Topics:

Current Perspectives on Anal Cancer

Current Perspectives on Anal Cancer

ABSTRACT: Anal cancer accounts for 1.5% of digestive system malignancies in the United States. In the past 30 years, substantial progress has been made in understanding the pathophysiology and treatment of the disease. Anal cancer was once believed to be caused by chronic local inflammation of the perianal area, and treatment was abdominoperineal resection. From epidemiologic and clinical studies, we now know that the development of anal cancer is associated with human papillomavirus infection and that the disease has a pathophysiology similar to that of cervical cancer. Less invasive treatments have also been developed, and the majority of patients with anal cancer can now be cured with preservation of the anal sphincter using concurrent external-beam radiation therapy and fluorouracil (5-FU)/mitomycin (Mutamycin) chemotherapy. Current areas under investigation include the incorporation of platinum agents into the chemotherapy regimen and the use of cytologic screening studies for high-risk populations.

Anal cancer is responsible for 1.5% of all digestive system malignancies in the United States, with 4,000 new cases anticipated in 2003.[1] The incidence of anal cancer in the general population ranges between 7 and 9 cases per million.[2] Certain groups have a higher incidence, including women,[3] human immunodeficiency virus (HIV)-positive patients,[4] patients with a history of human papillomavirus (HPV) infection, and patients who engage in anal receptive intercourse.[2] Over 90% of patients present with locoregional disease, and less than 20% of patients will present with or develop distant metastases.

In the past 30 years, much progress has been made in understanding the pathophysiology of anal cancer, and less invasive treatments have been developed.[5] Once thought to be the result of chronic perianal inflammation and treated with abdominoperineal resection, anal cancer is now known to be associated with HPV infection. The majority of patients can be cured with concurrent chemotherapy and radiation therapy alone.[6]

Anatomy and Histology

The anal canal extends from the junction of the puborectalis portion of the levator ani muscle and the external anal sphincter to the anal verge. The length of the canal varies but is approximately 4 cm. The transition from the rectal mucosa to the squamous mucosa on the hair-bearing anal margin can also vary among patients. The proximal portion of the anal canal is referred to as the transitional zone. In some patients, the distinction between the anal squamous mucosa and the rectal glandular mucosa is clear and abrupt, but others can have an intervening segment of urothelial-like pseudostratified epithelium with cuboidal or polygonal surface cells. This intervening segment was formerly referred to as junctional, basaloid, or cloacogenic mucosa. Tumors that arise from this epithelium are now called nonkeratinizing squamous cell carcinomas.

The biology and prognosis of keratinizing and nonkeratinizing squamous cell carcinomas of the anal canal are similar.[7,8] There is no easily identifiable landmark between the rectum and anus, so clinicians should rely on the pathologic classification of tumors in this area rather than the surgical or endoscopic classification. Adenocarcinomas of the anal canal are treated as rectal adenocarcinomas, as they share the same natural history.

Lymphatic drainage of anal cancers is dependent on the anatomic site of origin. Tumors located above the dentate line drain to the perirectal and paravertebral nodes, which is similar to rectal cancers. Tumors below the dentate line drain to the inguinal and femoral lymph nodes, and patients with anal cancer should undergo both physical and radiographic examination of these nodes.[9-11]

Staging

The American Joint Committee on Cancer and the International Union Against Cancer have established a tumor-node-metastasis (TNM) staging system for anal cancer (Table 1). Patients with T1 or T2 lesions have an 80% to 90% 5-year survival rate, whereas patients with T4 lesions have less than a 50% 5-year survival rate. For patients with lymph node metastases, the 5-year survival rate is approximately 50%.[12-15] At presentation, 50% to 60% of patients have a T1 or T2 lesion and 12% to 20% are nodepositive.[10,12,13,15,16] The probability of nodal spread is directly related to tumor size and location.

