Deenen MJ, Dewit L, Boot H, et al.
Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.
Int J Radiat Oncol Biol Phys. 2013; 85(5):e201-7 [PubMed]

PURPOSE: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses.
METHODS AND MATERIALS: Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinal lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m(2) (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m(2) b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD).
RESULTS: A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m(2) b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed.
CONCLUSIONS: SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m(2) b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.

Ogawa H, Haneda S, Shibata C, et al.
Adenocarcinoma associated with perianal fistulas in Crohn's disease.
Anticancer Res. 2013; 33(2):685-9 [PubMed]

AIM: The purpose of the present study was to examine the possible relation between anorectal carcinoma and infliximab therapy for Crohn's disease.
PATIENTS AND METHODS: This study reviewed the medical records of patients with perianal Crohn's disease, who have required surgical intervention at the Tohoku University Hospital since May 2002, when infliximab was approved as a remedy for Crohn's disease in Japan.
RESULTS: Ninety-two patients underwent surgery due to perianal Crohn's disease between May 2002 and December 2011. Four out of 92 patients were diagnosed as having anorectal carcinoma associated with perianal fistula. All four patients had advanced carcinoma, and received infliximab before the diagnosis of cancer was made. Infliximab was administered due to an exacerbated anal lesion in three patients.
CONCLUSION: Careful inspection and obtaining of a biopsy sample under anesthesia is recommended for patients with Crohn's disease who have long-standing anal fistulas, especially before infliximab administration due to a possible exacerbation of anal symptoms.

Grulich AE, Hillman R, Brotherton JM, Fairley CK
Time for a strategic research response to anal cancer.
Sex Health. 2012; 9(6):628-31 [PubMed]

Anal cancer was until recently regarded as a rare cancer of little consequence. The articles in this special edition of Sexual Health clearly demonstrate that anal cancer is increasing in incidence and, in some populations, it has become an urgent public health priority. In this summary paper, we will review the data presented in this issue and elsewhere on the magnitude of the issue, the means of prevention and treatment, and suggest a way forward.

Palefsky JM
Practising high-resolution anoscopy.
Sex Health. 2012; 9(6):580-6 [PubMed]

The incidence of anal cancer is increasing in the general population among both men and women. The incidence is particularly high among men who have sex with men and HIV-infected men and women. Anal cancer is similar to cervical cancer and is associated with human papillomavirus (HPV). Anal cancer is potentially preventable through primary prevention with HPV vaccination or secondary prevention. Secondary prevention is modelled after cervical cancer, where cytology is used as a screening tool to identify women who need colposcopy. Colposcopy includes magnification of the cervix, which, along with acetic acid and Lugol's solution, is used to visualise and biopsy potentially precancerous lesions, enabling treatment before progression to cervical cancer. Anal cancer is likely preceded by high-grade anal intraepithelial neoplasia (HGAIN), and a colposcope with acetic acid and Lugol's solution may similarly be used to visualise HGAIN to permit biopsy and treatment in an effort to prevent anal cancer. To distinguish it from cervical colposcopy, this technique is called high-resolution anoscopy (HRA). Many of the features that distinguish low-grade AIN from HGAIN are similar to those of the cervix, but HRA poses several additional challenges compared with cervical colposcopy. These include uneven topography; obscuring of lesions due to haemorrhoids, folds, stool or mucus; or lesions being located at the base of folds and anal glands. Consequently, a long learning curve is typically required before becoming fully competent in this technique. The technique of HRA, its uses and challenges in prevention of anal cancer are described in this article.

Machalek DA, Grulich AE, Jin F, et al.
The epidemiology and natural history of anal human papillomavirus infection in men who have sex with men.
Sex Health. 2012; 9(6):527-37 [PubMed]

Studies on the epidemiology and natural history of anal human papillomavirus (HPV) infection are essential to understand the significance of this virus in the aetiology of anal cancer in men who have sex with men (MSM). This paper presents a review of studies on anal HPV in MSM. For this review, a Medline search was performed to identify English-language articles published in peer-reviewed journals on the epidemiology, natural history and risk factors for anal HPV infection in MSM. Anal HPV prevalence is high in MSM and infection with multiple HPV types is common. The available prospective data suggest detection of new anal HPV infections may also be common. However, with limited epidemiological data available on infection dynamics and associated behavioural risk factors, it is difficult to draw conclusions on how persistent anal HPV infection is in this population.

Pandey P
Anal anatomy and normal histology.
Sex Health. 2012; 9(6):513-6 [PubMed]

The focus of this article is the anatomy and histology of the anal canal, and its clinical relevance to anal cancers. The article also highlights the recent histological and anatomical changes to the traditional terminology of the anal canal. The terminology has been adopted by the American Joint Committee on Cancer, separating the anal region into the anal canal, the perianal region and the skin. This paper describes the gross anatomy of the anal canal, along with its associated blood supply, venous and lymphatic drainage, and nerve supply. The new terminology referred to in this article may assist clinicians and health care providers to identify lesions more precisely through naked eye observation and without the need for instrumentation. Knowledge of the regional anatomy of the anus will also assist in management decisions.

