Endoanal ultrasound (EAUS) is a relatively inexpensive, safe and well-tolerated examination, which can be useful to evaluate the extent of local disease. There are limitations in patients with stenosis. In addition, the field of view is limited with an inability to assess distant mesorectal, inguinal or iliac nodes. In certain centres, EAUS is used to obtain two- or three-dimensional images to assess tumour location and spread within the anal canal and surrounding lymph nodes. The difficulty in assessing test characteristics such as sensitivity and specificity is that the majority of patients treated with chemoradiotherapy do not undergo pathological confirmation of node status. Some studies use a cut-off of 1 cm or larger for presumed positive lymph nodes [13]. Metastatic lymph nodes are typically round hypoechoic structures. Using size criteria alone, as mentioned above, may under-stage a significant percentage of patients.

Initial staging with magnetic resonance imaging may provide more useful information about local extent of pelvic disease, but it is more expensive and labour-intensive and may be contraindicated in certain patients (e.g. those with pacemakers). Anal canal tumours, when compared to the gluteus muscles, tend to have an intermediate signal intensity (SI) on T2-weighted images and isointense SI on T1-weighted images. Tumour involvement of the sphincter complex or urogenital structures can best be seen on T2-weighted MRI, as ill-defined intermediate SI infiltration or encasement [14]. Metastatic lymph nodes demonstrate similar signal intensity to the primary tumour. Perirectal lymph nodes with a maximum short-axis diameter of more than 5 mm and inguinal and pelvic sidewall nodes with a maximum short-axis diameter of more than 10 mm are often considered to contain carcinoma. Parikh et al. note similar limitations in both ultrasound and MRI with over-staging reactive lymph nodes and under-staging microscopic involvement. The European Society for Medical Oncology guidelines have recommended both EAUS and MRI in the primary staging of anal carcinoma. Ultrasound is felt to be more accurate for T stage, particularly early T stage, whereas MRI may identify more lymph nodes [13].

Several studies have evaluated the role of MRI in assessing the tumour before and after CRT. It has been found to be useful in assessing the primary tumour size, signal intensity and infiltration of adjacent structures [15]. Tumour response was assessed by recording change in tumour size and signal intensity. After treatment, a decrease in tumour size accompanied by reduction and stability of the MR T2 signal characteristics at 1 year after CRT was associated with favourable outcomes. There are clear limitations to MRI including posttreatment oedema and scarring, but this tends to stabilise in T2-weighted SI and scar size after 1 year. Other studies have failed to identify predictive MRI features in the early posttreatment period for outcomes such as locoregional recurrence [16].

At diagnosis, ¹⁸fluorodeoxyglucose uptake on positron emission tomography/computed tomography (FDG-PET/CT) is also used to evaluate lymph node status and distant metastases. FDG-PET/CT can be used for radiation therapy treatment planning by clearly defining sites of metabolically active tumour [17]. With FDG-PET/CT, the detection rate of non-excised tumours on initial examination was 93 % [18].

PET scan may provide additional information as a biomarker with higher maximum standardised uptake value (SUV) associated with an increased risk of nodal metastasis at diagnosis and worse disease-free survival. Patients with high anal tumour SUV (max) at diagnosis were at an increased risk of persistent or recurrent disease on post-therapy FDG-PET at 4 months. An SUV (max) ≥5.6 was associated with poorer disease-free survival [19]. In addition, PET/CT can upstage anal cancers and influence further management. In one study, 12.5 % of patients had a change in management based on PET/CT results, including 7.5 % (n = 3) who were found to have FDG-avid inguinal lymph nodes that led to broader radiation fields. One patient had a FDG-avid periaortic node which was included in the radiation field, and one patient had a lung metastasis treated with metastasectomy [20].

Sentinel lymph node biopsy (SLNB) has been studied as an adjunct to physical exam for evaluating for node-positive disease. 99mTc colloid is injected into the peri-tumoral tissue and lymphoscintigraphy performed. During the surgery, blue dye can also be used. The sentinel inguinal node is identified by a handheld gamma probe and dye visualisation. Multidirectional lymphatic drainage (mesenteric, iliac, inguinal) can occur in up to 56 % patients [21]. As many as 27 % of patients were found to have metastases in a lymph node that was not evident on clinical exam [22]. Other authors voice concerns over the use of sentinel lymph node biopsies to make decisions to omit inguinal radiation, particularly in patients with high-risk primary lesion. Several small series have reported 7–14 % rate of subsequent inguinal lymph node metastases within 2 years, despite negative SLNB on histopathology. Many of these patients did not have the inguinal lymph nodes included in the initial radiation fields. These were considered false-negative SLNB [21, 23]. De Jong’s review of the literature included eight studies with a total of 143 patients. There was a 96.5 % detection rate of the sentinel lymph node, but the authors were unable to calculate a false-negative SLN detection rate. Further studies are needed before this can be broadly applied.