Epidemiology

Epidemiologic studies over the past 10 years have identified several risk factors for anal cancer, including the presence of sexually transmitted disease, the practice of anal receptive intercourse, a history of more than 10 sexual partners, and a history of cervical, vulvar, or vaginal cancers.[17-23] These risk factors are due to a link between HPV and anal cancer. Human papillomavirus can cause premalignant anal squamous intraepithelial lesions (ASIL), which can be low grade (LSIL) or high grade (HSIL). Progression of ASIL to invasive anal cancer is affected by HIV seropositivity, low CD4 count, the subtype of HPV, and high DNA levels of high-risk HPV subtypes in the anal canal.[24] Although not completely clear, there seems to be a relationship between HIV infection and anal cancer.

Patients with HIV are more likely to have HPV infection, and the risk of HPV infection evolving into HSIL and invasive anal cancer is also greater among these patients.[25] These risks appear to be inversely related to the patient's CD4 count.[24,26-28] A possible mechanism for the increased incidence of anal cancer among HIVpositive patients is immunosuppression. However, a large US study in acquired immunodeficiency syndrome (AIDS) patients found that the incidence of ASIL increases after the onset of AIDS while the risk of invasive anal cancer does not, bringing into question the relationship between immune status and the development of invasive anal cancer.[29]

Moreover, with the widespread use of highly active antiretroviral therapy (HAART), the incidence of other HIV-associated cancers such as Kaposi's sarcoma and non-Hodgkin's lymphoma have decreased while the incidence of anal cancer has not.[30] Given the high risk for ASIL among homosexual and bisexual men, investigators have conducted studies of the potential cost-effectiveness of screening these men with anal cytology every 2 to 3 years. The results of two trials that evaluated screening in both HIV-positive and HIV-negative homosexual or bisexual men suggested that such screening would be costeffective and have life expectancy benefits.[31,32]

Individuals with other causes of chronic immunosuppression including renal transplant patients and those on chronic glucocorticoid therapy also appear to be at increased risk for ASIL and anal cancer, typically associated with HPV infection.[33-38] In addition, smoking is associated with a higher risk of developing invasive anal cancer.[17,39,40]

Treatment

Before 1980, an abdominoperineal resection was the treatment of choice for tumors of the anal canal. Surgical series prior to 1980 found the overall 5-year survival rate after an abdominoperineal resection to range between 40% and 70%. Patients with large tumors and nodal metastases had poorer outcomes.[9,12,13,18,41-43] In an attempt to improve surgical outcome, Nigro and colleagues at Wayne State evaluated preoperative chemotherapy with fluorouracil (5-FU) and mitomycin (Mutamycin) combined with intermediate-dose radiation therapy (30 Gy). Unexpectedly, the investigators found that the first three patients who received treatment achieved complete responses.[44] Multiple institutional series subsequently demonstrated that chemoradiation in patients with anal cancer resulted in a colostomyfree survival of 66% to 70% as well as a 5-year survival of 58% to 92% (Table 2).[6,9,45-68]

The combination of chemotherapy and radiation therapy was also found to be generally well-tolerated and effective in patients with HIV, but patients with CD4 counts less than 200/μL and those who received greater than 30 Gy of irradiation had poorer tolerance.[69-71] In addition, trials using radiation therapy alone, given as external-beam irradiation or brachytherapy, reported good local tumor control and cure rates ranging from 70% to 90%.[15,67,72-80] However, local control and cure rates were less than 50% for patients with tumors greater than 5 cm and/or lymph node involvement.[15,81]

Chemoradiation vs Radiotherapy Alone

Attempting to evaluate the relative benefit of chemoradiation compared to radiation therapy alone, the United Kingdom Coordination Committee on Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC) each embarked on phase III studies (Table 3).[8,82] The first was conducted by the Anal Cancer Trial Working Party of the UKCCCR; 585 patients were randomized to receive either radiation therapy (45 Gy of external-beam treatment with either a 15-Gy external-beam boost or a 25-Gy brachytherapy boost) or the same radiation therapy in combination with concurrent 5-FU and mitomycin. Chemoradiation improved local control (39% vs 61%) and disease-specific survival (28% vs 30%), but the overall survival rate was not significantly different between the two groups.[82]