Fairley CK, Brotherton JM, Hillman R, Grulich AE
Why a special issue on anal cancer and what is in it?
Sex Health. 2012; 9(6):501-3 [PubMed]

This editorial describes the contents of this special issue of Sexual Health devoted to anal cancer. The aim of the issue is to provide readers with information to assist them in making decisions about what to do about detecting anal cancer early in men who have sex with men with HIV. Should they be advocating screening? It discusses the epidemiology of HPV infection, anal intraepithelial neoplasia, and anal cancer in MSM, heterosexual men and women; anal cancer screening and treatment of anal cancer. And most importantly, what should be done about vaccinating boys with the HPV vaccine.

Jacomini C, Junqueira AE, Almeida AL, et al.
Anal canal mucinous adenocarcinoma with invasion of gluteus and perineum treated with surgery and hyperbaric oxygen therapy.
Undersea Hyperb Med. 2012 Nov-Dec; 39(6):1115-8 [PubMed]

The case of a 66-year-old female patient with late diagnosis of giant anal canal mucinous adenocarcinoma invading the gluteal and vulvar regions is reported. Because of the patient's severe clinical status and disease morbidity, surgical resection of the lesion was accomplished, with no adjuvant chemo- or radiotherapy. In the postoperative period, the patient received hyperbaric oxygen therapy, which facilitated and even accelerated local healing. Total closure of the raw flesh area was achieved, with no recurrence signals of cancer being detected after one-year follow-up. We are convinced that, in this difficult case, hyperbaric oxygen therapy played a crucial role in patient recovery and wound healing, allowing for early closure with good progression.

Mistrangelo DM, Bellò M, Cassoni P, et al.
Value of staging squamous cell carcinoma of the anal margin and canal using the sentinel lymph node procedure: an update of the series and a review of the literature.
Br J Cancer. 2013; 108(3):527-32 [PubMed] Article available free on PMC after 19/02/2014

BACKGROUND: Inguinal metastases in patients affected by anal cancer are an independent prognostic factor for local failure and overall mortality. Since 2001, sentinel lymph node biopsy was applied in these patients. This original study reports an update of personal and previous published series, which were compared with Literature to value the incidence of inguinal metastases T-stage related and the overall incidence of false negative inguinal metastases at sentinel node.
METHODS: In all, 63 patients diagnosed with anal cancer submitted to inguinal sentinel node. Furthermore a research in the Pub Med database was performed to find papers regarding this technique.
RESULTS: In our series, detection rate was 98.4%. Inguinal metastases were evidentiated in 13 patients (20.6%). Our median follow-up was 35 months. In our series, no false negative nodes were observed.
CONCLUSION: Sentinel node technique in the detection of inguinal metastases in patients affected by anal cancer should be considered as a standard of care. It is indicated for all T stages in order to select patients to be submitted to inguinal radiotherapy, avoiding related morbidity in negative ones. An overall 3.7% rate of false negative must be considered acceptable.

Olsen J, Jørgensen TR, Kofoed K, Larsen HK
Incidence and cost of anal, penile, vaginal and vulvar cancer in Denmark.
BMC Public Health. 2012; 12:1082 [PubMed] Article available free on PMC after 19/02/2014

BACKGROUND: Besides being a causative agent for genital warts and cervical cancer, human papillomavirus (HPV) contributes to 40-85% of cases of anal, penile, vaginal and vulvar cancer and precancerous lesions. HPV types 16 & 18 in particular contribute to 74-93% of these cases. Overall the number of new cases of these four cancers may be relatively high implying notable health care cost to society. The aim of this study was to estimate the incidence and the health care sector costs of anal, penile, vaginal and vulvar cancer.
METHODS: New anogenital cancer patients were identified from the Danish National Cancer Register using ICD-10 diagnosis codes. Resource use in the health care sector was estimated for the year prior to diagnosis, and for the first, second and third years after diagnosis. Hospital resource use was defined in terms of registered hospital contacts, using DRG (Diagnosis Related Groups) and DAGS (Danish Outpatient Groups System) charges as cost estimates for inpatient and outpatient contacts, respectively. Health care consumption by cancer patients diagnosed in 2004-2007 was compared with that by an age- and sex-matched cohort without cancer. Hospital costs attributable to four anogenital cancers were estimated using regression analysis.
RESULTS: The annual incidence of anal cancer in Denmark is 1.9 per 100,000 persons. The corresponding incidence rates for penile, vaginal and vulvar cancer are 1.7, 0.9 and 3.6 per 100,000 males/females, respectively. The total number of new cases of these four cancers in Denmark is about 270 per year. In comparison, the total number of new cases cervical cancer is around 390 per year. The total cost of anogenital cancer to the hospital sector was estimated to be 7.6 million Euros per year. Costs associated with anal and vulvar cancer constituted the majority of the costs.
CONCLUSIONS: Anogenital cancer incurs considerable costs to the Danish hospital sector. It is expected that the current HPV vaccination program will markedly reduce this burden.

