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Radiation Oncology

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Open Access 01-12-2006 | Research

Local tumor control and toxicity in HIV-associated anal carcinoma treated with radiotherapy in the era of antiretroviral therapy

Authors: Christoph Oehler-Jänne, Burkhardt Seifert, Urs M Lütolf, I Frank Ciernik

Published in: Radiation Oncology | Issue 1/2006

Abstract

Purpose

To investigate the outcome of HIV-seropositive patients under highly active antiretroviral treatment (HAART) with anal cancer treated with radiotherapy (RT) alone or in combination with standard chemotherapy (CT).

Patients and methods

Clinical outcome of 81 HIV-seronegative patients (1988 – 2003) and 10 consecutive HIV-seropositive patients under HAART (1997 – 2003) that were treated with 3-D conformal RT of 59.4 Gy and standard 5-fluorouracil and mitomycin-C were retrospectively analysed. 10 TNM-stage and age matched HIV-seronegative patients (1992 – 2003) were compared with the 10 HIV-seropositive patients. Pattern of care, local disease control (LC), overall survival (OS), cancer-specific survival (CSS), and toxicity were assessed.

Results

RT with or without CT resulted in complete response in 100 % of HIV-seropositive patients. LC was impaired compared to matched HIV-seronegative patients after a median follow-up of 44 months (p = 0.03). OS at 5 years was 70 % in HIV-seropositive patients receiving HAART and 69 % in the matched controls. Colostomy-free survival was 70 % (HIV+) and 100 % (matched HIV-) and 78 % (all HIV-). No HIV-seropositive patient received an interstitial brachytherapy boost compared to 42 % of all HIV-seronegative patients and adherence to chemotherapy seemed to be difficult in HIV-seropositive patients. Acute hematological toxicity reaching 50 % was high in HIV-seropositive patients receiving MMC compared with 0 % in matched HIV-seronegative patients (p = 0.05) or 12 % in all HIV-seronegative patients. The rate of long-term side effects was low in HIV-seropositive patients.

Conclusion

Despite high response rates to organ preserving treatment with RT with or without CT, local tumor failure seems to be high in HIV-positive patients receiving HAART. HIV-seropositive patients are subject to treatment bias, being less likely treated with interstitial brachytherapy boost probably due to HIV-infection, and they are at risk to receive less chemotherapy.

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Bower M, Powles T, Newsom-Davis T, Thirlwell C, Stebbing J, Mandalia S, Nelson M, Gazzard B: HIV-Associated Anal Cancer: Has Highly Active Antiretroviral Therapy Reduced the Incidence or Improved the Outcome? J Acquir Immune Defic Syndr 2004,37(5):1563-1565.CrossRefPubMed

Chiao EY, Schrag D: Anal cancer incidence in relation to HIV epidemiology. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 4080; 2004.

Melbye M, Cote TR, Kessler L, Gail M, Biggar RJ: High incidence of anal cancer among AIDS patients. The AIDS/Cancer Working Group. Lancet 1994,343(8898):636-639. 10.1016/S0140-6736(94)92636-0CrossRefPubMed

Goedert JJ: The epidemiology of acquired immunodeficiency syndrome malignancies. Semin Oncol 2000,27(4):390-401.PubMed

Nilsson PJ, Svensson C, Goldman S, Ljungqvist O, Glimelius B: Epidermoid anal cancer: a review of a population-based series of 308 consecutive patients treated according to prospective protocols. Int J Radiat Oncol Biol Phys 2005,61(1):92-102. 10.1016/j.ijrobp.2004.03.034CrossRefPubMed

Flam M, John M, Pajak TF, Petrelli N, Myerson R, Doggett S, Quivey J, Rotman M, Kerman H, Coia L, Murray K: 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 1996,14(9):2527-2539.PubMed

Efron JE, Pikarsky AJ, Gervaz P, Locker G, Weiss EG, Wexner SD, Nogueras JJ: The efficacy of chemoradiation therapy in HIV seropositive patients with squamous cell carcinoma of the anus. Colorectal Dis 2001,3(6):402-405. 10.1046/j.1463-1318.2001.00281.xCrossRefPubMed

