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Cancers of the anal canal: diagnosis, treatment and future strategies Emma Bown1, Vikas Shah2, Thiagarajan Sridhar3, Kirsten Boyle1, David Hemingway1 & Justin M Yeung*,1

ABSTRACT: Anal cancer is an uncommon cancer; however, it is rising in incidence. There is confusion regarding nomenclature and the distinction between anal canal cancer and anal margin cancer. This article discusses the modern definition, etiology and staging of anal canal and anal margin cancers. Modern chemotherapy and radiotherapy regimens are discussed, in addition to modern imaging and radiotherapy techniques. Future preventative strategies and potential novel treatments are discussed. Cancers of the anal canal: diagnosis, treatment & future strategies Anal cancer is an uncommon condition; however, it is an important condition as it requires a multidisciplinary approach in its management. The aim of this article is to give an outline on the etiology, nomenclature, staging and management of anal cancer, including modern oncological treatments and surgical options for residual or recurrent disease. In addition, future preventative strategies and potential novel treatment modalities are discussed.

KEYWORDS 

• anal canal cancer • anal margin cancer • human papillomavirus • salvage

APER

Incidence & demographics Anal cancer is a relatively uncommon cancer in the UK, with only 916 new diagnoses of anal cancer reported in England in 2010 (age-specific incidence of 1.2 per 100,000 person-years in men and 1.6 per 100,000 person-years in women). In the USA, similar rates of incidence are seen (1.5 per 100,000 person-years in men and 1.9 per 100,000 person-years in women) [1] . As a comparison, 33,218 new cases of colorectal cancer were reported in England in 2010 (Office for National Statistics 2010) [2] . Anal cancer has a variable geographical and ethnic incidence, with a lower number seen within Asian and Pacific Islanders (incidence of 0.5 per 100,000 person-years in men and 0.6 per 100,000 person-years for women) and a relatively higher incidence in male African–Americans (1.9 per 100,000 men) compared with those of Caucasian (1.5 per 100,000 men) or Hispanic ethnicity (1.0 per 100,000 men). The ethnic distribution in females is different with highest rates in Caucasian Americans (2.1 per 100,000) compared with African– and Hispanic–Americans (1.6 per 100,000 and 1.4 per 100,000, respectively) [1] . The median age at the time of diagnosis is 60 years with 7.8% of people diagnosed between the ages of 35–45 years, 51.7% aged 45–64 years, 18.7% aged 65–74 years, 15% aged 75–84 years and 6.4% over 85 years old [1] . However, unlike colorectal cancers, the overall incidence of newly diagnosed anal cancers in England has remained static over the last 10 years (Office for National Statistics data) [2] . In comparison, for other countries, such as USA [3,4] , Australia [5] and Denmark [6,7] , the incidence of anal cancer is increasing. Department of Colorectal Surgery, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK Department of Radiology, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK 3 Department of Clinical Oncology, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK *Author for correspondence: Tel.: +44 116 256 857; [email protected] 1 2

10.2217/FON.14.23 © 2014 Future Medicine Ltd

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Review  Bown, Shah, Sridhar, Boyle, Hemingway & Yeung Pathology of anal canal tumors Anal cancer is a conglomerate term that has historically encompassed both anal canal and anal margin tumors. However, anal canal and anal margin cancers are separate clinical entities. The accurate definition of these tumors is important due to the different staging systems, treatment and prognosis. Variations in terminology and anatomical classification can cause difficulties in interpreting historical data, as anal canal and anal margin cancers may not always have been considered separately. In the surgical definition, the anal canal is a functional unit that extends from the distal intestinal tract to the anal verge, enclosed by the internal anal sphincter muscle (i.e., from the anorectal junction down to the junction of nonkeratinized squamous epithelium with the hair-bearing perianal skin). The anal margin is usually defined as the area extending from the anal verge to 5 cm circumferentially outward on the perineal skin. It is this surgical classification that is used by the American Joint Committee on Cancer (AJCC) to accurately differentiate cancers involved in this area and to which the remainder of this review refers [8] . ●●Anal canal cancer histology

Squamous carcinoma is the most common histological type of anal canal malignancy, and accounts for between 80 and 85% of all anal canal carcinomas [9] . Anal canal tumors arising in the upper third of the anal canal may be more likely to be nonkeratinizing and less differentiated than more distal tumors [10] . There are other histological variants, including cloacogenic, basaloid and transitional tumors, but they are all classified and managed in the same way as they all have a similar natural history, treatment response and prognosis. Adenocarcinomas are the second most common anal canal carcinomas, constituting between 5 and 18% of all anal canal tumors [11] . These should be investigated and managed as low rectal cancers [12] . Rarer anal canal cancers include mucinous adenocarcinomas, small cell carcinomas, undifferentiated carcinomas, carcinoid tumors, nonepithelial tumors, melanomas and other ­secondary tumors. Malignant melanoma accounts for less than 1% of anal canal cancers and has a very poor prognosis owing to late clinical presentation and the tendency for early distant metastases.