Pettit L, Meade S, Sanghera P, et al.
Can radiobiological parameters derived from squamous cell carcinoma of the head and neck be used to predict local control in anal cancer treated with chemoradiation?
Br J Radiol. 2013; 86(1021):20120372 [PubMed] Article available free on PMC after 01/01/2014

OBJECTIVES: Parameters have been derived in head and neck cancer to account for the additional biological effective dose provided by synchronous chemotherapy. The purpose of this study was to establish whether such parameters could be used to predict local control differences in anal cancer.
METHODS: In anal cancer two randomised trials of radiotherapy vs chemoradiotherapy and two trials randomising between different synchronous chemotherapy regimens were identified. To predict differences in local control between the arms of the first two studies, a global value of 9.3 Gy for the chemotherapy biologically effective dose was employed. For the last two trials, values specific to differing chemotherapy schedules were derived. These values were added to the calculated biological effective dose for the radiotherapy component in order to predict local control outcomes in anal cancer trials.
RESULTS: The predicted difference in local control using the global value of 9.3 Gy for the addition of synchronous chemotherapy in the trials of radiotherapy vs radiotherapy and synchronous chemotherapy was 24.6% compared with the observed difference of 21.4%. Using schedule-specific values for the contribution of chemotherapy, the predicted differences in local control in the two trials of differing synchronous chemotherapy schedules were 7.2% and 12% compared with the observed 18% and 0%.
CONCLUSION: The methods initially proposed require modification to result in adequate prediction. If the decreased cisplatin dose intensity employed in anal cancer is modelled, more satisfactory predictions for such trials can be achieved. ADVANCES IN KNOWLEDGE: This revised modelling may be hypothesis generating.

Bazan JG, Koong AC, Kapp DS, et al.
Metabolic tumor volume predicts disease progression and survival in patients with squamous cell carcinoma of the anal canal.
J Nucl Med. 2013; 54(1):27-32 [PubMed]

UNLABELLED: PET imaging has become a useful diagnostic tool in patients with anal cancer. We evaluated the prognostic value of metabolic tumor volume (MTV) in patients with anal cancer treated with definitive chemoradiotherapy.
METHODS: Patients with anal cancer who underwent PET imaging for pretreatment staging or radiation therapy planning from 2003 to 2011 were included. PET parameters included MTV and maximum standardized uptake value (SUVmax). Total MTV (MTV-T) was defined as the sum of the volumes above a standardized uptake value 50% of the SUVmax within the primary tumor and involved nodes. Kaplan-Meier and Cox regression models were used to test for associations between metabolic or clinical endpoints and overall survival (OS), progression-free survival (PFS), and event-free survival (EFS). Results: Thirty-nine patients were included. Median follow-up for the cohort was 22 mo. Overall, 6 patients died and 9 patients had disease progression. The 2-y OS, PFS, and EFS for the entire cohort were 88%, 74%, and 69%, respectively. Higher MTV-T was associated with worse OS (P = 0.04), PFS (P = 0.004), and EFS (P = 0.002) on univariate analysis. Patients with an MTV greater than 26 cm(3) had worse PFS than did those with an MTV of 26 cm(3) or less (33% vs. 82%, P = 0.003). SUVmax was not prognostic for any outcome. Higher T classification (T3/T4 vs. T1/T2) was associated with worse PFS and EFS. When adjusting for T classification, MTV-T remained a significant predictor for PFS (P = 0.01) and EFS (P = 0.02).
CONCLUSION: MTV-T yields prognostic information on PFS and EFS beyond that of established prognostic factors in patients with anal cancer.

Macaya A, Muñoz-Santos C, Balaguer A, Barberà MJ
Interventions for anal canal intraepithelial neoplasia.
Cochrane Database Syst Rev. 2012; 12:CD009244 [PubMed]

BACKGROUND: Anal canal intraepithelial neoplasia (AIN) is a pre-malignant condition of the anal canal transitional epithelium that is associated with human papillomavirus (HPV) infection. The incidence and prevalence of AIN and anal cancer are increasing rapidly in HIV-positive men who have sex with men (MSM). Other groups like HIV-negative MSM, immunosuppressed patients and people affected by other HPV diseases like genital warts and cervical intraepithelial neoplasia (CIN) may also develop AIN. The condition is complicated by its multicentric and multifocal nature and high rates of relapse and morbidity. Targeted excisions using ablative treatments such as cautery, infrared coagulation (IRC) and cryotherapy have been used as first-line therapeutic strategies, and there are many other options. There is no consensus about the optimal management of AIN.
OBJECTIVES: To evaluate the effects of therapeutic interventions for anal canal intraepithelial neoplasia (AIN).
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 4), MEDLINE and EMBASE (to October 2011). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies, and contacted experts in the field and manufacturers of any AIN and HPV-specific treatments.
SELECTION CRITERIA: Randomized controlled trials (RCTs) that assessed any type of intervention for AIN.
DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. If it was possible, the data were synthesised in a meta-analysis.
MAIN RESULTS: We found only one RCT, which included 53 patients, that met our inclusion criteria. This trial reported data on imiquimod versus placebo. There was no statistically significant difference in the risk of disease cure but there was a trend for imiquimod to downgrade the AIN to a low-risk stage. The lack of statistical power of the trial may be due to the small number of patients in each group. The risk of bias was estimated as moderate.
AUTHORS' CONCLUSIONS: The included trial failed to demonstrate any statistically significant efficacy of imiquimod in the management of anal intraepithelial neoplasia (AIN). The absence of reliable evidence for any of the interventions used in AIN precludes any definitive guidance or recommendations for clinical practice. Prospective cohort studies and retrospective studies have not been included in this review as they are considered to provide lower quality evidence. Well designed RCTs are needed.