The EORTC randomized 110 patients to receive radiotherapy (45 Gy of external-beam administration with either a 15-Gy or 30-Gy external boost) or radiotherapy with concurrent 5-FU and mitomycin. Again, chemoradiation improved local control but did not have a significant impact on overall survival. The EORTC study also demonstrated a 32% higher colostomy-free survival among patients treated with chemoradiation. Skin ulceration and nodal involvement were poor prognostic indicators, and women had better local control and survival than men.[8]

These European trials showed that, compared to radiation therapy alone, chemoradiation offers patients a better chance of achieving local control, disease-free survival, and colostomyfree survival but does not improve overall survival, possibly because of the impact of an abdominoperineal resection as salvage therapy.

Role of Mitomycin

The Radiation Therapy Oncology Group (RTOG) and Eastern Cooperative Oncology Group (ECOG) then evaluated the role of mitomycin in the combined-modality regimen.[7] Mitomycin is not a known radiation sensitizer, and its renal, pulmonary, and bone marrow toxicity raised concerns about its safety.[83,84] The 310 patients entered into the trial were randomly assigned to receive radiation therapy with either concurrent 5-FU or 5-FU/mitomycin.

Patients who received mitomycin had a significantly lower 5-year rate of locoregional recurrence, lower colostomy rate, and better disease-free survival compared to patients who did not receive mitomycin. The overall survival, disease-specific survival, and posttherapy negative biopsy rate did not differ between groups. On subset analysis, the addition of mitomycin in patients with T3 or T4 tumors did not have a significant impact on outcome.

The investigators concluded that mitomycin plays a significant role in combined-modality therapy for anal cancer. The drug remains a component of the standard chemoradiation arm in the most recent RTOG trial of such therapy.

Role of Cisplatin

Platinum compounds were not available when combination regimens were originally tested, but because they have been found to be active against squamous cell carcinomas, they are now being evaluated in the treatment of anal cancers. In 1996, Doci and colleagues combined 5-FU and cisplatin with concurrent radiation therapy in 35 patients. The 3-year colostomy-free survival rate was 86%, and the complete response rate was 94%.[85] These results have been confirmed in other studies (Table 4).[85-90]

A Cancer and Leukemia Group B (CALGB) study evaluated induction 5-FU and cisplatin as well as 5-FU, cisplatin, and external-beam radiotherapy, and the preliminary results were presented at the 2000 meeting of the American Society of Clinical Oncology (ASCO); 80% of patients achieved a complete response, and the overall survival rate was 78%.[90] Currently, an ongoing multicenter, randomized Intergroup trial in the United States is comparing the same induction/concurrent regimen of 5-FU and cisplatin vs the standard mitomycin, 5-FU, and radiation therapy in patients with anal cancer; results of this study will help to define the optimal chemotherapy regimen.

Persistent or Recurrent Disease

Response to treatment is assessed approximately 6 to 8 weeks following the completion of combined chemotherapy and radiation therapy. Whether the response to treatment should be assessed by physical examination alone or in combination with a biopsy is controversial. Squamous cell carcinomas tend to regress slowly over 3 to 12 weeks after therapy.[90] In the US Intergroup study evaluating the role of mitomycin in combination with 5-FU, patients had follow-up biopsies 6 weeks after the completion of therapy. Residual disease was found in 8% of patients.

These patients were then treated with a salvage regimen of 5-FU/cisplatin and 9 Gy of external radiation; 55% achieved a complete response.[7] However, it was unclear whether this high salvage rate was due to the added therapy or the possibility that the tumors of these patients were slower to regress after primary therapy. Given the morbidity of the procedure, there is no consensus on the use and timing of biopsy in patients who have had a complete clinical response to therapy. It is reasonable to biopsy persistent abnormalities at 3 months after chemoradiation, as most tumor should be eradicated by that point.