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Median survival of between 8 and 22 months has been reported in this subgroup [13,14] . Wide local excision or abdominoperineal excision of the rectum (APER) may be used for local control; however, there is very limited evidence for a survival advantage [15] except perhaps in smaller tumors [16] . ●●Anal margin cancer

Tumors of the anal margin are less common compared with anal canal tumors, and they are classified, staged and managed as skin cancers. Survival is better in this group compared with anal canal cancer as these tumors are often well differentiated, slow growing and have lower rates of distant metastases [17] . The differentiation of anal margin cancers from anal canal carcinoma may not always be possible on histological grounds alone unless skin appendages, such as hair follicles, are seen to which would indicate an anal margin cancer [18] . 5-year survival figures between 60 and 100% have been reported for anal margin cancers [19] . Surgical excision alone and close follow-up may be adequate treatment for smaller anal margin cancers (T1, N0), but with larger tumors, those that are locally invasive or those that are close to the anal verge, definitive chemoradiotherapy is indicated. Risk factors Risk factors for the development of anal canal cancer common to both men and women include receptive anal intercourse, the total lifetime number of sexual partners, perianal condylomata, as well as cigarette smoking [20] . For women, additional risk factors include any history of high-grade vulval intraepithelial neoplasia, vulval cancer [21] or cervical cancer [22,23] . In addition, those people who are immuno­suppressed, such as following organ t­ransplantation, have an increased risk of anal cancer [24–26] . ●●Human papillomavirus exposure

Many of the risk factors above are thought to increase the risk of exposure to human papillomavirus (HPV). HPV has an established association with a number of cancers of the squamous epithelium and especially carcinomas of the ­oropharynx and female genital tract. HPV has also become more widely established as an etiological factor in anal cancer and is now thought to play a role in up to 90% of anal cancers [27] . The evidence to support this in part has been the identification and isolation of

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Cancers of the anal canal: diagnosis, treatment & future strategies  HPV DNA in up to 97% of invasive anal cancers [28] . The most common subtype of HPV linked with anal carcinogenesis is HPV 16 (up to 75% of invasive anal cancers) with HPV 18 the next most common, and with HPV variants 6, 11, 31, 33 and 45 also linked to anal cancer formation [28,29] . The rates of HPV associated anal cancers have increased over the last 30 years, whereas that of non-HPV-associated histological types has plateaued in that similar period [7] . There is an increasing incidence of anal cancer in HIV-positive patients, in particular, men who have sex with men [30,31] . In these groups, the risk of anal cancer may be up to 40-times greater than the background population [32] , with anal cancer becoming the fourth most common cancer in patients with HIV [33] . HIV-positive patients with HPV infection are also more likely to develop anal cancer than HIV-negative patients with HPV infection [34,35] . Over 90% of HIV-positive men who have sex with men have evidence of anal HPV infection, often with more than one HPV subtype [36] . Interestingly, the modern treatment of HIV with highly active anti-retroviral therapy has not had an effect on reducing the rising incidence of anal cancer in HIV-positive patients [37] . This may be explained by the fact that the pattern of perianal HPV infection in HIV-positive individuals is also different from immunocompetent individuals in that the virus does not clear as readily and persistent HPV infection occurs [38] . ●●Anal intraepithelial neoplasia

Anal intraepithelial neoplasia (AIN) is associated with both HPV infection and the potential progression to invasive anal squamous carcinoma [39,40] . Histologically, it is characterized by cellular and nuclear atypia, which is confined to the basement membrane. It is classified (grades I to III) in relation to the depth of the epithelium affected [41] . Grade I affects the lower third, grade II the lower two thirds and grade III affects the whole depth of epithelium. Grade III AIN may also be called severe dysplasia or carcinoma in situ. AIN is often mutifocal and patients may have more than one type of AIN present, which means small biopsies may not be representative [42] . While patients may present with local perianal symptoms, it can often be diagnosed incidentally, after hemorrhoidectomy or skin tag excision, for example. Pathological staging of AIN can be problematic as poor interobserver ­correlation between AIN grades is well documented [43] .