The most important prognostic factors in anal cancer are thought to be T, N and M stages [24]. Locoregional control rates vary from 50 % at 3 years seen in the large (585 patients) UKCCCR randomised trial to 71.5 % at 5 years (88 % for stage I, 69 % for stage II, 77 % for stage IIIA and 60 % for stage IIIB) as reported in a group of 286 patients from France [25].

As the tumour size increases, there is a clear increase in local recurrence. Wright et al. in their series of 180 patients from Memorial Sloan-Kettering Cancer Center describe a 3-year locoregional failure rate of 15 % in T1/T2 patients compared with 42 % in T3/T4 patients (p = 0.0009) [26]. Larger tumour size (higher T stage) is also associated with a decrease in survival (T1, 94 %; T2, 79 %; T3, 53 %; and T4, 19 %) [27].

The impact of nodal involvement on outcomes is weaker. The Radiation Therapy Oncology Group trial (RTOG 87-04) found those with node-positive disease had a higher colostomy rate (an indirect marker for local failure). Similarly, the European Organization for the Research and Treatment of Cancer (EORTC) trial comparing radiation alone to CRT showed significantly higher local failure rates (p = 0.0017) and lower survival (p = 0.045) in those with positive nodes, regardless of treatment arm, compared to node negative patients, but the extent or size of nodal spread did not influence prognosis [4]. In a 12-year review of 167 anal cancer patients, both increasing T stage (HR 1.7) and N stage (HR 1.47) were significantly associated with locoregional failure [28].

Certain pathological subtypes, such as basaloid subtype, and patients with human immunodeficiency virus have been shown to have a lower overall survival rate [28]. Additional factors found to be significant for worse prognosis on multivariate analysis included older age [3, 29] failure to complete radiation therapy [24], HIV-positive status [30] and dose intensity of chemotherapy less than or equal to 75 % [3]. Tobacco smoking has also been identified as a risk factor. Those who smoke tend to have the diagnosis of SCC at a younger age and have more frequent recurrence (32 % of smokers vs. 20 % of non-smokers) at a shorter interval. In addition, smokers had a significantly worse overall 5-year survival (45 % in smokers and 20 % in non-smokers; p = 0.05) [31].

Historically, surgical excision was the first-line treatment prior to the development of combined modality therapy championed by Nigro in the 1970s [32]. Before this sentinel publication, local excision was acceptable for lesions smaller than 2 cm with favourable pathological feature, confined to the mucosa or submucosa. The data on these small lesions is often skewed by the inclusion of those with anal margin cancer. Greenall et al. reported that 10 % of the anal canal lesions were amenable to local excision [33]. There was a 41 % rate of local recurrence and a 64 % overall 5-year survival. Those treated with abdominoperineal resection had a 38–71 % 5-year survival rate. With surgery alone, local pelvic or perineal recurrence accounted for 50–70 % of failures, and only 10–20 % died from distant metastases.

Current strategies favour combined modality therapy (CMT) first, with radical resection of anal squamous cell cancer reserved for those with persistent or recurrent disease after CMT, those who are unable to tolerate CMT and those who are not candidates for CMT.

Radiation therapy results in an antitumour response in the majority of patients. Most protocols since Nigro’s publications in 1974 have included chemotherapy with the radiation. However, external beam radiation therapy alone or in conjunction with brachytherapy was used in the 1980s and 1990s. With radiation alone, local control rates range from 61 to 100 % with overall 5-year survival rates of 50–94 % [34].

Two randomised controlled trials compare concomitant radiotherapy and chemotherapy to radiotherapy alone as definitive treatment for anal SCC.