Giraldi G, De Luca d'Alessandro E
The HPV infection in males: an update.
Ann Ig. 2012 Nov-Dec; 24(6):497-506 [PubMed]

The role of Human papillomavirus (HPV) in malignant and non-malignant genital diseases in females is well known and the corresponding epidemiological burden has been widely described, in males instead, less is known about the role of the virus in anal, penile and head and neck cancer, and the burden of malignant and non-malignant HPV-related diseases. There are many types of HPV that can infect the epithelium: some types can cause genital warts (low risk genotype), other types (high risk genotypes) can cause cancers of the penis, anus or oropharynx. Relative to females, males tend to be less knowledgeable about the infection: some may view its consequences as less likely and severe for themselves than for females, and thus could perceive vaccination as unnecessary. Including boys in the vaccination program generally exceeded conventional thresholds of good value for money, even under favorable conditions of vaccine protection and health benefits; however, uncertainty still exists in many areas that can either strengthen or attenuate the findings achieved.

Moscicki AB, Schiffman M, Burchell A, et al.
Updating the natural history of human papillomavirus and anogenital cancers.
Vaccine. 2012; 30 Suppl 5:F24-33 [PubMed]

This chapter addresses the natural history of anogenital human papillomavirus (HPV) infection. Cervical infections are the best understood HPV infection. Cervical HPV persistence is the known necessary event for the development of cervical cancer. New infections appearing at any age are benign unless they persist. Several long-term natural history studies have now shed light on the very low risk of cervical intraepithelial neoplasia (CIN) 3+ in women past the peak of HPV acquisition (e.g., 30 or older) who are HPV-negative or clear their HPV. Although data on transmission of HPV are finally emerging, rates of transmission between heterosexual couples vary widely among studies. Factors that affect the calculations of these rates include a) intervals between testing points, b) rates of concordance or discordance at baseline, and c) difficulty in defining established infections versus contamination. Both cervix to anus and anus to cervix autoinoculation in the same woman appears to be quite common. Whether either site serves as a long-term reservoir is unknown. Studies show that anal infections in women and in men who have sex with men are quite common with cumulative rates up to 70-90%. Similarly, clearance of anal HPV is also common, with few individuals showing persistence unless they are human immunodeficiency virus (HIV)-infected. HIV strongly influences the development of anal intraepithelial neoplasia (AIN). The few studies on the natural history of AIN in HIV-infected men suggest that high-grade AIN is a precursor to invasive anal cancer. Although no natural history studies of AIN are available in women, women with other HPV-associated lesions, including CIN3+ and vulvar cancer, have higher rates of anal cancer. Data on the natural history of HPV of the male genitalia are also emerging, although penile intraepithelial neoplasia is poorly understood. Cumulative rates of HPV are extremely high in men and risks are associated with sexual behavior. Unlike women, prevalence rates are steady across all ages, suggesting that men do not develop protection against reinfection. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Forman D, de Martel C, Lacey CJ, et al.
Global burden of human papillomavirus and related diseases.
Vaccine. 2012; 30 Suppl 5:F12-23 [PubMed]

The worldwide prevalence of infection with human papillomavirus (HPV) in women without cervical abnormalities is 11-12% with higher rates in sub-Saharan Africa (24%), Eastern Europe (21%) and Latin America (16%). The two most prevalent types are HPV16 (3.2%) and HPV18 (1.4%). Prevalence increases in women with cervical pathology in proportion to the severity of the lesion reaching around 90% in women with grade 3 cervical intraepithelial neoplasia and invasive cancer. HPV infection has been identified as a definite human carcinogen for six types of cancer: cervix, penis, vulva, vagina, anus and oropharynx (including the base of the tongue and tonsils). Estimates of the incidence of these cancers for 2008 due to HPV infection have been calculated globally. Of the estimated 12.7 million cancers occurring in 2008, 610,000 (Population Attributable Fraction [PAF]=4.8%) could be attributed to HPV infection. The PAF varies substantially by geographic region and level of development, increasing to 6.9% in less developed regions of the world, 14.2% in sub-Saharan Africa and 15.5% in India, compared with 2.1% in more developed regions, 1.6% in Northern America and 1.2% in Australia/New Zealand. Cervical cancer, for which the PAF is estimated to be 100%, accounted for 530,000 (86.9%) of the HPV attributable cases with the other five cancer types accounting for the residual 80,000 cancers. Cervical cancer is the third most common female malignancy and shows a strong association with level of development, rates being at least four-fold higher in countries defined within the low ranking of the Human Development Index (HDI) compared with those in the very high category. Similar disparities are evident for 5-year survival-less than 20% in low HDI countries and more than 65% in very high countries. There are five-fold or greater differences in incidence between world regions. In those countries for which reliable temporal data are available, incidence rates appear to be consistently declining by approximately 2% per annum. There is, however, a lack of information from low HDI countries where screening is less likely to have been successfully implemented. Estimates of the projected incidence of cervical cancer in 2030, based solely on demographic factors, indicate a 2% increase in the global burden of cervical cancer, i.e., in balance with the current rate of decline. Due to the relative small numbers involved, it is difficult to discern temporal trends for the other cancers associated with HPV infection. Genital warts represent a sexually transmitted benign condition caused by HPV infection, especially HPV6 and HPV11. Reliable surveillance figures are difficult to obtain but data from developed countries indicate an annual incidence of 0.1 to 0.2% with a peak occurring at teenage and young adult ages. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Moureau-Zabotto L, Ortholan C, Hannoun-Levi JM, et al.
Role of brachytherapy in the boost management of anal carcinoma with node involvement (CORS-03 study).
Int J Radiat Oncol Biol Phys. 2013; 85(3):e135-42 [PubMed]

