficial and deep inguinal node dissection for residual or recurrent tumor.

Stage IV Anal Cancer

Patients in this stage should be considered candidates for clinical trials. There is no standard chemotherapy for patients with metastatic disease. Palliation of symptoms from the primary lesion is of major importance.

Treatment options:

1. Palliative surgery. 2. Palliative irradiation. 3. Palliative combined chemotherapy and radiation therapy. 4. Clinical trials.

Recurrent Anal Cancer

Local recurrences after treatment with either radiation therapy and chemotherapy or surgery as the primary treatment can be effectively controlled in a substantial number of patients by using the alternate treatment (surgical resection after radiation and vice versa).1 Clinical trials are exploring the use of radiation therapy with chemotherapy and/or radiosensitizers to improve local control.

References:

1. Longo WE, Vernava AM, Wade TP, et al.: Recurrent squamous cell carcinoma of the anal canal: predictors of initial treatment failure and results of salvage therapy. Annals of Surgery 220(1): 40-49, 1994.