• Persistent Disease—The therapy for persistent disease after primary chemoradiation is abdominoperineal resection. In the UKCCCR trial, 29 patients who achieved less than a 50% response to primary therapy underwent a salvage abdominoperineal resection; 83% became disease-free, but 42% went on to develop a local relapse.[82]

Salvage chemoradiation was also evaluated in this study. Patients with persistent disease were given 5-FU with cisplatin and radiation. The complete response rate in this group was 55%. Among patients who responded, one-third remained disease-free, one-third died (75% of those patients from progressive anal cancer), and one-third required resection and continue to be disease-free. All but one of the patients who did not respond to salvage therapy underwent abdominoperineal resection. At 4 years, 30% were alive without recurrent disease, and 60% developed recurrent disease and subsequently died.[7]

• Recurrent Disease—Like patients with persistent disease, those with locally recurrent disease after chemoradiation typically undergo an abdominoperineal resection. Such a salvage procedure will cure approximately 50% of patients with recurrent disease.[91-93] Although no formal trial of salvage chemotherapy and radiation therapy has been conducted, the salvage regimen for persistent disease from the RTOG/ECOG trial may also be effective in these patients.[7]

Distant recurrence occurs in 10% to 17% of patients who receive combination therapy.[8,82] The most common site of distant metastasis is the liver. No known cure exists for metastatic anal cancer, and the effectiveness of chemotherapy in these patients is unknown.[11,68,92] There are some reports of partial responses to cisplatin, 5-FU, and semustine (methyl-CCNU),[94-96] but there is little available information on the response of metastatic disease to newer agents such as taxanes, gemcitabine (Gemzar), or irinotectan (CPT-11, Camptosar).

Complications of Therapy

Complications of therapy for anal cancer depend on the treatment modality used. Late toxicity from radiation therapy includes anal ulcers, stenosis, and necrosis requiring colostomy in 6% to 12% of patients. The risk of these complications is related to the dose of radiation therapy.[15,73,92] Adding chemotherapy to radiation increases the frequency and degree of acute toxicity. Patients who receive chemoradiation are at risk for diarrhea, exfoliative dermatitis, mucositis, and myelosuppression.[7,82]