PURPOSE: To assess retrospectively the clinical outcome in anal cancer patients, with lymph node involvement, treated with split-course radiation therapy and receiving a boost through external beam radiation therapy (EBRT) or brachytherapy (BCT).
METHODS AND MATERIALS: From 2000 to 2005, among 229 patients with invasive nonmetastatic anal squamous cell carcinoma, a selected group of 99 patients, with lymph node involvement, was studied. Tumor staging reported was T1 in 4 patients, T2 in 16 patients, T3 in 49 patients, T4 in 16 patients, and T unknown in 14 patients and as N1 in 67 patients and N2/N3 in 32 patients. Patients underwent a first course of EBRT (mean dose, 45.1 Gy) followed by a boost (mean dose, 18 Gy) using EBRT (50 patients) or BCT (49 patients). All characteristics of patients and tumors were well balanced between the BCT and EBRT groups. Prognostic factors of cumulative rate of local recurrence (CRLR), cumulative rate of distant (including nodal) recurrence (CRDR), colostomy-free survival (CFS) rate, and overall survival (OS) rate were analyzed for the overall population and according to the nodal status classification.
RESULTS: The median follow-up was 71.5 months. The 5-year CRLR, CRDR, CFS rate, and OS rate were 21%, 19%, 63%, and 74.4%, respectively. In the overall population, the type of node involvement (N1 vs N2/N3) was the unique independent prognostic factor for CRLR. In N1 patients, by use of multivariate analysis, BCT boost was the unique prognostic factor for CRLR (4% for BCT vs 31% for EBRT; hazard ratio, 0.08; P=.042). No studied factors were significantly associated with CRDR, CFS, and OS. No difference with regard to boost technique and any other factor studied was observed in N2/N3 patients for any kind of recurrence.
CONCLUSION: In anal cancer, even in the case of initial perirectal node invasion, BCT boost is superior to EBRT boost for CRLR, without an influence on OS, suggesting that N1 status should not be a contraindication to use of a BCT boost technique, as well as emphasizing the important of investigating the benefit of BCT boost in prospective randomized trials.

Sahasrabuddhe VV, Castle PE, Follansbee S, et al.
Human papillomavirus genotype attribution and estimation of preventable fraction of anal intraepithelial neoplasia cases among HIV-infected men who have sex with men.
J Infect Dis. 2013; 207(3):392-401 [PubMed] Article available free on PMC after 01/02/2014

BACKGROUND: The prevention of human papillomavirus (HPV)-induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use.
METHODS: HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines.
RESULTS: HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥ 2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (P(trend) < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%.
CONCLUSIONS: Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.

Luu HN, Amirian ES, Beasley RP, et al.
Association between smoking and size of anal warts in HIV-infected women.
Int J STD AIDS. 2012; 23(11):792-8 [PubMed]

While the association between smoking and human papillomavirus infection, cervical cancer, and anal cancer has been well studied, evidence on the association between cigarette smoking and anal warts is limited. The purpose of this study was to investigate if cigarette smoking status influences the size of anal warts over time in HIV-infected women in a sample of 976 HIV-infected women from the Women's Interagency HIV Study (WIHS). A linear mixed model was used to determine the effect of smoking on anal wart size. Even though women who were currently smokers had larger anal warts at baseline and slower growth rate of anal wart size after each visit than women who were not current smokers, there was no association between size of anal wart and current smoking status over time. Further studies on the role of smoking and interaction between smoking and other risk factors, however, should be explored.

Corti M, Villafañe MF, Marona E, Lewi D
Anal squamous carcinoma: a new AIDS-defining cancer? Case report and literature review.
Rev Inst Med Trop Sao Paulo. 2012; 54(6):345-8 [PubMed]

Squamous anal cell carcinoma is a rare malignancy that represents the 1.5% to 2% of all the lower digestive tract cancers. However, an increased incidence of invasive anal carcinoma is observed in HIV-seropositive population since the widespread of highly active antiretroviral therapy. Human papillomavirus is strongly associated with the pathogenesis of anal cancer. Anal intercourse and a high number of sexual partners appear to be risk factors to develop anal cancer in both sexes. Anal pain, bleeding and a palpable lesion in the anal canal are the most common clinical features. Endo-anal ultrasound is the best diagnosis method to evaluate the tumor size, the tumor extension and the infiltration of the sphincter muscle complex. Chemoradiotherapy plus antiretroviral therapy are the recommended treatments for all stages of localized squamous cell carcinoma of the anal canal in HIV-seropositive patients because of its high rate of cure. Here we present an HIV patient who developed a carcinoma of the anal canal after a long time of HIV infection under highly active antiretroviral therapy with a good virological and immunological response.

