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Squamous cell carcinoma of the anus in patients with AIDS
Clinical Oncology (1995) 7:50-51 © 1995 The Royal College of Radiologists
Clinical Oncology
Case Report Squamous Cell Carcinoma of the Anus in Patients with AIDS M. Harrison 1'2, D. T o m l i n s o n 2 a n d S. S t e w a r t 2 1Clare Hall L a b o r a t o r i e s , I m p e r i a l C a n c e r R e s e a r c h F u n d , South M i m m s , H e r t f o r d s h i r e ; and 2St M a r y ' s Hospital, P r a e d Street, L o n d o n , U K
Abstract. Squamous cell carcinoma of the anus accounts for 2%-3% of all malignancies of the lower gastrointestinal tract. There is an increased incidence in homosexual males who practise receptive and anal intercourse [1]. We report on three cases of squamous cell carcinoma of the anus in patients with the acquired immune deficiency syndrome (AIDS), all of whom were treated with conventional radiotherapy. Increased normal tissue damage with delayed healing was a severe problem in each patient. This led to prolonged delays in delivering an adequate dose of radiotherapy to the site of disease. Reasons for this are explored and suggestions made for the treatment of such patients in the future.
Keywords: AIDS; Anal carcinoma; Radiotherapy
INTRODUCTION Anal cancer in the general population has an incidence of 1/200 000 per year. There is an increased incidence in the male homosexual population who practise receptive anal intercourse. A number of factors are implicated in this process, including human papillomavirus (HPV) infection and anal irritation [1-5]. Unlike cervical cancer, anal cancer is not an AIDS defining illness in patients who are infected with the human immunodeficiency virus (HIV). Treatment of anal cancer may be with surgery, radiotherapy, or combined radiotherapy and chemotherapy. Response rates are high, with 5-year survival rates of 70% or higher for patients with early stage disease. Conventional treatment with radiotherapy involves fractionated external beam treatment to the primary site of disease and draining lymph nodes, with concomitant chemotherapy and the possibility of an interstitial implant to increase the local tumour dose [6-9].
Correspondence and offprint requests to: M. Harrison, Clinical Research Fellow, Clare Hall Laboratories, Imperial Cancer Research Fund, South Mimms, Hertfordshire EN6, UK.
PATIENTS All patients had AIDS according to the 1993 Center for Disease Control revised classification. Prior infection due to Pneumocystis carinii was seen in two cases and the presence of Kaposi's sarcoma in the other. All three had CD4 counts of less than 200/mm 3.
Patient 1 A 25-year-old male prostitute presented with T2N0 anal cancer diagnosed following a routine medical examination as follow-up for AIDS. Squamous cell carcinoma was confirmed by biopsy and a defunctioning colostomy formed. Radiotherapy was initiated with 6 MV photons using parallel opposed fields to the disease site and draining nodes. After eight fractions at 2 Gy per fraction, treatment was halted due to severe normal tissue reaction with breakdown around the tumour. Treatment was stopped for 14 days then re-initiated and stopped again after three further fractions. Treatment was then delayed for a further 21 days whilst the patient required inpatient care and opiate analgesia. A final five fractions of treatment were given using 250 KV as a direct anal field. In total, a dose of 32 Gy in 16 fractions over 51 days was given. Followup at 4 weeks subsequent to treatment showed no tumour but there was severe, continued normal tissue damage. A review at 3 months found no evidence of recurrence, with some healing in the area of normal tissue damage. The patient died prior to the next follow-up due to Pcarinii pneumonia.
