Anal Carcinomas in HIV-Positive Patients: High-Dose Chemoradiotherapy Is Feasible in the Era of Highly Active Antiretroviral Therapy

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1 Anal Carcinomas in HIV-Positive Patients: High-Dose Chemoradiotherapy Is Feasible in the Era of Highly Active Antiretroviral Therapy Anne Blazy, M.D., 1 Christophe Hennequin, M.D., Ph.D., 1 Jean-Marc Gornet, M.D., 2 André Furco, M.D., 3 Laurence Gérard, M.D., 4 Marc Lémann, M.D., Ph.D., 2 Claude Maylin, M.D. 1 1 Service de Cancérologie-Radiothérapie, Hôpital Saint-Louis, Paris, France 2 Service de Gastro-entérologie, Hôpital Saint-Louis, Paris, France 3 Service des Maladies Infectieuses, Hôpital Saint-Louis, Paris, France 4 Service d Immuno-Hématologie, Hôpital Saint-Louis, Paris, France BACKGROUND: Anal carcinoma, a common disease in HIVpositive patients, is usually treated with chemoradiotherapy. Generally tolerance was poor before the availability of highly active antiretroviral therapies. We report our experience of treating anal carcinoma in the era of new antiviral drugs. PATIENTS AND METHODS: Between 1997 and 2001, nine men on highly active antiretroviral therapies with good immune status before chemoradiotherapy received concomitant chemoradiotherapy consisting of 5-fluorouracil and cisplatinum, and high-dose radiotherapy (60 70 Gy) for anal carcinoma. Six cancers were Stage I, two were Stage II, and one was Stage III. CD4+ cell counts were <200/ml for four patients, between 200/ml and 500/ml for four, and >500/ml for one. RESULTS: All patients received the planned dose of radiation ( 60 Gy). The chemotherapy dose was reduced 25 percent in six patients. Overall treatment time was 58 days. Grade 3 hematologic or skin toxicity occurred in four patients. No association was observed between high-grade toxicity and CD4+ cell count. None of the patients developed opportunistic infections during follow-up. Eight patients were disease-free after a median follow-up of 33 months. Among them, four had no or minor anal function impairment at the last follow-up visit. One Correspondence to: Christophe Hennequin, M.D., Ph.D., Service de Cancérologie-Radiothérapie, 1, avenue Claude Vellefeaux, 75475, Paris Cedex 10, France, christophe.hennequin@ sls.ap-hop-paris.fr Dis Colon Rectum 2005; 48: DOI: /s The American Society of Colon and Rectal Surgeons Published online: 27 April 2005 patient with T4N2 disease relapsed locally one year after treatment and underwent salvage abdominoperineal excision. CONCLUSION: High-dose chemoradiotherapy for anal carcinomas is feasible with low toxicity in HIV-positive patients treated with highly active antiretroviral therapies. Local control is similar to that obtained for HIV-negative patients. [Key words: Anal carcinoma; HIV; AIDS; Chemoradiotherapy] I n the general population, squamous-cell anal carcinoma is two times more frequent in women than in men and accounts for 1.5 percent of digestive tract cancers. 1 Human immunodeficiency virus positive (HIV+) patients are at higher risk of developing anal carcinoma 2,3 but, unlike cervical carcinoma, it is not considered an AIDS-defining illness. The risk of anal cancer is linked to human papilloma virus (HPV) infection. 4 6 Anal genital warts caused by HPV are significantly more frequent in homosexual men (10 to 50 percent of subclinical infections) 1,4 and anal cancer is more common among men with a history of anal intercourse, even those who are HIV negative. 7 The use of anal screening tests for HPV in HIV-infected patients remains controversial. 8 Immunodeficiency from HIV infection probably impairs the body s ability to clear HPV after sexual exposure and favors the progression of high-grade ano- 1176