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As with cervical intraepithelial neoplasia (CIN), AIN grades I and II may regress, but grade III rarely so, although the natural history and progression of AIN is uncertain [39] . Progression of AIN grade III to invasive cancer has been reported in up to 13% of patients over a 5-year period [39] , and the detection of associated invasive cancer has been reported in between 8.8 and 26% of resection specimens for AIN III [39,40] . In those patients who are systemically immunosuppressed, progression to invasive cancer may be as high as 50% at 5 years [39] . AIN may be found in up to 5% of women with CIN or vulval intraepithelial neoplasia [44] . HIV-positive patients are at particularly high risk of AIN with prevalence rates ranging from 26 to 89%. It is thought that AIN in HIV-positive individuals may follow a more aggressive course and, as such, routine surveillance using anal cytology has been suggested by some for these individuals [45,46] . However, there is little good evidence that such screening reduces the incidence or mortality of anal cancer in this group [47] , and routine screening for AIN is not currently recommended by the CDC in the USA. Notably, screening for AIN cannot be directly compared with successes in screening for CIN, as the progression of AIN to invasive cancer seems to be lower when compared with ­similarly staged CIN lesions and cervical cancer [46] . Treatment options for AIN grades I and II are unclear but include regular surveillance and observation as progression in these cases is uncertain. For AIN grade III, a variety of treatments, including photodynamic therapy, topical treatments (e.g., trichloroacetic acid, 5-fluorouracil [5FU], 5% imiquimod or cidofovir), local ablation (e.g., thermal coagulation, cryotherapy and laser treatment) and local excision have all been advocated. Local excision for small lesions may be preferable to allow histological examination of the specimen. Topical use of 5% imiquimod has been shown to cause both grade regression and resolution of AIN in addition to intra­c ellular HPV [29,48] . Ablative techniques unfortunately can be painful with significant risks of recurrence [49] . A recent Cochrane review of the management of AIN found that there was a lack of quality data on the natural progression of AIN. The limited number of randomized trials on the management of AIN mean clear conclusions and recommendations for management were difficult to make [50] .

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Review  Bown, Shah, Sridhar, Boyle, Hemingway & Yeung Clinical presentation & diagnosis Patients can present with a variety local perianal symptoms, but most commonly they present with pain, bleeding, swelling, pruritis and discharge. Symptoms of fecal incontinence, pelvic pain or the presence of a rectovaginal fistula are more worrying and suggest advanced disease (Figure 1) . Anal margin lesions and anal canal lesions distal to the dentate line drain into superficial inguinal lymph nodes. Lesions at or above the dentate line drain towards the anorectal, pararectal and paravertebral nodes and also to some of the internal iliac nodes. Careful clinical examination of the anal canal and inguinal lymph nodes is A

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required in all cases as inguinal metastases may be present in up to 29% of patients at presentation [1] . Inguinal lymphadenopathy may be the first presenting symptom in some patients, with the primary anal lesion subsequently found on examination of the anal canal. Examination under anesthesia is often required to fully assess tumor size and to obtain a biopsy for histological confirmation. Lesions in the upper anal canal may be nodular, while in the lower anal canal they tend to present as an infiltrating ulcer [51] . Involvement of the bladder, vagina or prostate may be seen in up to 20% of patients at presentation [51] . Females should also

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Figure 1. MRI T2-weighted images showing anal cancer involving the vagina pre- and post-treatment with chemoradiotherapy. (A) Baseline axial and (B) coronal MRI T2-weighted images showing an intermediate soft tissue anal mass invading the vagina indicating T4 disease (asterix). (C) Postradiotherapy axial and (D) coronal MRI T2-weighted images showing development of fibrosis at site of tumor indicating good response.