Kim JH, Sarani B, Orkin BA, Young HA, White J, Tannebaum I, Stein S, Bennett B: HIV-positive patients with anal carcinoma have poorer treatment tolerance and outcome than HIV-negative patients. Dis Colon Rectum 2001,44(10):1496-1502. 10.1007/BF02234605CrossRefPubMed

Vatra B, Sobhani I, Aparicio T, Girard PM, Puy Montbrun TD, Housset M, Baillet F, Hecht F, Chossidow D, Soule JC: [Anal canal squamous-cell carcinomas in HIV positive patients: clinical features, treatments and prognosis]. Gastroenterol Clin Biol 2002,26(2):150-156.PubMed

10.

Bottomley DM, Aqel N, Selvaratnam G, Phillips RH: Epidermoid anal cancer in HIV infected patients. Clin Oncol (R Coll Radiol) 1996,8(5):319-322.CrossRef

11.

Peddada AV, Smith DE, Rao AR, Frost DB, Kagan AR: Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 1997,37(5):1101-1105. 10.1016/S0360-3016(96)00596-2CrossRefPubMed

12.

Chadha M, Rosenblatt EA, Malamud S, Pisch J, Berson A: Squamous-cell carcinoma of the anus in HIV-positive patients. Dis Colon Rectum 1994,37(9):861-865. 10.1007/BF02052589CrossRefPubMed

13.

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

14.

Place RJ, Gregorcyk SG, Huber PJ, Simmang CL: Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum 2001,44(4):506-512. 10.1007/BF02234322CrossRefPubMed

15.

Hocht S, Wiegel T, Kroesen AJ, Berdel WE, Runkel N, Hinkelbein W: Low acute toxicity of radiotherapy and radiochemotherapy in patients with cancer of the anal canal and HIV-infection. Acta Oncol 1997,36(8):799-802.CrossRefPubMed

16.

Hoffman R, Welton ML, Klencke B, Weinberg V, Krieg R: 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 1999,44(1):127-131. 10.1016/S0360-3016(98)00528-8CrossRefPubMed

17.

Allen-Mersh T, Hanna-Morris AJ, Goldstone SE, Sparano JA, Elrafei T, Bower M: Is chemoradiation the treatment of choice for anal squamous cell carcinoma developing in HIV-positive patients with access to highly active antiretroviral therapy? 2004, 233.

18.

Kinsella TJ, Kinsella MT, Reynolds H, Remick S:Comparable Tumor Response and Acute/Late Normal Tissue Toxicities with Standard Combined Modality Treatment for anal Squamous Cell Carcinomas in HIV+ and HIV- Patients. Volume 63. Int J Radiat Oncol Biol Phys; 2005:S16.

19.

AJCC: Cancer Staging Handbook, TNM Classification of Malignant Tumors, 6th edition. 2002, 139-144.

20.

CTCAE: Common Terminology Criteria for Adverse Events v3.0. http://ctepcancergov 2003.

21.

Bhaskaran K, Brettle R, Porter K, Walker AS: Systemic non-Hodgkin lymphoma in individuals with known dates of HIV seroconversion: incidence and predictors. Aids 2004,18(4):673-681.CrossRefPubMed

22.

Bourboulia D, Aldam D, Lagos D, Allen E, Williams I, Cornforth D, Copas A, Boshoff C: Short- and long-term effects of highly active antiretroviral therapy on Kaposi sarcoma-associated herpesvirus immune responses and viraemia. Aids 2004,18(3):485-493. 10.1097/00002030-200402200-00015CrossRefPubMed

23.

Palefsky JM, Holly EA, Gonzales J, Berline J, Ahn DK, Greenspan JS: Detection of human papillomavirus DNA in anal intraepithelial neoplasia and anal cancer. Cancer Res 1991,51(3):1014-1019.PubMed

24.

Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, Berry JM, Jay N, Darragh TM: Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV-positive and HIV-negative homosexual men. J Acquir Immune Defic Syndr Hum Retrovirol 1998,17(4):314-319.CrossRefPubMed

25.

Palefsky JM: Human papillomavirus infection and anogenital neoplasia in human immunodeficiency virus-positive men and women. J Natl Cancer Inst Monogr 1998, 15-20.

26.

Palefsky JM: Anal squamous intraepithelial lesions: relation to HIV and human papillomavirus infection. J Acquir Immune Defic Syndr 1999, 21 Suppl 1: S42-8.PubMed

27.

Baillargeon J, Pollock BH, Leach CT, Gao SJ: The association of neoplasms and HIV infection in the correctional setting. Int J STD AIDS 2004,15(5):348-351. 10.1258/095646204323012869PubMedCentralCrossRefPubMed

28.

Piketty C, Darragh TM, Da Costa M, Bruneval P, Heard I, Kazatchkine MD, Palefsky JM: High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse. Ann Intern Med 2003,138(6):453-459.CrossRefPubMed

29.

Heard I, Palefsky JM, Kazatchkine MD: The impact of HIV antiviral therapy on human papillomavirus (HPV) infections and HPV-related diseases. Antivir Ther 2004,9(1):13-22.PubMed

30.

Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997,277(5322):112-116. 10.1126/science.277.5322.112CrossRefPubMed

31.

Imami N, Antonopoulos C, Hardy GA, Gazzard B, Gotch FM: Assessment of type 1 and type 2 cytokines in HIV type 1-infected individuals: impact of highly active antiretroviral therapy. AIDS Res Hum Retroviruses 1999,15(17):1499-1508. 10.1089/088922299309784CrossRefPubMed

32.

Plana M, Garcia F, Gallart T, Tortajada C, Soriano A, Palou E, Maleno MJ, Barcelo JJ, Vidal C, Cruceta A, Miro JM, Gatell JM: Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection. Aids 2000,14(13):1921-1933. 10.1097/00002030-200009080-00007CrossRefPubMed

33.

Behbahani H, Landay A, Patterson BK, Jones P, Pottage J, Agnoli M, Andersson J, Spetz AL: Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2000,25(2):150-156. 10.1097/00042560-200010010-00009CrossRefPubMed

34.

Macias J, Japon MA, Leal M, Saez C, Pineda JA, Segura DI, Ortega J, Lissen E: Structural normalization of the lymphoid tissue in asymptomatic HIV-infected patients after 48 weeks of potent antiretroviral therapy. Aids 2001,15(18):2371-2378. 10.1097/00002030-200112070-00004CrossRefPubMed

35.

Parato KG, Kumar A, Badley AD, Sanchez-Dardon JL, Chambers KA, Young CD, Lim WT, Kravcik S, Cameron DW, Angel JB: Normalization of natural killer cell function and phenotype with effective anti-HIV therapy and the role of IL-10. Aids 2002,16(9):1251-1256. 10.1097/00002030-200206140-00007CrossRefPubMed

36.

Hardy GA, Imami N, Sullivan AK, Pires A, Burton CT, Nelson MR, Gazzard BG, Gotch FM: Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness. Clin Exp Immunol 2003,134(1):98-106. 10.1046/j.1365-2249.2003.02256.xPubMedCentralCrossRefPubMed

37.

Ciernik IF, Cone RW, Fehr J, Weber R: Impaired liver function and retroviral activity are risk factors contributing to HIV-associated thrombocytopenia. Swiss HIV Cohort Study. Aids 1999,13(14):1913-1920. 10.1097/00002030-199910010-00014CrossRefPubMed

38.

Aukrust P, Haug CJ, Ueland T, Lien E, Muller F, Espevik T, Bollerslev J, Froland SS: Decreased bone formative and enhanced resorptive markers in human immunodeficiency virus infection: indication of normalization of the bone-remodeling process during highly active antiretroviral therapy. J Clin Endocrinol Metab 1999,84(1):145-150. 10.1210/jc.84.1.145PubMed

39.