2 Vol. 48, No. 6 ANAL CARCINOMAS IN HIV+ PATIENTS 1177 genital dysplasia to cancer lesions. 1,4,9 The rate of high-grade squamous intraepithelial lesion or neoplasia is higher in HIV+ patients than in HIV-negative men, and the risk of anal cancer is higher when the CD4+ cell count is <500/ml. 9,10 However, the direct role of HIV itself in the occurrence of anal cancer remains controversial. Highly active antiretroviral therapies (HAART) do not appear to modify the natural history of HPV infections. 10 Treatment of anal carcinomas in HIV-negative patients is based on concomitant chemoradiotherapy. 11,12 But this regimen is poorly tolerated by HIV+ patients and some authors have recommended lowering the dose and/or intensity of chemotherapy or radiotherapy. 13,14 Most of the patients from such studies were treated before the era of HAART. The availability of these new agents has rapidly changed the natural history and therapeutic results obtained in AIDS patients. However, the impact of HAART on the feasibility and outcome of high-dose chemoradiotherapy for anal carcinoma in HIV+ patients has been poorly assessed. We reviewed our experience of treating nine HIV+ men with anal carcinomas. All received concomitant high-dose chemoradiotherapy consisting of a two-drug regimen combining 5-fluorouracil (5-FU) and cisplatin and a total radiation dose ranging from 60 to 70 Gy. All nine were on HAART and their immune status was good when they underwent chemoradiotherapy for anal carcinoma. PATIENTS AND METHODS Population Between December 1997 and December 2001, nine HIV+ men were given concomitant chemoradiotherapy for squamous-cell carcinoma of the anal canal. Their characteristics are reported in Table 1. None had distant metastasis and the median tumor size was 2.4 cm. Most of them suffered from local pain, requiring opiates. Four patients had anal warts. Staging was clinically determined; endorectal ultrasonography was not routinely performed. Enlarged nodes were considered positive; no confirmatory biopsies were performed. However, the three patients considered node positive had very large tumors and the nodal involvement was not in doubt. All patients also had an abdominal and pelvic computed tomography (CT) scan to eliminate distant metastasis. Table 1. Patient Characteristics Parameter Centers for Disease Control and Prevention HIV Stage According to the Centers for Disease Control and Prevention (CDC) classification of HIV infection, four patients were in Group A, two were in Group B, and three were in Group C, which corresponds to AIDS. CD4+ cell counts were <200/ml in four patients, between 200/ml and 500/ml for four patients, and >500/ml for one patient. HIV serology has been known to be positive for a mean of six years (range, 3 months to 17 years). All patients were taking a combination of three or four HAARTs when diagnosed with anal cancer. No relationship between CDC HIV stage and tumor stage was found. Chemoradiotherapy Schedule Value Patients (n) 9 Mean age in years (range) 36 (35 49) Mean follow-up in months (range) 36 (12 60) Squamous-cell carcinoma 9 (100%) Disease location (n) Anal canal 6 Invasion of the rectum 2 Canal anal and anal margin 1 Stage (n) T1,N0,M0 1 T2,N0,M0 3 T3,N0,M0 2 T3,N1,M0 2 T4,N2,M0 1 Partial excision before CRT (n (%)) 3 (33%) Symptoms (n) Pain 6 Genital warts 4 Rectal symptoms 2 CDC stage (n) A1 1 A2 2 A3 1 B2 1 B3 1 C2 1 C3 2 CDC = Centers for Disease Control and Prevention; CRT = chemoradiotherapy. The three-week combined chemoradiotherapy regimen was as follows. During the first week the regimen was 5-FU (1,000 mg/m2/day from Day 1 to Day 3) as a continuous infusion, cisplatin 50 mg/m2/ day on Days 1 and 2 infused in one hour, and five

3 1178 BLAZY ET AL Dis Colon Rectum, June 2005 sessions (2 Gy) of external beam irradiation (EBRT). During the second week, patients had five sessions (2 Gy) of EBRT, with no therapy during the third week. Three cycles were administered, according to the clinical response; the total radiation dose ranged from 60 to 70 Gy. Chemotherapy was administered during a threeday hospitalization period. Cisplatin was given with a standard prehydration and posthydration protocol. Full-dose chemotherapy was given only if leukocytes were >2,000/ml, neutrophils >1,000/ml, and platelets >100,000/ml. If these conditions were not met, the dose was reduced by 25 percent. In case of renal insufficiency, defined as renal clearance <70 ml/min, cisplatin was replaced by carboplatine. During hospitalization, local care was