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Cancers of the anal canal: diagnosis, treatment & future strategies  have assessment of the female urogenital tract for vulval or cervical lesions due to the association with HPV-related disease at these locations [52] . Consideration of HIV testing should be made due to the increased association of anal cancer in HIV-positive individuals. Staging The staging and management of anal canal and anal margin cancers have been defined separately by the AJCC (vide supra), with anal margin cancer being staged as per squamous skin carcinoma. Box 1 & Table 1 shows the AJCC TNM staging system for anal canal cancer. The National Comprehensive Cancer Network (NCCN) 2012 guidelines on anal cancer raised concerns, however, that the 7th edition of the AJCC cutaneous squamous carcinoma staging is now less suitable for anal margin cancers and there may be a risk of understaging tumors and, therefore, undertreating patients and recommend using anal canal staging systems for both the anal canal and margin tumors [53] . Following histological confirmation, computed tomography (CT) of the chest, abdomen and pelvis is required in addition to MRI of the pelvis in order to adequately stage pelvic nodal disease and look for disseminated disease (examples of T2 and T3 anal cancers on MRI are shown in Figure 2) . For anal canal cancers, N1 disease consists of the presence of metastases in perirectal lymph nodes; N2 disease is the presence of metastases in unilateral internal iliac and/or inguinal lymph node and for N3 disease there are metastases in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes (Box 1, Figures 3, 4 & 5) . Suspicious inguinal lymph nodes should be sampled with fine-needle aspiration but there is a risk that nodal disease may be understaged by fine-needle aspiration alone. In addition, lymph node metastases may be present in lymph nodes less than 5 mm, making radiological confirmation difficult [55] . The use of sentinel lymph node biopsy has been advocated as a tool to reduce over treatment of the inguinal regions with radiotherapy [56] . The draining sentinel nodes have been detectable in 66–100% of cases [57] . Lymph node metastases are found in 7.1–42% of patients [57,58] with false-negative rates of 3.7% [58,59] . PET/CT is being used increasingly in the management of patients with anal cancer [60] . The vast majority of anal cancers are fluorodeoxyglucose avid [61] . The additional information gleaned from the PET/CT includes the volume

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Box 1. TNM staging criteria for anal canal cancer. Tumor stage ●● T X: primary tumor cannot be assessed ●● T0: no evidence of primary tumor ●● Tis: carcinoma in situ (i.e., Bowen disease, high-grade squamous intraepithelial lesion and anal intraepithelial neoplasia II–III) ●● T1: tumor ≤2 cm in the greatest dimension ●● T2: tumor >2 cm, but ≤5 cm in the greatest dimension ●● T3: tumor >5 cm in the greatest dimension ●● T4: tumor of any size invades adjacent organ(s), for example, vagina, urethra and bladder Lymph nodes ●● NX: regional lymph nodes cannot be assessed ●● N0: no regional lymph node metastasis ●● N1: metastases in perirectal lymph node(s) ●● N2: metastases in unilateral internal iliac and/or inguinal lymph node(s) ●● N3: metastases in perirectal and inguinal lymph nodes and/or bilateral internal iliac and/or inguinal lymph nodes Metastases ●● M0: no distant metastasis ●● M1: distant metastasis Reproduced with permission from [54].

of the primary tumor, increased uptake of inguinal, mesorectal and internal iliac lymph nodes, and increased uptake in more distant nodes and metastases. While PET/CT can be highly sensitive for both regional and inguinal nodes, as with CT and MRI, assessment of nodes less than 8 mm is limited [61] . When compared with MRI alone, PET/CT has been shown to both downstage and upstage patients on both T and N staging, and, in theory, this could impact on the initial management; however, no changes in planned treatments were made because of this, as the fields used encompassed the inguinal regions routinely [62] . Other authors, however, have found that that pretreatment PET/CT resulted in changes in management in between 3.7 [63] and 12% [61] of patients. With the advent of intensity-modulated radiotherapy (IMRT), PET/CT may enable more selective radiation and reduce associated morbidity. In patients being considered for radical resection, PET/CT enables the exclusion of distant disease, which would otherwise preclude radical therapy and initiate a palliative pathway. Consideration of the use of PET/CT scanning for nodal staging and treatment planning has

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Review  Bown, Shah, Sridhar, Boyle, Hemingway & Yeung Table 1. Clinical staging of anal canal cancer. Stage

T

N

M

0 I II

Tis T1 T2 T3 T1 T2 T3 T4 T4 Any T Any T Any T

N0 N0 N0 N0 N1 N1 N1 N0 N1 N2 N3 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1

IIIA

IIIB

IV

Reproduced with permission from [54].

been recommended by the NCCN, although its use for assessing treatment response has not been recommended due to concern of overtreatment for clinically insignificant nodes [53] . The Association of Coloproctology of Great Britain and Ireland have not recommended routine PET/CT owing to concerns regarding appropriate validation of its use. However, they have advocated its use in assessing indeterminate lesions on CT/MRI and for assessing suspected local disease relapse [64] . More recent work has used PET to assess the metabolic response of the primary anal tumor to standard chemoradiation and found the degree of metabolic response to be a more accurate predictor of progression-free survival and overall survival than T or N stage [65] . PET/CT should be used at diagnosis as both radiotherapy and surgical planning may be influenced by up- or downstaging of the tumor, however, further data are required to evaluate the true impact of PET/CT in changing the initial management strategy, particularly with the advent of newer radiotherapy techniques. With regards to surveillance, there are insufficient data to support routine use; however, PET/CT is useful as a problem-solving tool for indeterminate lesions on CT or MRI, and for assessing local relapse. Oncological treatments Modern treatment goals for anal cancer consist of eradication of the primary tumor with preservation of the structure and function of the anal sphincters. Historically, anal cancer was primarily managed with an APER, but work published by Nigro et al. in the 1970s showed complete tumor regression in surgical resection specimens after patients were treated with a combination of 5FU radiation and either mitomycin or porifiromycin