Gunderson LL, Winter KA, Ajani JA, et al.
Long-term update of US GI intergroup RTOG 98-11 phase III trial for anal carcinoma: survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin.
J Clin Oncol. 2012; 30(35):4344-51 [PubMed] Article available free on PMC after 10/12/2013

PURPOSE: On initial publication of GI Intergroup Radiation Therapy Oncology Group (RTOG) 98-11 [A Phase III Randomized Study of 5-Fluorouracil (5-FU), Mitomycin, and Radiotherapy Versus 5-Fluorouracil, Cisplatin and Radiotherapy in Carcinoma of the Anal Canal], concurrent chemoradiation (CCR) with fluorouracil (FU) plus mitomycin (MMC) decreased colostomy failure (CF) when compared with induction plus concurrent FU plus cisplatin (CDDP), but did not significantly impact disease-free survival (DFS) or overall survival (OS) for anal canal carcinoma. The intent of the updated analysis was to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free survival [CFS]), CF, and relapse (locoregional failure [LRF], distant metastasis) in this patient group.
PATIENTS AND METHODS: Stratification factors included sex, clinical node status, and primary size. DFS and OS were estimated univariately by the Kaplan-Meier method, and treatment arms were compared by log-rank test. Time to relapse and CF were estimated by the cumulative incidence method and treatment arms were compared by using Gray's test. Multivariate analyses used Cox proportional hazard models to test for treatment differences after adjusting for stratification factors.
RESULTS: Of 682 patients accrued, 649 were analyzable for outcomes. DFS and OS were statistically better for RT + FU/MMC versus RT + FU/CDDP (5-year DFS, 67.8% v 57.8%; P = .006; 5-year OS, 78.3% v 70.7%; P = .026). There was a trend toward statistical significance for CFS (P = .05), LRF (P = .087), and CF (P = .074). Multivariate analysis was statistically significant for treatment and clinical node status for both DFS and OS, for tumor diameter for DFS, and for sex for OS.
CONCLUSION: CCR with FU/MMC has a statistically significant, clinically meaningful impact on DFS and OS versus induction plus concurrent FU/CDDP, and it has borderline significance for CFS, CF, and LRF. Therefore, RT + FU/MMC remains the preferred standard of care.

Chin JY, Hong TS, Ryan DP
Mitomycin in anal cancer: still the standard of care.
J Clin Oncol. 2012; 30(35):4297-301 [PubMed]

A 52-year-old woman presents with a 2-month history of bright red blood per rectum. Her bleeding is associated with bowel movements and a sense of incomplete evacuation. She denies fecal incontinence or change in stool caliber. On digital rectal examination, the tumor is palpated approximately 3 cm from the anal verge, posterior and slightly to the right, positioned at the top of the anal canal and extending into the rectum, measuring approximately 2.5 cm. Additionally, a firm 1.5-cm left-sided inguinal node is palpated. The patient is then referred for colonoscopy, which reveals a mass in the anal canal; biopsy of the mass shows squamous cell carcinoma. Positron emission tomography-computed tomography (PET-CT) demonstrates thickening in the low rectum with [(18)F]fluorodeoxyglucose (FDG) avidity (Figs 1A, 1B). The left inguinal node is visualized, as is a perirectal lymph node with associated FDG avidity (Figs 1C, 1D). The patient is staged as having T2N3 squamous cell carcinoma of the anal canal (Table 1). Her medical history is otherwise unremarkable, including for HIV, prior abnormal Papanicolaou smears, and other risk factors for human papillomavirus (HPV) exposure.

Fakhrian K, Sauer T, Klemm S, et al.
Radiotherapy with or without chemotherapy in the treatment of anal cancer: 20-year experience from a single institute.
Strahlenther Onkol. 2013; 189(1):18-25 [PubMed]

PURPOSE: To report the efficacy and toxicity of radio(chemo)therapy (RCT) in the management of squamous cell anal carcinoma (SQ-AC) and to evaluate the prognostic factors influencing the outcomes.
PATIENTS AND METHODS: A consecutive cohort of 138 patients with cT1-4, cN0-3, cM0 SQ-AC were treated with RCT between 1988 and 2011 at our department. Median follow-up time for surviving patients from the start of RCT was 98 months (range, 1-236 months). Patients were treated with a median radiation dose of 56 Gy (range, 4-61 Gy). Concurrent chemotherapy was administered to 119 patients (86%).
RESULTS: The survival rates at 2, 5, and 10 years were 88 ± 3, 82 ± 4, and 59 ± 6%, respectively, with a median overall survival (OS) of 167 months. The cumulative incidence for local recurrence at 2 and 5 years was 8 ± 2 and 11 ± 3%, respectively. The median disease-free survival (DFS) and colostomy-free survival (CFS) times were 132 and 135 months, respectively. In 19 patients (14%), a distant metastasis was diagnosed after a median time of 19 months. In the multivariate analysis, UICC (International Union Against Cancer) stage I-II, female gender, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and good/moderate histologic differentiation (G1-2) were significantly associated with a better OS, DFS, and CFS. Conformal radiotherapy planning techniques were significantly associated with a lower cumulative incidence of local recurrence (11 ± 3% vs. 38 ± 19% at 5 years, p = 0.006). A higher radiation dose beyond 54 Gy was not associated with an improvement in outcome, neither for smaller-(T1/T2) nor for larger tumors (T3/T4).
CONCLUSION: RCT leads to excellent outcomes-especially in patients with stage I/II and G1/G2 tumors-with acceptable toxicity. The probable advantages of high-dose radiotherapy should be considered carefully against the risk of a higher rate of toxicity. Future studies are needed to investigate the role of a more intensified (systemic) treatment for patients with unfavorable prognostic factors such as T3/T4, N+, and/or poor cell differentiation.