Conclusions

Remarkable progress has been made in understanding the pathophysiology and treatment of anal cancer in the past 30 years. HPV has been clearly implicated in the development of a majority of anal cancers, raising the possibility of screening programs for high-risk patients in the future. The use of sphincter-sparing chemoradiation therapy has remarkably improved quality of life and survival in patients with anal cancer. Ongoing studies are evaluating the role of cisplatin in the chemoradiation regimen.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5- 26, 2003.
2. Palefsky JM: Anal human papillomavirus infection and anal cancer in HIV-positive individuals: An emerging problem. AIDS 8:283- 295, 1994.
3. Greenlee RT, Hill-Harmon MB, Murray T, et al: Cancer statistics, 2001. CA Cancer J Clin 51:15-36, 2001.
4. Melbye M, Cote TR, Kessler L, et al: High incidence of anal cancer among AIDS patients. The AIDS/Cancer Working Group. Lancet 343:636-639, 1994.
5. Myerson RJ, Karnell LH, Menck HR: The National Cancer Data Base report on carcinoma of the anus. Cancer 80:805-815, 1997.
6.Klotz RG Jr, Pamukcoglu T, Souilliard DH: Transitional cloacogenic carcinoma of the anal canal. Clinicopathologic study of three hundred seventy-three cases. Cancer 20:1727- 1745, 1967.
7. 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 14:2527-2539, 1996.
8. Bartelink H, Roelofsen F, Eschwege F, et al: Concomittant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 15:2040-2049, 1997.
9. Beahrs OH, Wilson SM: Carcinoma of the anus. Ann Surg 184:422-428, 1976.
10. Frost DB, Richards PC, Montague ED, et al: Epidermoid cancer of the anorectum. Cancer 53:1285-1293, 1984.
11. Greenall MJ, Quan SH, Stearns MW, et al: Epidermoid cancer of the anal margin: Pathologic features, treatment, and clinical results. Am J Surg 149:95-101, 1985.
12. Pintor MP, Northover JM, Nicholls RJ: Squamous cell carcinoma of the anus at one hospital from 1948 to 1984. Br J Surg 76:806- 810, 1989.
13. Boman BM, Moertel CG, O’Connell MJ, et al: Carcinoma of the anal canal: A clinical and pathologic study of 188 cases. Cancer 54:114-125, 1984.
14. Schlienger M, Krzisch C, Pene F, et al: Epidermoid carcinoma of the anal canal: Treatment results and prognostic variables in a series of 242 cases. Int J Radiat Oncol Biol Phys 17:1141-1151, 1989.
15. Touboul E, Schlienger M, Buffat L, et al: Epidermoid carcinoma of the anal canal: Results of curative-intent radiation therapy in a series of 270 patients. Cancer 73:1569-1579, 1994.
16. Klas JV, Rothenberger DA, Wong WD, et al: Malignant tumors of the anal canal: The spectrum of disease, treatment, and outcomes. Cancer 85:1686-1693, 1999.
17. Holly EA, Whittemore AS, Aston DA, et al: Anal cancer incidence: Genital warts, anal fissure or fistula, hemorrhoids, and smoking. J Natl Cancer Inst 81:1726-1731, 1989.
18. Melbye M, Rabkin C, Frisch M, et al: Changing patterns of anal cancer incidence in the United States, 1940-1989. Am J Epidemiol 139:772-780, 1994.
19. Frisch M, Melbye M, Moller H: Trends in incidence of anal cancer in Denmark. Br Med J 306:419-422, 1993.
20. Frisch M, Glimelius B, van den Brule AJ, et al: Sexually transmitted infection as a cause of anal cancer. N Engl J Med 337:1350- 1358, 1997.
21. Melbye M, Sprogel P: Aetiological parallel between anal cancer and cervical cancer. Lancet 338:657-659, 1991.
22. Frisch M, Olsen JH, Melbye M: Malignancies that occur before and after anal cancer: Clues to their etiology. Am J Epidemiol 140:12- 19, 1994.
23. Rabkin CS, Biggar RJ, Melbye M, et al: Second primary cancers following anal and cervical carcinoma: Evidence of shared etiologic factors. Am J Epidemiol 136:54-58, 1992.
24. Palefsky JM, Holly EA, Hogeboom CJ, et al: Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIVpositive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 17:314-319, 1998.