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preoperatively [66] . Subsequent studies confirmed this finding and chemoradiotherapy is now the first-line therapy for anal cancers [67] . Major surgical resection is reserved for those who have residual disease or relapse following treatment. The aim of chemoradiotherapy is to achieve a ‘complete response’ (CR) where there is complete resolution of tumor on both clinical and radiological grounds. CR is achieved with combined chemoradiotherapy in up to 90.5% of patients with the remaining patients either having a ­partial response or progressive disease [68,69] . There have been few large randomized studies in patients with anal canal carcinoma. The ACT I trial randomized 585 patients (a third of the UK national incidence between 1987 and 1994) with anal cancer to radiotherapy alone versus radiotherapy and chemotherapy with 5FU and mitomycin. The treatment regimen consisted of a continuous infusion of 5FU for 4 or 5 days in the first and last week of radiotherapy and with an infusion of mitomycin on day 1. The radiotherapy dose used was 45 Gy over 4 or 5 weeks with a boost of radiotherapy (15 Gy in six fractions and 25 Gy via brachytherapy) to the anal canal given if a clinical response was seen at six weeks in the primary tumor. A ‘good’ response rate was seen in 89% of patients (as defined by either a complete clinical response or greater than 50% reduction in volume). This study showed a 46% reduction in risk of local recurrence with combined chemoradiotherapy with a reduction in anal cancer related deaths, but no difference in overall survival [70] . This finding was confirmed by the EORTC trial of 110 patients using a similar treatment algorithm [13] . Cummings et al. showed that radiotherapy with combination 5FU and mitomycin had improved 5-year

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Cancers of the anal canal: diagnosis, treatment & future strategies  cause-specific survival compared ­radiotherapy and 5FU alone (76 vs 64%) [67] . Current NCCN guidelines recommend radiotherapy treatment to include a dose of at least 45 Gy to the primary tumor and involved nodal regions, with elective (and lower dose) coverage of uninvolved regional nodes. It is recommended that patients with node-positive, T3/T4 disease or residual T2 disease should receive a further radiotherapy boost of 9–14 Gy [53,71] . The ACCORD 03 trial examined the role of higher radiation boost doses with standard chemotherapy treatment (5FU and mitomycin) on colostomy-free survival. A total of 307 patients with tumors greater than 40 mm or less than 40 mm, but with N1–N3 disease were randomized, and after treatment, 79% of patients had a CR, whereas 28% relapsed, at a median time of 13 months. The 5-year colostomy-free survival was 75%. No advantage in colostomy-free survival was seen in those who had high-dose induction chemotherapy or a dose escalation of radiotherapy boost in addition to cisplatin and 5FU [72] . Cisplatin based chemotherapy has been advocated for metastatic disease as no other ­treatment modality is of proven benefit [53] . The ACT II trial was the largest randomized controlled trial in anal cancer to date (970 patients enrolled during the study) and was designed to compare the effects of 5FU and cisplatin versus 5FU and mitomycin. It showed that that there was no improvement in CR rate or 3-year progression-free survival when 5FU plus cisplatin A

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chemo­radiation is compared with 5FU plus mitomycin chemoradiation [68] . The RTOG 98-11 study also examined the difference between mito­ mycin versus cisplatin in addition to standard 5FU and radiotherapy regimens and found mitomycin improved disease-free survival and overall survival with borderline significance on colostomy-free ­survival and locoregional ­failure [73] . The current UK practice is to administer concurrent chemoradiation with mitomycin and 5FU in week 1 and 5FU in week 5. The radiotherapy technique is currently planned in two phases depending on the involvement on local and regional lymph nodes and is discussed further below. For T3/T4 and node-positive tumors, a dose of 45 Gy to the pelvis and a further boost of 9 Gy is the preferred option. Local boost can be carried out with electrons or brachytherapy using iridium implants, which could deliver higher local doses. By using modern techniques, such as IMRT, the hope is to minimize the toxicity to the pelvic structures, but improving dose to the tumor and the nodes [68] . The RGOG 0529 trial compared adverse effects of IMRT with data from the RTOG 98-11 study and found a reduction in hematological, dermatological and gastrointestinal adverse effects, although the primary end point of a 15% reduction in adverse effects was not met [74] . Management of regional nodes Inguinal lymph node metastases are usually unilateral and between 3 and 35% of patients B