Viani RM, Dankner WM, Muelenaer PA, Spector SA: Resolution of HIV-associated nephrotic syndrome with highly active antiretroviral therapy delivered by gastrostomy tube. Pediatrics 1999,104(6):1394-1396. 10.1542/peds.104.6.1394CrossRefPubMed

40.

Chang L, Ernst T, Leonido-Yee M, Witt M, Speck O, Walot I, Miller EN: Highly active antiretroviral therapy reverses brain metabolite abnormalities in mild HIV dementia. Neurology 1999,53(4):782-789.CrossRefPubMed

41.

Antoniou T, Tseng AL: Interactions Between Antiretrovirals and Antineoplastic Drug Therapy. Clin Pharmacokinet 2005,44(2):111-145. 10.2165/00003088-200544020-00001CrossRefPubMed

42.

Sparano JA, Wiernik PH, Hu X, Sarta C, Henry DH, Ratech H: Saquinavir enhances the mucosal toxicity of infusional cyclophosphamide, doxorubicin, and etoposide in patients with HIV-associated non-Hodgkin's lymphoma. Med Oncol 1998,15(1):50-57.CrossRefPubMed

43.

Pajonk F, Himmelsbach J, Riess K, Sommer A, McBride WH: The human immunodeficiency virus (HIV)-1 protease inhibitor saquinavir inhibits proteasome function and causes apoptosis and radiosensitization in non-HIV-associated human cancer cells. Cancer Res 2002,62(18):5230-5235.PubMed

44.

Shepherd NA, Scholefield JH, Love SB, England J, Northover JM: Prognostic factors in anal squamous carcinoma: a multivariate analysis of clinical, pathological and flow cytometric parameters in 235 cases. Histopathology 1990,16(6):545-555.CrossRefPubMed

45.

Greenall MJ, Quan SH, Stearns MW, Urmacher C, DeCosse JJ: Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results. Am J Surg 1985,149(1):95-101. 10.1016/S0002-9610(85)80016-7CrossRefPubMed

46.

Stearns MWJ, Urmacher C, Sternberg SS, Woodruff J, Attiyeh F: Cancer of the anal canal. Curr Probl Cancer 1980,4(12):1-44.CrossRefPubMed

47.

Cleator S, Fife K, Nelson M, Gazzard B, Phillips R, Bower M: Treatment of HIV-associated invasive anal cancer with combined chemoradiation. Eur J Cancer 2000,36(6):754-758. 10.1016/S0959-8049(00)00009-5CrossRefPubMed

48.

Stadler RF, Gregorcyk SG, Euhus DM, Place RJ, Huber PJ, Simmang CL: Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy. Dis Colon Rectum 2004,47(8):1305-1309. 10.1007/s10350-004-0584-1CrossRefPubMed

49.

Adler W, Lee FC, Wong G: Capecitabine, mitomycin C & radiation for HIV patients with anal squamous cell carcinoma. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 4239; 2004.

50.

Blazy A, Hennequin C, Gornet JM, Furco A, Gerard L, Lemann M, Maylin C: Anal carcinomas in HIV-positive patients: high-dose chemoradiotherapy is feasible in the era of highly active antiretroviral therapy. Dis Colon Rectum 2005,48(6):1176-1181. 10.1007/s10350-004-0910-7CrossRefPubMed

51.

Bartelink H, Roelofsen F, Eschwege F, Rougier P, Bosset JF, Gonzalez DG, Peiffert D, van Glabbeke M, Pierart M: Concomitant 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 1997,15(5):2040-2049.PubMed

52.

Chauveinc L, Buthaud X, Falcou MC, Mosseri V, De la Rochefordiere A, Pierga JY, Girodet J, Salmon RJ: Anal canal cancer treatment: practical limitations of routine prescription of concurrent chemotherapy and radiotherapy. Br J Cancer 2003,89(11):2057-2061. 10.1038/sj.bjc.6601378PubMedCentralCrossRefPubMed

53.