intensive. Patients were educated to maintain good local hygiene by taking regular Sitz baths with gentle cleaning agents, drying their hair with a hair drier set at the cold position, and wearing ample clothing. Radiation Therapy The first part of EBRT irradiated the anal canal and inguinal and internal, external and primary iliac node areas. The superior border was set at the S2-S3 interval and the lower border included the entire perineum. A dose of 40 Gy was delivered by means of a four-field box technique with 10 or 18 MV photons. For inguinal nodes, one-third of the dose was delivered by 9 MeV electrons. A rest period of two to three weeks was scheduled before starting the second part of EBRT (corresponding to the third chemotherapy cycle), which delivered the boost dose to the tumor itself and inguinal nodes if they were considered positive. This dose was delivered by direct perineal field in most of the patients, or with the four-field box technique when the tumor invaded the rectum. Toxicity Toxicity was recorded according to the World Health Organization guidelines 15 and was considered to be acute when it occurred within the two months following treatment. Assessment of Response and Follow-Up At the end of chemoradiotherapy, each patient underwent complete tumor restaging with a physical examination, abdominopelvic CT scan, rectal ultrasonography when considered necessary, and biopsy when suspicious lesions were detected. All patients have since been reexamined every six months in case of complete response. Anal function was evaluated by patient report. No rectal sonography or manometric measurements were performed. RESULTS Feasibility of Chemoradiotherapy Protocol Three patients with CDC HIV infection Stage A or B received the full-dose chemotherapy schedule. Two Stage B3 patients received 75 percent of the theoretic dose because of neutropenia. No patients received granulocyte colony stimulating factor. For the three AIDS patients (Group C), we chose to lower the dose by 25 percent as of the first cycle to avoid hematologic toxicity. No other dose reduction was required. All patients received the planned irradiation dose, which was 60 Gy. Two patients who achieved partial responses at 40 Gy received 64 and 70 Gy. Mean overall treatment time was 58 (range, 42 72) days. Only one patient developed Grade 3 epitheliitis requiring an interruption longer than one week. It should be recalled that a split course was incorporated into the protocol to allow cicatrization of such lesions. Toxicity Four patients experienced Grade 2 or Grade 3 nausea and vomiting, which were well controlled by antiemetics. Most of the patients developed Grade 1 diarrhea, which could also be attributed to HAART. No oral mucitis was observed. For one patient whose creatinine clearance rose, cisplatine was replaced by carboplatin. Skin toxicity occurred mainly at the end of the second cycle and was the main adverse event observed: four patients had Grade 2 and four patients (44 percent) had Grade 3 epidermitis. For the latter group, CD4+ cell counts were above or below 200/ml for two each and serum HIV loads were detectable or not for two each. Neither acute nor late skin toxicity differed according to the presence or absence of condyloma. Four (44 percent) patients developed Grade 3 neutropenia after Cycle 2 or 3: all were classified as having Stage C HIV disease. Two each had CD4+ cell counts above or below 200/ml and detectable or undetectable serum HIV loads. Four patients experienced Grade 1 or 2 anemia after the third cycle. No