Figure 2. MRI T2-weighted image showing soft tissue mass. (A)  Coronal MRI T2-weighted image showing 2.5 cm intermediate signal anal soft tissue mass, classified as T2 disease. (B) Sagittal MRI T2-weighted image showing 5.4 cm intermediate signal anal soft tissue mass, classified as T3 disease.

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Figure 3. MRI and PET/computed tomography showing abnormal mesorectal lymph node. (A) Axial T1-weighted image showing abnormal signal and morphology left mesorectal lymph node (arrow). (B) Axial fused PET/computed tomography image showing avid uptake in the mesorectal node indicating N1 disease (arrow).

will have clinical, radiological or pathological evidence of malignant lymphadenopathy at presentation [65,68] . Risks of nodal involvement increase with increasing T stage but up to 15% of patients with T1 disease can have inguinal node involvement [68] . Without elective nodal radiotherapy, up to one-quarter of patients initially staged as having node-negative disease will go on to develop lymph node disease [75] . Inguinal lymph node involvement at diagnosis is a poor prognostic indicator. Lymph node spread is an independent predictor of poorer locoregional control, reduced disease-free s­urvival and reduced overall survival [13,56,76] . Optimal management strategies for malignant inguinal lymphadenopathy at the time of presentation remain unclear [77] . The most commonly adopted regimen for malignant inguinal lymph node involvement is to include the inguinal nodes in the radiotherapy boost given to the anal canal with formal lymph node dissection reserved for residual or recurrent ­d isease [64,78] . In the ACT II study, all patients received Phase I radiotherapy using parallel opposed fields to include both macroscopic anal disease

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and both inguinal and femoral regions (30.6 Gy in 17 fractions). Subsequent radiotherapy is determined by the presence of involved local or regional nodes clinically or radiologically. For those with N0 disease at the time of diagnosis, Phase II radiotherapy of 19.8 Gy in 11 fractions is delivered to a 3 cm margin around the gross anal tumor volume alone. For those with inguinal, femoral or pelvic lymphadenopathy (N1+) at the time of diagnosis a further 19.8 Gy is delivered in 11 fractions, but the field is extended to include a 3 cm margin beyond all involved anal and nodal tissue [68] . If inguinal nodes are involved alone, Phase II radio­ therapy is delivered with parallel opposed fields to include them, but if inguinal nodes are clear and only the local nodes are involved, a three- or field-field t­echnique is employed. Prophylactic irradiation of negative inguinal lymph nodes can reduce the incidence of inguinal lymph node recurrence [79] . Metachronous lymph node metastases have been shown to occur in up to 25% of patients without positive inguinal nodes at the time of primary treatment, compared with 2–5% of those patients with initially node-negative disease who received prophylactic irradiation [75,79] . Some authors believe this may be overtreatment with the risk of unnecessary morbidity from inguinal irradiation (especially in node-negative T1 or T2 tumors) and have suggested that a watchand-wait policy may be appropriate in these groups [64] . However, up to 12.5% of patients with T1 or T2 tumors who did not receive prophylactic irradiation have been found to develop inguinal metastases up to 5 years ­following diagnosis [56,79] . Surgical management Surgical management of anal canal cancer is usually reserved for residual or recurrent disease. Residual disease is defined as the presence of tumor within 6 months of treatment and recurrent disease as tumor developing more than 6 months after a CR. Local disease recurrence can occur in between 30 and 40% of patients, the majority within the first 3 years [80] ; the risk of recurrence is associated with increased T stage on presentation and radiotherapy doses less than 50 Gy in those unable to have chemotherapy [80] . Salvage surgery by APER necessitates excision of all irradiated skin and the perineum in order to achieve a clear resection margin, and

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Cancers of the anal canal: diagnosis, treatment & future strategies  can be significantly more radical than APER performed for a low rectal cancer. Extended resection with removal of adjacent pelvic viscera is often required [81] and a considerable perineal defect may result. Salvage surgery carries significant risks of mortality and morbidity with up to 45% of patients developing a significant complication, including delayed perineal healing for greater than 3 months [80] . For this reason, perineal reconstruction using autologous tissue may be required using methods such as rectus abdominis myocutaneous flaps, gluteal flaps, gracilis flaps or free latissimus dorsi flaps [82] , which may reduce wound breakdown rates in the heavily irradiated tissues [83,84] . Salvage surgery can achieve 5-year survival ranging from 29 to 75% [81,83,85–87] . A