Patient 2 A 39-year-old man had a T2No squamous cell cancer of the anus diagnosed after a 4-week history of anal discomfort and bleeding. The patient was on a study of chemotherapy for Kaposi's sarcoma. A defunctioning colostomy was formed and radiotherapy given as an inpatient; 45 Gy in 20 fractions over 4 weeks was given to the primary site and draining nodes with 6 MV photons. There was severe normal tissue breakdown in the second and third week of treatment, but treatment continued. Inpatient care was required for 2 months
after completion of radiotherapy. Wound debridement was necessary on two occasions and superadded Pseudomonas aeruginosa required three courses of systemic intravenous antibiotics. Follow-up at 7 months showed no evidence of recurrent disease but continued normal tissue breakdown.
Patient 3 A 62-year old man presented with a 1month history of anal pain and bleeding. Squamous cell carcinoma was diagnosed on biopsy and staged as T2No. A defunctioning colostomy was refused at this stage. Radiotherapy was initiated but halted after ten fractions at 2 Gy per fraction, due to severe normal tissue breakdown. Hospice care was required for analgesia and wound toilet. Twenty-one days later radiotherapy was restarted but stopped again after nine further fractions, due to the recurrence of severe wound breakdown. Inpatient care was necessary. Poor healing necessitated the formation of a defunctioning colostomy. Postoperative recovery was poor and the patient died after 7 days.
DISCUSSION Most AIDS patients who develop cancer develop Kaposi's sarcoma or high grade non-Hodgkin's lymphoma; other, solid tumours are relatively uncommon [10]. Treatment of anal cancer in patients with AIDS has not been reported. The pathogenesis of anal cancer in homosexual men is causally related to a variety of factors. Receptive anal intercourse predisposes to anal irritation, HPV transmission, and the development of anal intraepithelial neoplasia. This is reflected in the increased incidence of anal cancer in a cohort of younger, homosexual men than would otherwise be expected [1-3]. The same group of patients at risk for anal cancer are also the same risk group for developing AIDS and one would expect that, within this group, a higher incidence of anal cancer would be noted. Epidemiological evidence data confirming this are not yet available. Cervical squamous cell carcinoma, in HIV infected women is now an AIDS defining illness and similar risk factors for cervical
S q u a m o u s Cell Carcinoma of the A n u s in Patients with A I D S cancer would also be risk factors for m e n with anal cancer. H P V s 16, 18 and 31 have all been demonstrated within both cervical cancer tissues and anal cancer tissues [11,12]. T h e increasing i m m u n o s u p p r e s s i o n found with H I V infection leads to an associated increase in viral wart infection [13]. Direct activation of H P V by H I V has also been reported [14]. The incidence of anal abnormalities within H I V infected m e n correlates with m o r e advanced stage disease. Within this group cytological abnormalities progress relatively rapidly [15]. T h e patients within our study were all seen regularly, and in all three cases s y m p t o m s lasted less than 6 weeks. T u m o u r s were all T2. Increasing length of survival of patients with A I D S , due to improved m a n a g e m e n t of opportunistic infections and the use of antiretroviral agents, has led to an increased n u m b e r of patients requiring treatment of cancer. Strategies for the treatment of these malignancies differ, in that palliation rather than attempted cure is m o r e important, given the underlying disease. In the general population, treatment of anal cancer with surgery results in a cure for approximately 50% of patients, though at the expense of an abdominoperineal resection and p e r m a n e n t colostomy. Combined radiotherapy and c h e m o t h e r a p y leads to response rates in excess of 70%, with relatively low complication rates. The current United K i n g d o m Co-ordinating C o m m i t t e e on Cancer R e s e a r c h ( U K C C R ) study advises a dose of 45 Gy in 20 fractions, with or without concomitant chemotherapy, and a follow-up examination under anaesthetic 6 weeks after the completion of external b e a m radiotherapy. Patients receiving conventional radiotherapy of this type would be expected to tolerate the treatment well, with signs of early normal tissue damage occurring at the end of the second week of radiotherapy. It is rare for t r e a t m e n t to be stopped due to severe, acute side effects. In all three of our patients, the acute early normal tissue damage was m u c h m o r e