Mallari AO, Schwartz TM, Luque AE, et al.
Anal cancer screening in HIV-infected patients: is it time to screen them all?
Dis Colon Rectum. 2012; 55(12):1244-50 [PubMed]

BACKGROUND: Annual screening for anal cancer is recommended only for HIV patients at increased risk: men who have sex with men, individuals with a history of anogenital warts, and women with cervical dysplasia.
OBJECTIVE: The aim of this study was to examine the screening outcomes between HIV populations with and without these risk factors.
METHODS: We reviewed the records of all HIV patients referred for anal cytology and high-resolution anoscopy from June 2009 to June 2010. Patients were stratified into an increased-risk group or a standard-risk group.
MAIN OUTCOME: Of the 329 evaluable patients, 285 (89.8% men, 10.2% women, mean age 46 ± 10 years) were classified to the increased-risk group, whereas 44 (72.7% men, 27.3% women, mean age 52 ± 8 years) were included in the standard-risk group. Male sex, white race, sexual orientation, past and current receptive anal intercourse, noncompliance with condom use, and absence of a new sexual partner were significantly different in the increased-risk group in comparison with the standard-risk group. In the increased-risk group, 187 (66.5%) patients had biopsy-proven dysplasia of which 118 (42.0%) had high-grade disease. In the standard-risk group, 15 (34.9%) patients had biopsy-proven dysplasia of which 7 (16.3%) had high-grade disease. Cytology detected biopsy-confirmed high-grade dysplasia only in 23 of 118 (19.5%) patients in the increased-risk group and in 2 of 7 (28.6%) patients in the standard-risk group. Kappa agreement in detecting high-grade disease was low for both increased-risk and standard-risk groups: 0.16 (95% CI 0.07-0.23) and 0.40 (95% CI 0.02-0.40).
LIMITATIONS: Our study is a chart-based retrospective review of data with a small female population. Histology reports came from 2 different laboratories.
CONCLUSION: High-grade anal dysplasia was prevalent even among HIV patients who only have standard risk factors. Anal cytology and high-resolution anoscopy have poor agreement. We suggest considering annual screening by using high-resolution anoscopy in addition to cytology for all HIV patients regardless of risk factors.

Mengjun B, Zheng-Qiang W, Tasleem MM
Extramammary Paget's disease of the perianal region: a review of the literature emphasizing management.
Dermatol Surg. 2013; 39(1 Pt 1):69-75 [PubMed]

UNLABELLED: BACKGROUD: Perianal Paget's disease is a rare malignant condition affecting the epidermal apocrine gland that is usually complicated, with a confusing clinical picture, and diagnosis is therefore often delayed. Although, more than 100 years has gone by since its first description by Darier and Coulillaud in 1893, proper treatment guidelines have yet to be established.
OBJECTIVE: To review the available literature, emphasizing various current treatment strategies and aiming to increase clinicians' awareness of this rare disease, along with its management, for better practice and improvement of patient prognosis.
METHODS: The review of the concerned literature was done by searching and compiling data available on PubMed, Medline, and other databases using the key words "perianal Paget's disease," "extramammary Paget's disease," "intraepithelial adenocarcinoma," and "apocrine glands."
CONCLUSIONS: Surgery is the mainstay of treatment. Some noninvasive therapeutic modalities were also reported to be effective, such as photodynamic therapy, imiquimod, radiotherapy, chemotherapy, anti-androgen therapy, and carbon dioxide. Management of perianal Paget's disease remains difficult, and large controlled, multicentric studies should be performed to compare the effectiveness of current therapeutic modalities.

Smigielski J, Rychter A, Fijuth J, Brocki M
Advanced anal squamous cell carcinoma -- radiotherapy or surgery?
Chirurgia (Bucur). 2012 Sep-Oct; 107(5):626-30 [PubMed]

UNLABELLED: BACKROUND: Anal and rectal cancers occupy the third position of death causes in Poland. Adenocarcinoma is the most frequent among the tumours in this group. Squamous cell carcinoma can be relatively less common. This kind of carcinoma may rather affect the anus than the rectum. Although the lesion is perceived as not very malignant and as such responsive to radiant energy therapy, some cases may require surgical treatment. Methods: Within 1999-2008 (the observation period of 10 years) there were 18 patients treated for anal squamous cell carcinoma at the Department of Thoracic Surgery, General and Oncological Surgery of the Medical University of Lodz, at the Surgical Department of the Ministry of Interior and Administration Hospital in Lodz and at the Teleradiotherapy Department of Mikolaj Kopernik Voivodship Specialist Hospital in Lodz. Each patient underwent radiochemotherapy with Mitomycin and 5-Fluorouracil and Lucovorin. The applied radiation doses ranged between 45-54 Gy in eighteen 2.0 Gy fractions. The abdomino-perineal resection of the rectum (APR) was performed in 3 patients (16.5%) who did not show full regression of the carcinoma. In all three cases the histopathological diagnosis preceded the surgical procedure. Results: For the total number of 18 patients with anal squamous cell carcinoma the mean observation period was 5.5 years, in the group of the operated patients the mean survival rate was 48 months (the median of 14-74 months) while for the group of the patients treated conservatively the mean survival rate amounted to 55 months (the median of 17-82 months, p=0.23). The mean 5-year disease-free survival rate was rather similar to the same rate of the general group, whereas the post-operative complications occurred in 66% of surgical procedures and 27% of teleradiotherapeutic procedures.
CONCLUSIONS: Combined radiotherapy and chemotherapy can be the method of choice in treating anal squamous cell carcinoma. Surgery should be used in advanced cases, when complete regression on radiochemotherapy cannot be observed. The abdomino-perineal resection of the rectum is the kind of a procedure that may be accompanied with a vast number of complications. Nevertheless, it still remains a necessary therapeutic method in the described cases.