4 Vol. 48, No. 6 ANAL CARCINOMAS IN HIV+ PATIENTS 1179 relationship was observed between this acute toxicity (hematologic or cutaneous) and the CD4+ lymphocyte count or serum HIV load. No late toxicity, especially radiation enteritis, was observed. Carcinologic Results Mean follow-up was 36 (range, 12 60) months. The overall survival rate was 100 percent at two years. All patients were in complete response at the end of treatment. The patient with T4,N2 disease relapsed one year after the end of chemoradiotherapy and underwent salvage abdominoperineal excision. Histologic examination of the resected tissues showed active residual disease, with four perirectal positive nodes; resection was considered complete. He was still disease-free six months after surgery. All the others were considered controlled at the last date of follow-up. Among the eight patients locally controlled, three had slight to severe anal incontinence. Two of these patients, with extensive anal warts requiring multiple surgical excisions before treatment, had poorer sphincter control (anal incontinence) at the last follow-up visit. One other suffered from occasional stool loss. One other patient had local necrosis after irradiation that had not healed at the time of the last visit. Before chemoradiotherapy this patient had an anal abscess that had been surgically drained. Finally, four of eight patients had poor sphincter function. A colostomy was proposed to two of these incontinent patients, but they preferred retaining their sphincter. The patient who experienced a local relapse suffered from persistent local pain until the salvage surgery. Follow-Up of HIV Infection All patients were followed concurrently by infectious disease specialists. No opportunistic infection potentially facilitated by chemoradiotherapy was reported. DISCUSSION It is widely accepted that first-line treatment for anal carcinoma is based on concomitant chemoradiotherapy. 1 Two randomized trials demonstrated the benefit of such therapy, using 5-FU and mitomycin C, 11,12 whereas other studies found the combination of 5-FU cisplatin and radiotherapy to be feasible, achieving excellent local control and long-term survival The total radiation dose seems to be an important factor for local control, and a dose over 55 Gy is usually recommended. 19,20 Only small series of anal carcinomas in HIV+ patients treated with concomitant chemoradiotherapy have been reported. 14,21 26 Although the efficacy of this therapeutic approach is not in doubt, concerns about its tolerance have been raised because of the immune-deficient status of these patients. In vitro studies on fibroblasts from HIV+ patients with Kaposi s sarcomas showed them to be more radiosensitive than those from normal subjects. 27 Chadha et al. 14 treated nine HIV+ patients; six developed Grade 3 to 4 skin toxicity and eight suffered Grade 3 to 4 hematologic toxicity. Others authors have also described poor tolerance of chemoradiation. 13,26 In a retrospective study, 13 HIV+ patients had a poorer tolerance and efficacy of chemoradiotherapy than 60 HIVnegative patients. 22 Acute toxicity was observed in 80 percent of the seropositive patients vs. 30 percent of the seronegative patients. Late toxicity was also more common, and local cancer control was poor. Another retrospective comparison also noted a higher overall treatment failure rate for HIV+ patients than for HIVnegative patients (45 percent vs. 12 percent, respectively). 28 A poor survival for HIV+ subjects with invasive squamous-cell carcinomas has also been observed. 26 However, most of these patients were treated before 1995 and did not benefit from HAART. Because of this severe acute toxicity, some authors have proposed reserving concomitant chemoradiotherapy for patients in good condition and without prior opportunistic infections. 14 Others lowered the radiation dose to 30 Gy, given in 15 fractions, 23 and claimed comparable efficacy for the eight patients included in their study. It should be noted that in most of the studies 5-FU mitomycin was combined with radiation. On the basis of only four patients, 22 other authors have claimed good tolerance of radiotherapy or chemoradiotherapy. More importantly, some factors predictive of tolerance and cancer control have been identified, particularly the CD4+ cell count before chemoradiotherapy. Hoffman and colleagues 24 treated 17 patients with chemoradiation. All nine with an initial CD4+ cell count >200/ml were locally controlled, whereas of the patients with CD4 counts <200/ml, two failed and two others required colostomies for therapy-related complications. Toxicity was more severe for patients having CD4 counts <200/ml.