severe than would be expected. R e a s o n s for this acute normal tissue toxicity when irradiating patients with A I D S remain unclear, but they are probably multifactorial, with increased cellular damage associated with a local i m m u n e defect secondary to the decreased T 4 cell count. Conventional treatment regimens thus appear to be too toxic for consideration in patients with anal cancer and AIDS. Options for treatment include surgery (though this is also a marked risk in patients with AIDS), local therapies such as liquid nitrogen and laser therapy (which, for larger lesions, would be inappropriate), and anal implants (perhaps to a lower total dose). For future patients we will r e c o m m e n d a defunctioning colostomy and implant if possible. If external b e a m radiotherapy is the only treatment option then inpatient care, with scrupulous attention to the irradiated site and daily on-treatment review, will be necessary. A n initial course of 20-25 Gy in 2 Gy fractions, followed by a detailed review, is probably optimal. For patients who tolerate this, a further 10-15 Gy should be given with a view to stopping if there is any sign of skin breakdown. In patients who do not. tolerate such treatm e n t , a rest should be given and treatment only restarted if the benefits of radiotherapy are thought to outweigh the deficits. For m a n y patients at this stage of H I V infection survival is only a matter of m o n t h s , and adequate palliation rather than attempted cure is essential.
References 1. Daling JR, Weiss NS, Hislop TG, et al. Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 1987;317:973-7. 2. Palefsky JM, Holly EA, Gonzales J, et al. Detection of human papillomavirus DNA in anal intra-epithelial neoplasia and anal cancer. Cancer Res 1991;51:1014-9. 3. Beckmann, AM, Daling JR, Sherman KJ, et al. Human papillomavirus infection and anal cancer. Int J Cancer 1989;43:1042-9.
51 4. Judson FN. Interactions between human papillomavirus and human immunodeficiency virus infections In: Munoz N, Bosch FX, Shah KV, Meheus A. The epidemiology of cervical cancer and human papilloma virus. IARC Scientific Publications No. 9 1992: 199-207. 5. Palefsky JM. Human papillomavirusassociated anogenital neoplasia and other solid tumours in human immunodeficiency virus-infected individuals. Curr Opin Oncol i991 ;3:881-5. 6. Cummings BJ. Anal cancer. Int J Radiat Oncol Biol Phys 1990;19:1309-15. 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 1985;11:1587-93. 8. Shank B, Cohen AM, Kelsen ND. Cancer of the anal region. In DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and practice of oncology. 3rd ed. 1989:96578. 9. Cantrill ST, Green JP, Schall GL, et al. Primary radiation therapy in the treatment of anal carcinoma. Int J Radiat Oncol Biol Phys 1983;9:1271-8. 10. Levine A. AIDS related malignancies - the emerging epidemic. J Natl Cancer Inst 1993;85:1382-97. 11. Feingold AR, Vermund SH, Burk RD, et ah Cervical cytologic abnormalities and papillomavirus in women infected with human immunodeficiency virus. J Acquir Immune Defic Syndr 1990;3:896-903. 12. Palefsky JM, Gonzales J, Greenblatt RM, et ah Anal intraepithelial neoplasia and anal papillomavirus infection among homosexual males with group IV HIV disease. JAMA 1990 ;263:1911-6. 13. Caussy D, Goedert JJ, Palefsky JM, et al. Interactions of human immunodeficiency and papiUomaviruses: Association with anal epithelial abnormality in homosexual men. Int J Cancer 1990;46:214-9. 14. Vernon SD, Hart CE, Reeves WC, et al. The HIV 1 tat protein enhances E2 dependent human papillomavirus 16 transcription. Virus Res 1993;27:133-45. 15. Palefsky JM, Holly EA, Gonzales J, et al. Natural history of anal cytologic abnormalities and papillomavirus infection with group IV HIV disease. J Acquire Immune Defic Syndr 1992;5:1258-65.