25. Palefsky JM, Holly EA, Ralston ML, et al: Anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual and bisexual men: Prevalence and risk factors. J Acquir Immune Defic Syndr Hum Retrovirol 17:320-326, 1998.
26. Sun XW, Kuhn L, Ellerbrock TV, et al: Human papillomavirus infection in women infected with the human immunodeficiency virus. N Engl J Med 337:1343-1349, 1997.
27. Critchlow CW, Surawicz CM, Holmes KK, et al: Prosepective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: Influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS 9:1255-1262, 1995.
28. Palefsky JM, Holly EA, Ralston ML, et al: Prevalence and risk factors for human papillomavirus infection of the anal canal in human immunodeficiency virus (HIV)-positive and HIV-negative homosexual men. J Infect Dis 177:361-367, 1998.
29. Frisch M, Biggar RJ, Goedert JJ: Human Papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst 92:1500-1510, 2000.
30. International Collaboration on HIV and Cancer: Highly active antiretroviral therapy and the incidence of cancer in human immunodeficiency virus-infected adults. J Natl Cancer Inst 92:1823-1083, 2000.
31. Goldie SJ, Kuntz KM, Weinstein MC, et al: The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 281:1822-1829, 1999.
32. Goldie SJ, Kuntz KM, Weinstein MC, et al: Cost-effectiveness of screening for anal squamous intraepithelial lesions and anal cancer in human immunodeficiency virus-negative homosexual and bisexual men. Am J Med 108:634- 641, 2000.
33. Penn I: Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 12:S328-336, 1993.
34. Penn I: Cancers of the anogenital region in renal transplant recipients. Analysis of 65 cases. Cancer 58:611-616, 1986.
35. Arends MJ, Benton EC, McLaren KM, et al: Renal allograft recipients with high susceptibility to cutaneuos malignancy have an increased prevalence of human papillomavirus DNA in skin tumors and a greater risk of anogenital malignancy. Br J Cancer 75:722-728, 1997.
36. Sillman FH, Stanek A, Sedlis A, et al: The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women. Am J Obstet Gynecol 150:300-308, 1984.
37. Sillman FH, Sedlis A: Anogenital papillomavirus infection and neoplasia in immunodeficient women: An update. Dermatol Clin 9:353-369, 1991.
38. Sillman FH, Fruchter RG, Chen YS, et al: Vaginal intraepithelial neoplasi: Risk factors for persistence, recurrence, and invasion and its management. Am J Obstet Gynecol 176:93-99, 1997.
39. Holmes F, Borek D, Owen-Kummer M, et al: Anal cancer in women. Gastroenterology 95:107-111, 1988.
40. Daling JR, Sherman KJ, Hislop TG, et al: Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol 135:180-189, 1992.
41. Singh R, Nime F, Mittleman A: Malignant epithelial tumors of the anal canal. Cancer 48:411-415, 1981.
42. Greenall MJ, Quan SH, Urmacher C, et al: Treatment of epidermoid carcinoma of the anal canal. Surg Gynecol Obstet 161:509-517, 1985.
43. Dougherty BG, Evans HL: Carcinoma of the anal canal: A study of 79 cases. Am J Clin Pathol 83:159-164, 1985.
44. Nigro ND, Vaitkevicius VK, Considine B Jr: Combined therapy for cancer of the anal canal: A preliminary report. Dis Colon Rectum 17:354-356, 1974.
45. Hughes LL, Rich TA, Delclos L, et al: Radiotherapy for anal cancer: Experience from 1979-1987. Int J Radiat Oncol Biol Phys 17:1153-1160, 1989.
46. Cummings BJ, Keane TJ, O’Sullivan B, et al: Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 21:1115-1125, 1991.
47. 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 2:205-211, 1996.
48. Doci R, Zucali R, Bombelli L, et al: Combined chemoradiation therapy for anal cancer: A report of 56 cases. Ann Surg 215:150- 156, 1992.
49. Doci R, Zucali R, LaMonica G, et al: Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: Results in 35 consecutive patients. J Clin Oncol 14:3121-3125, 1996.
50. Sischy B, Dogett 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 81:850-856, 1989.