5 1180 BLAZY ET AL Dis Colon Rectum, June 2005 Some recent series included patients on HAART. It seems that these patients tolerate chemoradiotherapy better and local control of their cancers is improved, 25,26 compared with those treated before the availability of HAART. However, despite the use of HAART, acute and late toxicity continues to be a major problem. 29 Although our population is small, our results demonstrate that concomitant chemoradiotherapy with high-dose irradiation (60 70 Gy) and 5-FU cisplatin is feasible and effective in HIV+ patients. We observed Grade 3 skin toxicity in four of nine patients and Grade 3 hematologic toxicity, also in four of nine patients. It must be emphasized that treatment rest periods were systematically scheduled between Weeks 2 and 3 of a given cycle, and between the second and third cycles during the boost dose. Pertinent to these results is the finding that 17 percent of HIV patients developed severe skin toxicity after receiving the combination arm of the UKCCCR trial. 12 In a prospective Phase II trial of 5-FU cisplatin and irradiation with neoadjuvant chemotherapy, 86 percent of the patients experienced Grade 3 or 4 acute toxicity. 18 These are comparable to results we observed. Even though this treatment was feasible, acute toxicity was common. A decrease in the total radiation dose will not automatically attenuate acute toxicity. In fact, the booster dose after 40 to 45 Gy was usually delivered to a reduced field, which did not exacerbate the skin or result in hematologic toxicity. Reduction of field size, by excluding inguinal areas, for example, would be a good way to spare some normal tissue. Moreover, the upper limit of the anterior-posterior (AP/PA) fields should not be higher than the midpelvic line when no involved nodes are detected by endosonography. In our experience, an irradiation dose of approximately 60 Gy achieved local cancer control in more than 90 percent of the patients. Only one local relapse occurred in a patient with initial T4,N2 disease. Four patients became incontinent. For HIV-negative patients, 54 to 92 percent of the colostomy-free patients retained good anal function Colostomy for radiation sequelae has been performed in 5 to 10 percent of patients in most studies. Our results seem poorer than those usually reported, but two of our incontinent patients had previously undergone local surgery to remove genital warts, a factor previously incriminated in radiation-induced sphincter dysfunction. 30 Moreover, sphincter status of our patients had not been evaluated before chemoradiotherapy. It must be emphasized that all of our patients were on HAART with good immune status at the time of chemoradiotherapy. In other reports on HIV+ patients with anal carcinomas, the survival rates were lower than ours, but more of those deaths were attributed to AIDS progression. Despite the good results obtained with our combined regimen, which included a split course of one week, the optimal chemoradiotherapy schedule for HIV+ patients remains to be determined. Other prospective studies evaluating more precisely the late effects of such treatment are needed. REFERENCES 1. Ryan D, Compton C, Mayer R. Carcinoma of the anal canal. N Engl J Med 2000;342: Frisch M, Biggar R, Engels E, Goedert J. Association of cancer with AIDS-related immnosuppression in adults. JAMA 2001;285: Melbye M, Cote T, Kessler L, Gail M, Biggar R. High Incidence of anal cancer among AIDS patients: The AIDS/Cancer Working group. Lancet 1994;343: Frisch M, Glimelius B, van den Brule A, et al. Sexually transmitted infection as a cause of anal cancer. N Engl J Med 1997;337: Tilston P. Anal human papillomavirus and anal cancer. J Clin Pathol 1997;50: Beckmann A, Daling J, Sherman K, et al. Human papillomavirus infection and anal cancer. Int J Cancer 1999; 43: Melbye M, Rabkin C, Frisch M, Biggar R. Changing patterns of anal cancer incidence in the United States, Am J Epidemiol 1994;139: Palefsky J, Holly E, Ralston M, Jay N, Berry J, Darragh T. High incidence of anal high-grade squamous intraepithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS 1998;12: Critchlow C, Surawicz C, Holmes K, et al. Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS 1995;9: Palefsky J, Holly E, Ralston M, Darragh T, Jay N, Berry M. The effect of HAART on the natural history of anal squamous intraepithelial lesion in HIV+ men [abstract]. J Acquir Immune Defic Syndr 1999;21:A Bartelink H, Roelofsen F, Eschwege F, et al. 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:

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