Received for publication March 1994 Accepted following revision April 1994
Clinical Oncology
Case Report Squamous Cell Carcinoma of the Anus in Patients with AIDS M. Harrison 1'2, D. T o m l i n s o n 2 a n d S. S t e w a r t 2 1Clare Hall L a b o r a t o r i e s , I m p e r i a l C a n c e r R e s e a r c h F u n d , South M i m m s , H e r t f o r d s h i r e ; and 2St M a r y ' s Hospital, P r a e d Street, L o n d o n , U K
Abstract. Squamous cell carcinoma of the anus accounts for 2%-3% of all malignancies of the lower gastrointestinal tract. There is an increased incidence in homosexual males who practise receptive and anal intercourse [1]. We report on three cases of squamous cell carcinoma of the anus in patients with the acquired immune deficiency syndrome (AIDS), all of whom were treated with conventional radiotherapy. Increased normal tissue damage with delayed healing was a severe problem in each patient. This led to prolonged delays in delivering an adequate dose of radiotherapy to the site of disease. Reasons for this are explored and suggestions made for the treatment of such patients in the future.
Keywords: AIDS; Anal carcinoma; Radiotherapy
INTRODUCTION Anal cancer in the general population has an incidence of 1/200 000 per year. There is an increased incidence in the male homosexual population who practise receptive anal intercourse. A number of factors are implicated in this process, including human papillomavirus (HPV) infection and anal irritation [1-5]. Unlike cervical cancer, anal cancer is not an AIDS defining illness in patients who are infected with the human immunodeficiency virus (HIV). Treatment of anal cancer may be with surgery, radiotherapy, or combined radiotherapy and chemotherapy. Response rates are high, with 5-year survival rates of 70% or higher for patients with early stage disease. Conventional treatment with radiotherapy involves fractionated external beam treatment to the primary site of disease and draining lymph nodes, with concomitant chemotherapy and the possibility of an interstitial implant to increase the local tumour dose [6-9].
Correspondence and offprint requests to: M. Harrison, Clinical Research Fellow, Clare Hall Laboratories, Imperial Cancer Research Fund, South Mimms, Hertfordshire EN6, UK.
PATIENTS All patients had AIDS according to the 1993 Center for Disease Control revised classification. Prior infection due to Pneumocystis carinii was seen in two cases and the presence of Kaposi's sarcoma in the other. All three had CD4 counts of less than 200/mm 3.
Patient 1 A 25-year-old male prostitute presented with T2N0 anal cancer diagnosed following a routine medical examination as follow-up for AIDS. Squamous cell carcinoma was confirmed by biopsy and a defunctioning colostomy formed. Radiotherapy was initiated with 6 MV photons using parallel opposed fields to the disease site and draining nodes. After eight fractions at 2 Gy per fraction, treatment was halted due to severe normal tissue reaction with breakdown around the tumour. Treatment was stopped for 14 days then re-initiated and stopped again after three further fractions. Treatment was then delayed for a further 21 days whilst the patient required inpatient care and opiate analgesia. A final five fractions of treatment were given using 250 KV as a direct anal field. In total, a dose of 32 Gy in 16 fractions over 51 days was given. Followup at 4 weeks subsequent to treatment showed no tumour but there was severe, continued normal tissue damage. A review at 3 months found no evidence of recurrence, with some healing in the area of normal tissue damage. The patient died prior to the next follow-up due to Pcarinii pneumonia.
Patient 2 A 39-year-old man had a T2No squamous cell cancer of the anus diagnosed after a 4-week history of anal discomfort and bleeding. The patient was on a study of chemotherapy for Kaposi's sarcoma. A defunctioning colostomy was formed and radiotherapy given as an inpatient; 45 Gy in 20 fractions over 4 weeks was given to the primary site and draining nodes with 6 MV photons. There was severe normal tissue breakdown in the second and third week of treatment, but treatment continued. Inpatient care was required for 2 months
after completion of radiotherapy. Wound debridement was necessary on two occasions and superadded Pseudomonas aeruginosa required three courses of systemic intravenous antibiotics. Follow-up at 7 months showed no evidence of recurrent disease but continued normal tissue breakdown.
