Anal cancer: Treatment - Health Professional Information [NCI PDQ]

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Anal Cancer Treatment (PDQ®)

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of anal cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

• Prognostic factors.
• Cellular classification.
• Staging.
• Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: Estimated new cases and deaths from anal cancer in the United States in 2007:[1]

• New cases: 4,650.
• Deaths: 690.

Anal cancer is usually curable. The three major prognostic factors are site (anal canal vs. perianal skin), size (primary tumors <2 cm in size have better prognoses), and nodal status.

Anal cancer is an uncommon malignancy and accounts 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.[2,3] Information about ongoing clinical trials is available from the NCI Web site.

Overall, the risk of anal cancer is rising, with data suggesting that persons engaging in certain sexual practices, such as receptive anal intercourse, or persons with a high lifetime number of sexual partners are at increased risk of anal cancer. These practices may have led to an increase in the number of individuals at risk for infection with human papillomavirus (HPV); HPV infection is strongly associated with anal cancer development and may be a necessary step in its carcinogenesis.[4,5,6,7]

References:

1. American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed September 7, 2007.
2. 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): 1731-6, 1995.
3. Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. J Am Coll Surg 185 (5): 494-505, 1997.
4. Johnson LG, Madeleine MM, Newcomer LM, et al.: Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973-2000. Cancer 101 (2): 281-8, 2004.
5. Daling JR, Weiss NS, Hislop TG, et al.: Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 317 (16): 973-7, 1987.
6. Palefsky JM, Holly EA, Gonzales J, et al.: Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 51 (3): 1014-9, 1991.
7. Ryan DP, Compton CC, Mayer RJ: Carcinoma of the anal canal. N Engl J Med 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 constitutes 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 papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 51 (3): 1014-9, 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] 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*

*Direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or the sphincter muscle(s) 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

AJCC Stage Groupings

Stage 0

• Tis, N0, M0

Stage I

• T1, N0, M0

Stage II

• T2, N0, M0
• T3, N0, M0

Stage IIIA

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

Stage IIIB

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

Stage IV

• Any T, any N, M1

References:

1. Anal canal. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 125-130.

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%, though high doses (=60 Gy) 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.[5,6,7,8,9,10] 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 chemoradiation therapy has been abdominoperineal resection. Alternately, patients may be treated with additional salvage chemoradiation therapy 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. Information about ongoing clinical trials is available from the NCI Web site.

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;[18,19] 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): 114-25, 1984.
2. Stearns MW Jr, Quan SH: Epidermoid carcinoma of the anorectum. Surg Gynecol Obstet 131 (5): 953-7, 1970.
3. Cummings BJ: The Role of Radiation Therapy With 5-Fluorouracil in Anal Cancer. Semin Radiat Oncol 7 (4): 306-312, 1997.
4. Cantril ST, Green JP, Schall GL, et al.: Primary radiation therapy in the treatment of anal carcinoma. Int J Radiat Oncol Biol Phys 9 (9): 1271-8, 1983.
5. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 78 (2): 211-5, 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. Int J Radiat Oncol Biol Phys 11 (9): 1587-93, 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. J Natl Cancer Inst 81 (11): 850-6, 1989.
8. Cummings BJ: Anal cancer. Int J Radiat Oncol Biol Phys 19 (5): 1309-15, 1990.
9. Zucali R, Doci R, Bombelli L: Combined chemotherapy--radiotherapy of anal cancer. Int J Radiat Oncol Biol Phys 19 (5): 1221-3, 1990.
10. Fuchshuber PR, Rodriguez-Bigas M, Weber T, et al.: Anal canal and perianal epidermoid cancers. J Am Coll Surg 185 (5): 494-505, 1997.
11. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiat Oncol Investig 2(3): 152-6, 1994.
12. John M, Pajak T, Flam M, et al.: Dose Escalation in Chemoradiation for Anal Cancer: Preliminary Results of RTOG 92-08 Cancer J Sci Am 2 (4): 205-11, 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. J Clin Oncol 14 (9): 2527-39, 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. Radiother Oncol 27 (3): 209-15, 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, RTOG-9811, Clinical trial, Closed.
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): 251-4, 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. Int J Radiat Oncol Biol Phys 37 (5): 1101-5, 1997.
18. Hoffman R, Welton ML, Klencke B, et al.: The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 44 (1): 127-31, 1999.
19. Place RJ, Gregorcyk SG, Huber PJ, et al.: Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum 44 (4): 506-12, 2001.

Stage 0 Anal Cancer

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.