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Positive initial lymph node status [87] and incomplete surgical excision with positive resection margins are significant prognostic indicators for long-term survival following salvage surgery [80,88] . Survival following salvage surgery in patients with recurrent disease has been found by some to be better than those with residual disease after chemoradiotherapy [85,89] although other studies has found the reverse to be true [89] . ●●Management of anal margin cancers

Anal margin cancers are less common than anal canal cancers. They tend to be slower growing, better differentiated with a better prognosis compared with anal canal cancer [90] . Small anal margin cancers may be suitable for local excision C

D

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Figure 4. Radiological images showing abnormal adenopathy. (A) Axial MRI T2-weighted image showing right inguinal adenopathy (arrow). (B) Axial MRI T2-weighted image showing left iliac adenopathy (arrow). (C) Fused axial PET/computed tomography image showing avid uptake in right inguinal and left iliac adenopathy, indicating N3 disease (arrows). (D) Fused coronal PET/computed tomography image showing large primary anal mass with left iliac adenopathy (arrows).

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Figure 5. PET/computed tomography showing uptake in abnormal lymph nodes. (A) Fused axial PET/computed tomography image showing avid uptake in subcarinal node (arrow). (B) Fused axial PET/computed tomography image showing avid uptake in porta hepatis node (arrow). (C) Fused coronal PET/computed tomography image showing avid uptake in mediastinal node and anal primary lesion, findings indicate M1 disease (arrow).

only as long as clear margins can be obtained and anal function maintained. It has been suggested that local excision with a 1 cm margin of T1 or T2 anal canal cancers may have a role in selected cases [91] . If surgical excision is not possible then combined treatment with chemoradiotherapy regimens using 5FU and mitomycin or radiotherapy alone may be used with 10-year cause-specific and disease-free survival of up to 92 and 88% reported [92] . Defunctioning colostomy rates A pre-emptive defunctioning colostomy may be required prior to commencement of chemoradiotherapy due to symptoms such as fecal incontinence, fistula formation or relating to pain or bowel obstruction. Colostomy rates vary widely and have been reported to be necessary in between 4 and 34% of patients [88,93–96] . Therapeutic colostomy may be required during or after completion of chemoradiotherapy [76] in up to a further 8% of patients due to local

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treatment side effects such as pain, incontinence and anal stenosis [96] . In the RTOG 98-11 trial, a secondary analysis demonstrated that pretreatment tumor size greater than 5 cm was the only independent predictor of colostomy rates and time to formation of a colostomy [97] . Once a colostomy has been performed in patients with anal cancer, the subsequent rates of reversal are very low. Some authors have shown than between 80 and 100% are never reversed [88,93] , and, as such, patients should be warned preoperatively of the high probability that their colostomy will be permanent. Overall prognosis The mortality to incidence ratio can be used as a marker of long-term survival [98] . For anal and anal canal cancer in the UK in 2010, the mortality to incidence ratio was 0.3 for men and 0.27 for women compared with 0.36 for cases of rectal cancer in both men and women (Office

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Cancers of the anal canal: diagnosis, treatment & future strategies  for National Statistics data) [2] . This suggests slightly better long-term survival for anal cancer than rectal cancer. The Office for National Statistics data uses the International Statistical Classification of Diseases and Related Health Problems 10th Revision classification, and, as such, AIN and carcinomas in situ are not included in the code ‘malignant neoplasm of the anus and anal canal’. Colostomy-free survival is an often used end point in anal cancer studies as it suggests absence of local disease and preservation of anal sphincter function (and hence low morbidity to the anal canal). Overall 5-year survival rates of between 70 and 79%, 5-year colostomy-free survival between 65 and 82% and 5-year disease-free survival and progression-free survival between 58 and 78% have been reported [68,71–72] . Follow-up There are no definitive guidelines on anal cancer follow-up following chemoradiotherapy. Clinical response should be assessed 6–8 weeks following chemoradiotherapy as 60–85% will have had a complete clinical response at this time [99] . It can take as long as 6 months following chemoradiotherapy for some tumors to completely regress. If visible tumor is present at initial follow-up, it can be observed for up to 6 months as long as there is continued regression [68] . The ACT II study followed patients up every 2 months in the first year, every 3 months the second year and 6 monthly thereafter until 5 years with a CT scan of the chest, abdomen and pelvis at 6 months [68] . Careful history and clinical examination of the perianal region and inguinal lymph nodes is the mainstay of follow-up with further investigations, such as MRI or biopsy based on clinical suspicion. There are limited data to recommend routine imaging for distal metastases owing to the limited therapeutic options in this scenario. Future strategies Strategies for prevention of anal cancer are primarily public health issues. They include the clinical screening and early detection of high-grade AIN, especially in high-risk groups, and reducing HPV-related disease by HPV vaccination. ●●HPV vaccination