Glynne-Jones R, Renehan A
Current treatment of anal squamous cell carcinoma.
Hematol Oncol Clin North Am. 2012; 26(6):1315-50 [PubMed]

The primary aim of anal cancer treatment is loco-regional control with preservation of anal function. Phase III trials consistently demonstrate radiotherapy with concurrent 5FU and mitomycin (MMC) chemoradiation is the standard of care for anal cancer. Salvage surgery is associated with considerable morbidity and requires specialised input. With current sophisticated radiological staging and the ability to spare critical normal tissues with intensity-modulated radiotherapy, a "one-size-fits-all" approach is probably inappropriate. Radiotherapy dose-escalation and intensification of the concurrent chemotherapy might improve local control, but may also adversely affect colostomy-free survival. Integration of biologic therapy with conventional chemotherapies looks hopeful in the future.

Wilkes G, Hartshorn K
Clinical update: colon, rectal, and anal cancers.
Semin Oncol Nurs. 2012; 28(4):e1-22 [PubMed]

OBJECTIVES: To present an updated review of the incidence, risk factors, staging, diagnosis, and treatment of colon, rectal, and anal cancers, as well as nursing care associated with managing patients diagnosed with these malignancies.
DATA SOURCES: Published research reports, epidemiologic data, published patient management guidelines, and institution-based clinical tools.
CONCLUSION: While significant advances in the management of colon, rectal, and anal cancers in the past decade have extended patient survival, there remain some unanswered questions. Further clinical and molecular research will help individualize patient care, refining current therapeutic strategies and treatment decision-making aids while minimizing symptoms of disease and treatment.
IMPLICATIONS FOR NURSING PRACTICE: Nurses need to be familiar with risk factors, disease course, and current and emerging therapies to assist patients with treatment decision-making, and to anticipate and intervene in managing disease and treatment-induced problems. Early identification and management of distressing symptoms can help to avoid life-threatening effects and promote patient adherence to prescribed therapies; timely patient/family education may minimize anxiety and promote self-management.

Gunia S, Koch S, May M
Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis?
J Clin Pathol. 2013; 66(2):109-12 [PubMed]

AIMS: Penile, vulvar and anal squamous cell carcinomas (SCCs) share histomorphological overlap and are prone to lymphatic dissemination into inguinal nodes. Anal SCCs might derive from the anorectal zone (ARZ), anal transitional zone, squamous zone or from perianal skin. These anatomically distinct zones differ in terms of their embryological development. We sought to investigate the role of caudal-related homeobox 2 (CDX2), a homeobox gene implicated in the development and anterior/posterior pattern specification from duodenum to rectum including the ARZ, in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with histologically confirmed inguinal lymph node metastasis.
METHODS: By immunohistochemistry (IHC) employing a panel of antibodies directed against CK5/6, CK7, CK20, p63, p16, CEA and CDX2, we compared 89 penile, 11 vulvar and eight anal SCCs with respect to their staining profiles. Moreover, anal SCCs were subjected to in situ hybridisation (ISH) for high-risk human papillomavirus (HPV) subtypes.
RESULTS: By IHC, CDX2 expression was observed in 2/8 anal SCCs (25%) while being absent from all penile and vulvar SCCs examined. High-risk HPV subtypes were detected by ISH in all anal SCCs examined, which were uniformly p16-positive by IHC.
CONCLUSIONS: CDX2 might be valuable in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with inguinal lymph node metastasis. However, despite its favourable specificity, the diagnostic benefit achieved by this observation is limited by the low sensitivity.

Patti R, Aiello P, Angelo GL, Di Vita G
Giant condyloma acuminatum quickly growing: case report.
G Chir. 2012; 33(10):327-30 [PubMed]

BACKGROUND: Giant Condyloma Acuminatum (GCA) is a rare, slow growing, large cauliflower tumor of the penile foreskin and perianal region with benign histologic appearance but high propensity for local invasion and recurrences. GCA is associated with Human Papilloma Virus (HPV) types 6 and 11 and it also has considerable risk of neoplastic transformation into fully invasive squamous cell carcinoma into about 5 years.
OBJECTIVE: Because of the rarity of perianal GCA, to date there is no general agreement on the best method for treatment. We wanted to know if surgical approach only was a good method to treat our case.
CASE REPORT: A 28 years old man, HIV-negative, with a 4 years history of perianal GCA quickly growing underwent full tickness local excision at least 0,7 cm margin of normal tissue with skin grafting taken from the thighs. Fecal contamination was avoided by diet and loperamide per os. At two years follow-up no recurrence was detected.
CONCLUSION: Surgical approach with full tickness excision and immediate skin-grafting and regular follow-up demonstrated effective to treat GCA and to minimize disease recurrence.