51. Martenson JA, Lipsitz SR, Wagner H Jr, et al: Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): An Eastern Cooperative Oncology Group study. Int J Radiat Oncol Biol Phys 35:745-749, 1996.
52. 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 76:1731-1736, 1995.
53. Enker WE, Heilwell M, Janov AJ, et al: Improved survival in epidermoid carcinoma of the anus in association with preoperative multidisciplinary therapy. Arch Surg 121:1386- 1390, 1986.
54. Michaelson RA, Magill GB, Quan SH, et al: Preoperative chemotherapy and radiation therapy in the management of anal epidermoid carcinoma. Cancer 51:390-395, 1983.
55. Nigro ND: Multidisciplinary management of cancer of the anus. World J Surg 11:446-451, 1987.
56. Nigro ND, Seydel HG, Considine B, et al: Combined preoperative radiation and chemotherapy for squamous cell carcinoma of the anal canal. Cancer 51:1826-1829, 1983.
57. Sischy B: The use of radiation therapy combined with chemotherapy in the management of squamous cell carcinoma of the anus and marginally respectable adenocarcinoma of the rectum. Int J Radiat Oncol Biol Phys 11:1587-1593, 1985.
58. Sischy B, Remington, JH, Hinson, EJ, et al: Definitive treatment of anal-canal carcinoma by means of radiation therapy and chemotherapy. Dis Colon Rectum 25:685-688, 1982.
59. John MJ, Flam M, Lovalvo LJ, et al: Feasibility of non-surgical definitive management of anal canal carcinoma. Int J Radiat Oncol Biol Phys 13:299-303, 1987.
60. Flam MS, John M, Lovalvo LJ, et al: Definitive nonsurgical therapy of epithelial malignancies of the anal canal: Report of 12 cases. Cancer 51:1378-1387, 1983.
61. 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 54:2062-2068, 1984.
62. Fung CY, Willett CG, Efird JT, et al: Chemoradiotherapy for anal carcinoma: What is the optimal radiation dose? Radiat Oncol Invest 2:152-156, 1994.
63. Johnson D, Lipsett J, Leong L, et al: Carcinoma of the anus treated with primary radiation therapy and chemotherapy. Surg Gynecol Obstet 177:329-334, 1993.
64. Meeker WR Jr, Sickle-Santanello BJ, Philpot G, et al: Combined chemotherapy, radiation, and surgery for epithelial cancer of the anal canal. Cancer 57:525-529, 1986.
65. John M, Flam M, Palma N: Ten-year results of chemoradiation for anal cancer: Focus on late morbidity. Int J Radiat Oncol Biol Phys 34:65-69, 1996.
66. Nigh SS, Smalley SR, Elman AJ, et al: Conservative therapy for anal carcinoma: An analysis of prognostic factors. Int J Radiat Oncol Biol Phys 21(suppl 1):224, 1991.
67. Allal A, Kurtz JM, Pipard G, et al: Chemoradiotherapy versus radiotherapy alone for anal cancer: A retrospective comparison. Int J Radiat Oncol Biol Phys 27:59-66, 1993.
68. Tanum G, Tveit K, Karlsen KO, et al: Chemotherapy and radiation therapy for anal carcinoma: Survival and late morbidity. Cancer 67:2462-2466, 1991.
69. Chadha M, Rosenblatt EA, Malamud S, et al: Squamous-cell carcinoma of the anus in HIV-positive patients. Dis Colon Rectum 37:861-865, 1994.
70. 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 37:1101-1105, 1997.
71. Hoffman R, Welton ML, Klencke B, et al: The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIVpositive patients with anal cancer. Int J Radiat Oncol Biol Phys 44:127-131, 1999.
72. Puthawala AA, Syed AM, Gates TC, et al: Definitive treatment of extensive anorectal carcinoma by external and interstitial irradiation. Cancer 50:1746-1750.
73. Cummings BJ, Thomas GM, Keane TJ, et al: Primary radiation therapy in the treatment of anal canal carcinoma. Dis Colon Rectum 25:778-782, 1982.
74. Cantril ST, Green JP, Schall GL, et al: Primary radiation therapy in the treatment of anal carcinoma. Int J Radiat Oncol Biol Phys 9:1271-1278, 1983.
75. Papillon J, Mayer M, Montbarbon JF, et al: A new approach to the management of epidermoid carcinoma of the anal canal. Cancer 51:1830-1837, 1983.