HPV vaccination has been shown to reduce the incidence of cervical intraepithelial

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Review

neoplasia  [100] and it has been proposed that vaccination against HPV may similarly reduce the risk of AIN, anal condylomata and HPVassociated anal cancer [101] . There is limited evidence of the efficacy of this strategy, but HPV vaccination has been shown to reduce rates of condyloma and AIN in HIV-negative men who have sex with men [102] . The quadrivalent HPV vaccine Gardasil® (Merck & Co., NJ, USA) was granted a license by the US FDA in 2010 for the ­prevention of AIN and anal cancer in men and women. ●●EGF receptor inhibitors

EGF receptors (EGFRs) have been found to be overexpressed in up to 90% of squamous anal carcinomas with low rates of KRAS and EGFR mutations suggesting a role for EGFR inhibitors [103] . Cetuximab is a monoclonal antibody against the EGFR and, in combination with systemic chemotherapy, has been shown to reduce size of liver metastases in advanced disease [104,105] . While the high rate of EGFR expression and low KRAS mutation rate makes the use of EGFR inhibitors attractive, there is little published work in this area. A published abstract of nine patients with locally advanced anal canal cancer combined cetuximab with combination radiotherapy and chemotherapy with 5FU and cisplatin found seven patients achieved a clinical response although the definition of this is ill defined [106] . An open-label Phase I–II trail is underway using panitumumab in combination with standard chemoradiotherapy with 5FU and mitomycin in patients with locally advanced tumors (T2 and above or any N1) without evidence of metastases [107] . Another trial is looking at 5FU, cisplatin, radiotherapy and cetuximab in stage I, II or II anal cancers [108] . ●●Immune therapy

Immune therapy using HPV vaccination is a novel treatment aimed at stimulating a host immune response against HPV-associated anal cancers through cell-mediated immunity. HPVinfected cells express the HPV E6 and E7 antigens constitutively, whereas normal cells do not; these antigens are necessary for the induction and maintenance of cellular transformation. A number of therapeutic vaccines have been developed targeting HPV E6 and/or E7 antigens, including live vector-based vaccines, peptide-/protein-based vaccines, nucleic acid-based

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Review  Bown, Shah, Sridhar, Boyle, Hemingway & Yeung vaccines and cell-based vaccines [109] . Phase I clinical trials are underway assessing the safety of a peptide based vaccine in anal canal cancers [110] and encapsulated plasmid DNA in highgrade AIN [111] , but as yet, there are limited data on efficacy. Conclusion The management of anal cancers requires a multidisciplinary approach for its diagnosis and management. Most anal cancers respond to chemoradiotherapy and only those who fail to respond will go on to have surgical treatment. Future perspective The management of anal canal cancers is likely to remain the preserve of the radiation oncologist with salvage surgery in reserve for those with residual or recurrent disease. It is likely that

future adaptations in the delivery of radiotherapy treatments as seen with IMRT will decrease local morbidity while continuing to deliver high rates of complete clinical response. The introduction of HPV vaccination and potential inclusion of boys in the national vaccination programs may have a significant impact on the incidence of anal canal cancer in the future. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or p­ending, or royalties. No writing assistance was utilized in the production of this manuscript.

EXECUTIVE SUMMARY ●●

Anal canal cancer is uncommon, but rising in incidence.

●●

Distinction between anal canal and anal margin cancer is based on surgical definition of the anal canal, with different management and prognosis.

●●

The highest rates of anal cancer are seen in HIV-positive men who have sex with men. The risk of anal cancer can be up to 40-times that of the background population.

●●

Human papillomavirus may be an etiological factor in up to 90% of cases.

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Management with chemoradiotherapy is the first-line treatment. Complete clinical response seen in up to 90% of patients.

●●

Radical surgery is reserved for residual or recurrent disease following chemoradiotherapy.

●●

Future preventative strategies in prevention of human papillomavirus infection through vaccination may play a role in reduction of incidence.

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