Patient 3 A 62-year old man presented with a 1month history of anal pain and bleeding. Squamous cell carcinoma was diagnosed on biopsy and staged as T2No. A defunctioning colostomy was refused at this stage. Radiotherapy was initiated but halted after ten fractions at 2 Gy per fraction, due to severe normal tissue breakdown. Hospice care was required for analgesia and wound toilet. Twenty-one days later radiotherapy was restarted but stopped again after nine further fractions, due to the recurrence of severe wound breakdown. Inpatient care was necessary. Poor healing necessitated the formation of a defunctioning colostomy. Postoperative recovery was poor and the patient died after 7 days.
DISCUSSION Most AIDS patients who develop cancer develop Kaposi's sarcoma or high grade non-Hodgkin's lymphoma; other, solid tumours are relatively uncommon [10]. Treatment of anal cancer in patients with AIDS has not been reported. The pathogenesis of anal cancer in homosexual men is causally related to a variety of factors. Receptive anal intercourse predisposes to anal irritation, HPV transmission, and the development of anal intraepithelial neoplasia. This is reflected in the increased incidence of anal cancer in a cohort of younger, homosexual men than would otherwise be expected [1-3]. The same group of patients at risk for anal cancer are also the same risk group for developing AIDS and one would expect that, within this group, a higher incidence of anal cancer would be noted. Epidemiological evidence data confirming this are not yet available. Cervical squamous cell carcinoma, in HIV infected women is now an AIDS defining illness and similar risk factors for cervical
S q u a m o u s Cell Carcinoma of the A n u s in Patients with A I D S cancer would also be risk factors for m e n with anal cancer. H P V s 16, 18 and 31 have all been demonstrated within both cervical cancer tissues and anal cancer tissues [11,12]. T h e increasing i m m u n o s u p p r e s s i o n found with H I V infection leads to an associated increase in viral wart infection [13]. Direct activation of H P V by H I V has also been reported [14]. The incidence of anal abnormalities within H I V infected m e n correlates with m o r e advanced stage disease. Within this group cytological abnormalities progress relatively rapidly [15]. T h e patients within our study were all seen regularly, and in all three cases s y m p t o m s lasted less than 6 weeks. T u m o u r s were all T2. Increasing length of survival of patients with A I D S , due to improved m a n a g e m e n t of opportunistic infections and the use of antiretroviral agents, has led to an increased n u m b e r of patients requiring treatment of cancer. Strategies for the treatment of these malignancies differ, in that palliation rather than attempted cure is m o r e important, given the underlying disease. In the general population, treatment of anal cancer with surgery results in a cure for approximately 50% of patients, though at the expense of an abdominoperineal resection and p e r m a n e n t colostomy. Combined radiotherapy and c h e m o t h e r a p y leads to response rates in excess of 70%, with relatively low complication rates. The current United K i n g d o m Co-ordinating C o m m i t t e e on Cancer R e s e a r c h ( U K C C R ) study advises a dose of 45 Gy in 20 fractions, with or without concomitant chemotherapy, and a follow-up examination under anaesthetic 6 weeks after the completion of external b e a m radiotherapy. Patients receiving conventional radiotherapy of this type would be expected to tolerate the treatment well, with signs of early normal tissue damage occurring at the end of the second week of radiotherapy. It is rare for t r e a t m e n t to be stopped due to severe, acute side effects. In all three of our patients, the acute early normal tissue damage was m u c h m o r e
severe than would be expected. R e a s o n s for this acute normal tissue toxicity when irradiating patients with A I D S remain unclear, but they are probably multifactorial, with increased cellular damage associated with a local i m m u n e defect secondary to the decreased T 4 cell count. Conventional treatment regimens thus appear to be too toxic for consideration in patients with anal cancer and AIDS. Options for treatment include surgery (though this is also a marked risk in patients with AIDS), local therapies such as liquid nitrogen and laser therapy (which, for larger lesions, would be inappropriate), and anal implants (perhaps to a lower total dose). For future patients we will r e c o m m e n d a defunctioning colostomy and implant if possible. If external b e a m radiotherapy is the only treatment option then inpatient care, with scrupulous attention to the irradiated site and daily on-treatment review, will be necessary. A n initial course of 20-25 Gy in 2 Gy fractions, followed by a detailed review, is probably optimal. For patients who tolerate this, a further 10-15 Gy should be given with a view to stopping if there is any sign of skin breakdown. In patients who do not. tolerate such treatm e n t , a rest should be given and treatment only restarted if the benefits of radiotherapy are thought to outweigh the deficits. For m a n y patients at this stage of H I V infection survival is only a matter of m o n t h s , and adequate palliation rather than attempted cure is essential.