76. Doggett SW, Green JP, Cantril ST: Efficacy of radiation therapy alone for limited squamous cell carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 15:1069-1072, 1988.
77. Hughes LL, Rich TA, Delclos L, et al: Radiotherapy for anal cancer: Experience from 1979-1987. Int J Radiat Oncol Biol Phys 17:1153-1160, 1989.
78. Cummings BJ, Keane TJ, O’Sullivan B, et al: Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 21:1115-1125, 1991.
79. Dubois JB, Garrigues JM, Pujol H: Cancer of the anal canal: Report on the experience of 61 patients. Int J Radiat Oncol Biol Phys 20:575-580, 1991.
80. Martenson JA Jr, Gunderson, LL: External radiation therapy without chemotherapy in the management of anal cancer. Cancer 71:1736-1740, 1993.
81. Eschwedge F, Lasser P, Chavy A, et al: Squamous cell carcinoma of the anal canal: Treatment by external beam radiation. Radiother Oncol 3:145-150, 1985.
82. UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: Results from the UKCCCR randomized trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348:1049-1054, 1996.
83. Kantarjian HM, Keating MJ, Walters RS, et al: Therapy-related leukemia and myelodysplastic syndrome: Clinical, cytogenetic, and prognostic features. J Clin Oncol 4:1748-1757, 1986.
84. Pedersen-Bjergaard J, Philip P, Larsen SO, et al: Therapy-related myelodysplasia and acute myeloid leukemia: Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant disease in the Copenhagen series. Leukemia 7:1975-1986, 1993.
85. Doci R, Zucali R, LaMonica G, et al: Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: Results in 35 consecutive patients. J Clin Oncol 14:3121-3125, 1996.
86. Martenson JA, Lipsitz SR, Wagner H Jr, et al: Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): An Eastern Cooperative Oncology Group study. Int J Radiat Oncol Biol Phys 35:745-749, 1996.
87. Peiffert D, Giovanni M, Ducreaux M, et al: High-dose radiation therapy and neoadjuvant plus concomitant chemotherapy with 5- fluorouracil and cisplatin in patients with locally advanced squamous-cell anal canal cancer: Final results of a phase II study. Ann Oncol 12:397-404, 2001.
88. Gerard JP, Ayzac L, Hun D, et al: Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracilcisplatinum. Long-term results in 95 patients. Radiother Oncol 46:249-256, 1998.
89. Javier A, Curcio E, Perez J, et al: Induction 5-fluorouracil (5-FU)/cisplatin (CP) followed by combined external beam radiation therapy (XRT) and chemotherapy in locally advanced anal canal cancer (abstract 1181). Proc Am Soc Clin Oncol 19:301a, 2000.
90. Meropol NJ, Niedzwiecki D, Shank B, et al: Combined-modality therapy of poor risk anal canal carcinoma: A phase II study of the Cancer and Leukemia Group B (CALGB) (abstract 909). Proc Am Soc Clin Oncol 18:237a, 1999.
91. Pocard M, Tiret E, Nugent K, et al: Results of salvage abdominoperineal resection for anal cancer after radiotherapy. Dis Colon Rectum 41:1488-1493, 1998.
92. Allal AS, Laurencet FM, Reymond MA, et al: Effectiveness of surgical salvage therapy for patients with locally uncontrolled anal carcinoma after sphincter-conserving treatment. Cancer 85:1686-1693, 1999.
93. Klas JV, Rothenberger DA, Wong WD, et al: Malignant tumors of the anal canal: The spectrum of disease, treatment, and outcomes. Cancer 86:405-409, 1999.
94. Zimm S, Wampler GL: Response of metastatic cloacogenic carcinoma to treatment with sestamustine. Cancer 48:2575-2576, 1981.
95. Khater R, Frenay M, Bourry J, et al: Cisplatin plus 5-fluorouracil in the treatment of metastatic anal squamous cell carcinoma: A report of two cases. Cancer Treat Rep 70:1345- 1346, 1986.
96. Ajani JA, Carrasco CH, Jackson DE, et al: Combination of cisplatin plus fluoropyrimidine chemotherapy effective against liver metastases from carcinoma of the anal canal. Am J Med 87:221-224, 1989.
 
Loading comments...
Please Wait 20 seconds or click here to close