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 1996,348(9034):1049-1054. 10.1016/S0140-6736(96)03409-5

54.

Bosset JF, Roelofsen F, Morgan DA, Budach V, Coucke P, Jager JJ, Van der Steen-Banasik E, Triviere N, Stuben G, Puyraveau M, Mercier M: Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinomas. Results of a phase II study of the European Organization for Research and Treatment of Cancer. Radiotherapy and Gastrointestinal Cooperative Groups. Eur J Cancer 2003,39(1):45-51. 10.1016/S0959-8049(02)00377-5CrossRefPubMed

55.

Cummings BJ, Keane TJ, O'Sullivan B, Wong CS, Catton CN: Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 1991,21(5):1115-1125.CrossRefPubMed

56.

Papillon J, Montbarbon JF, Gerard JP, Chassard JL, Ardiet JM: Interstitial curietherapy in the conservative treatment of anal and rectal cancers. Int J Radiat Oncol Biol Phys 1989,17(6):1161-1169.CrossRefPubMed

57.

Dubois JB, Garrigues JM, Pujol H: Cancer of the anal canal: report on the experience of 61 patients. Int J Radiat Oncol Biol Phys 1991,20(3):575-580.CrossRefPubMed

58.

Ager P, Samala E, Bosworth J, Rubin M, Ghossein NA: The conservative management of anorectal cancer by radiotherapy. Am J Surg 1979,137(2):228-230. 10.1016/0002-9610(79)90151-XCrossRefPubMed

59.

Ng Ying Kin NY, Pigneux J, Auvray H, Brunet R, Thomas L, Denepoux R: Our experience of conservative treatment of anal canal carcinoma combining external irradiation and interstitial implant: 32 cases treated between 1973 and 1982. Int J Radiat Oncol Biol Phys 1988,14(2):253-259.CrossRefPubMed

60.

Boman BM, Moertel CG, O'Connell MJ, Scott M, Weiland LH, Beart RW, Gunderson LL, Spencer RJ: Carcinoma of the anal canal. A clinical and pathologic study of 188 cases. Cancer 1984,54(1):114-125. PublisherFullText 10.1002/1097-0142(19840701)54:1<114::AID-CNCR2820540124>3.0.CO;2-PCrossRefPubMed

61.

Myerson RJ, Karnell LH, Menck HR: The National Cancer Data Base report on carcinoma of the anus. Cancer 1997,80(4):805-815. PublisherFullText 10.1002/(SICI)1097-0142(19970815)80:4<805::AID-CNCR20>3.0.CO;2-WCrossRefPubMed

62.

Goldman S, Auer G, Erhardt K, Seligson U: Prognostic significance of clinical stage, histologic grade, and nuclear DNA content in squamous-cell carcinoma of the anus. Dis Colon Rectum 1987,30(6):444-448.CrossRefPubMed

63.

Goldman S, Glimelius B, Glas U, Lundell G, Pahlman L, Stahle E: Management of anal epidermoid carcinoma--an evaluation of treatment results in two population-based series. Int J Colorectal Dis 1989,4(4):234-243. 10.1007/BF01644988CrossRefPubMed

Title: Local tumor control and toxicity in HIV-associated anal carcinoma treated with radiotherapy in the era of antiretroviral therapy
Authors: Christoph Oehler-Jänne
Burkhardt Seifert
Urs M Lütolf
I Frank Ciernik
Publication date: 01-12-2006
Publisher: BioMed Central
Published in: Radiation Oncology / Issue 1/2006
Electronic ISSN: 1748-717X
DOI: https://doi.org/10.1186/1748-717X-1-29

At a glance: The STEP trials

Springer Medicine

Local tumor control and toxicity in HIV-associated anal carcinoma treated with radiotherapy in the era of antiretroviral therapy

Abstract

Purpose

Patients and methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Patients and methods

Results

Conclusion

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