References 1. Daling JR, Weiss NS, Hislop TG, et al. Sexual practices, sexually transmitted diseases, and the incidence of anal cancer. N Engl J Med 1987;317:973-7. 2. Palefsky JM, Holly EA, Gonzales J, et al. Detection of human papillomavirus DNA in anal intra-epithelial neoplasia and anal cancer. Cancer Res 1991;51:1014-9. 3. Beckmann, AM, Daling JR, Sherman KJ, et al. Human papillomavirus infection and anal cancer. Int J Cancer 1989;43:1042-9.
51 4. Judson FN. Interactions between human papillomavirus and human immunodeficiency virus infections In: Munoz N, Bosch FX, Shah KV, Meheus A. The epidemiology of cervical cancer and human papilloma virus. IARC Scientific Publications No. 9 1992: 199-207. 5. Palefsky JM. Human papillomavirusassociated anogenital neoplasia and other solid tumours in human immunodeficiency virus-infected individuals. Curr Opin Oncol i991 ;3:881-5. 6. Cummings BJ. Anal cancer. Int J Radiat Oncol Biol Phys 1990;19:1309-15. 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 1985;11:1587-93. 8. Shank B, Cohen AM, Kelsen ND. Cancer of the anal region. In DeVita VT, Hellman S, Rosenberg SA, editors. Cancer: Principles and practice of oncology. 3rd ed. 1989:96578. 9. Cantrill ST, Green JP, Schall GL, et al. Primary radiation therapy in the treatment of anal carcinoma. Int J Radiat Oncol Biol Phys 1983;9:1271-8. 10. Levine A. AIDS related malignancies - the emerging epidemic. J Natl Cancer Inst 1993;85:1382-97. 11. Feingold AR, Vermund SH, Burk RD, et ah Cervical cytologic abnormalities and papillomavirus in women infected with human immunodeficiency virus. J Acquir Immune Defic Syndr 1990;3:896-903. 12. Palefsky JM, Gonzales J, Greenblatt RM, et ah Anal intraepithelial neoplasia and anal papillomavirus infection among homosexual males with group IV HIV disease. JAMA 1990 ;263:1911-6. 13. Caussy D, Goedert JJ, Palefsky JM, et al. Interactions of human immunodeficiency and papiUomaviruses: Association with anal epithelial abnormality in homosexual men. Int J Cancer 1990;46:214-9. 14. Vernon SD, Hart CE, Reeves WC, et al. The HIV 1 tat protein enhances E2 dependent human papillomavirus 16 transcription. Virus Res 1993;27:133-45. 15. Palefsky JM, Holly EA, Gonzales J, et al. Natural history of anal cytologic abnormalities and papillomavirus infection with group IV HIV disease. J Acquire Immune Defic Syndr 1992;5:1258-65.
Received for publication March 1994 Accepted following revision April 1994