STANDARD 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 chemoradiation therapy (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. 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.

STANDARD 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 (EBRT) with or without chemotherapy.[1,3,4,5,6,7,8,9]

   Chemotherapy with fluorouracil and mitomycin combined with primary radiation therapy appears to be more effective than radiation therapy alone.[10] The optimal dose of radiation with concurrent chemotherapy is under evaluation.[11,12,13]

   Selected tumors are also suitable for interstitial radiation therapy.[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 EBRT may convert some patients with residual disease into complete responders.[14]

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. J Clin Oncol 14 (9): 2527-39, 1996.
2. Enker WE, Heilwell M, Janov AJ, et al.: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Arch Surg 121 (12): 1386-90, 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): 1830-7, 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): 2062-8, 1984.
5. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 78 (2): 211-5, 1985.
6. James RD, Pointon RS, Martin S: Local radiotherapy in the management of squamous carcinoma of the anus. Br J Surg 72 (4): 282-5, 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. Int J Radiat Oncol Biol Phys 11 (9): 1587-93, 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. J Natl Cancer Inst 81 (11): 850-6, 1989.
9. Mitchell SE, Mendenhall WM, Zlotecki RA, et al.: Squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 49 (4): 1007-13, 2001.
10. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348 (9034): 1049-54, 1996.
11. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiat Oncol Investig 2(3): 152-6, 1994.
12. John M, Pajak T, Flam M, et al.: Dose Escalation in Chemoradiation for Anal Cancer: Preliminary Results of RTOG 92-08 Cancer J Sci Am 2 (4): 205-11, 1996.
13. 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, RTOG-9811, Clinical trial, Closed.
14. Sandhu AP, Symonds RP, Robertson AG, et al.: Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. Int J Radiat Oncol Biol Phys 40 (3): 575-81, 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.

STANDARD 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.[2,3,4,5,6,7,8]

   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.[10,11,12]

   Selected tumors are also suitable for interstitial radiation therapy.[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. Arch Surg 121 (12): 1386-90, 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): 1830-7, 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): 2062-8, 1984.
4. Leichman L, Nigro N, Vaitkevicius VK, et al.: Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 78 (2): 211-5, 1985.
5. James RD, Pointon RS, Martin S: Local radiotherapy in the management of squamous carcinoma of the anus. Br J Surg 72 (4): 282-5, 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. Int J Radiat Oncol Biol Phys 11 (9): 1587-93, 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. J Natl Cancer Inst 81 (11): 850-6, 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. J Clin Oncol 14 (9): 2527-39, 1996.
9. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 348 (9034): 1049-54, 1996.
10. Fung CY, Willett CG, Efird JT, et al.: Chemoradiotherapy for anal carcinoma: what is the optimal radiation dose? Radiat Oncol Investig 2(3): 152-6, 1994.
11. John M, Pajak T, Flam M, et al.: Dose Escalation in Chemoradiation for Anal Cancer: Preliminary Results of RTOG 92-08 Cancer J Sci Am 2 (4): 205-11, 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, RTOG-9811, Clinical trial, Closed.
13. Sandhu AP, Symonds RP, Robertson AG, et al.: Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. Int J Radiat Oncol Biol Phys 40 (3): 575-81, 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.

STANDARD TREATMENT OPTIONS:

1. Treatment used is the same as for stage I and II disease, including the use of radiation therapy plus chemotherapy.[1,2]
2. Radical resection is reserved for continued residual or recurrent cancer in the anal canal after nonoperative 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. J Natl Cancer Inst 81 (11): 850-6, 1989.
2. 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. J Clin Oncol 14 (9): 2527-39, 1996.

Stage IIIB Anal Cancer

The presence of inguinal nodes that are involved with metastatic disease (unilateral or bilateral) is a poor prognostic sign, though 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. Information about ongoing clinical trials is available from the NCI Web site.

STANDARD 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

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

STANDARD TREATMENT OPTIONS:

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

Recurrent Anal Cancer

Local recurrences and/or persistent disease after treatment with radiation therapy and chemotherapy or surgery as the primary treatment may be controlled 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. Information about ongoing clinical trials is available from the NCI Web site.

References:

1. Longo WE, Vernava AM 3rd, Wade TP, et al.: Recurrent squamous cell carcinoma of the anal canal. Predictors of initial treatment failure and results of salvage therapy. Ann Surg 220 (1): 40-9, 1994.

Changes to This Summary (11/02/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added Purpose of This PDQ Summary as a new section.

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Date Last Modified: 2007-11-02