The United Kingdom Coordinating Committee on Cancer Research (UKCCCR) randomised 585 patients with anal cancer to receive either 45 Gy in 20 or 25 fractions alone or with concurrent 5-fluorouracil during the first and last weeks of radiation and mitomycin on the first day of radiation [35]. They assessed for response at 6 weeks, and if there was >50 % tumour response, an additional boost of 25 Gy was given. Assessment of tumour response was done 2 months after completion of the boost. There was a higher incidence of early toxicity (within the first 2 months) with CMT, but the rates of late toxicity were similar. Early morbidities included leucopenia, thrombocytopenia, skin reactions and gastrointestinal and genitourinary symptoms. There were no significant differences in perineal wound complications. There were similar rates of treatment-related morbidities necessitating surgery in both groups; these were included in the local failure analysis.

In both groups the majority of local failures occurred within the first 18 months. There was a significant reduction in the local failure rate in the CMT group (39 %) compared with the XRT-only group (61 %) at 3 years. The 3-year overall survival rate between the two arms was not statistically different (XRT only = 58 %, CMT = 65 %). The mortality rate from anal cancer at 3 years was significantly higher in the XRT group at 39 % versus 28 % in the CMT group (p = 0.02). Long-term follow-up at 12 years shows that these significant differences persist [36].

Similarly, the European Organization for the Research and Treatment of Cancer (EORTC) radiotherapy and gastrointestinal cooperative group demonstrated that the addition of chemotherapy to radiotherapy in patients with greater than 5 cm (≥T3) primary tumours or positive lymph nodes resulted in a significant increase in the complete remission rate from 54 % for radiotherapy alone to 80 % for CMT [4]. The locoregional control rate improved by 18 % at 5 years, and the colostomy-free rate increased by 32 % in those who received CMT. There was no significant difference in late side effects, although anal ulcers were more frequently observed in the combined-treatment arm. Despite better locoregional control and better progression-free survival in the CMT group, the survival rate remained similar in both treatment arms. Several significant prognostic factors were identified; nodal involvement, skin ulceration and male sex showed worse local control, and nodal involvement and skin ulceration showed worse overall survival. The size of the primary and percent circumference did not show any prognostic value nor did the location of the primary (canal vs. margin). Both UKCCCR and EORTC studies showed improved local control and decreased stoma rates with CMT compared to radiation alone without increased toxicity.

There have been several studies to evaluate the use of other cytotoxic chemotherapy agents in conjunction with radiation therapy. The most prominent has been cisplatin (CP). The RTOG 98-11 multicenter trial published in 2008 showed that the mitomycin C (MMC) group compared to the CP group had similar 5-year disease-free survival rates (60 % vs. 54 %; p = 0.17), overall survival rates (75 % vs. 70 %; p = 0.10), locoregional recurrence (25 % vs. 33 %) and distant metastasis (15 % vs. 19 %). The rate of colostomy was significantly lower for the MMC group (10 % vs. 19 % p = 0.02). There was, however, more haematological toxicity in the MMC arm [5].

Similarly, the Anal Cancer Trial (ACT) II failed to confirm any advantage of CP in the CRT regimen or 5-FU- and CP-based maintenance chemotherapy [37]. Other long-term studies show equivalent results in overall survival with MMC and CP. A study from Brazil showed that the overall colostomy rate was not significantly different with MMC versus CP. The 10-year overall survival and disease-free survival rates for the MMC group were 52 and 53 % and for the CP group 54 and 49 %, respectively (p = 0.32 and p = 0.92) [38].

Modifications of the radiation therapy include intensity-modulated radiation therapy (IMRT), which involves using PET/CT to defining high-, intermediate- and low-risk planning target volumes (PTV). Using treatment-planning software, the dose of radiation is tailored to provide graded doses of radiation to these different risk PTV areas. The high-risk PTV typically includes primary tumour and grossly positive nodal disease. Intermediate-risk PTV includes the internal iliac region inferior to the SI joint, the perirectal nodes as well as the high-risk PTV. The low-risk PTV area includes the inguinal nodes, external iliac nodes and the internal iliac nodes superior to the inferior edge of the SI joint. A recent small retrospective study has shown the benefits of IMRT with chemotherapy. With IMRT the duration of treatment is significantly shorter, requiring less frequent treatment breaks. In addition, when comparing IMRT to conventional RT, IMRT showed significantly better 3-year overall survival (88 % vs. 52 %), locoregional control (92 % vs. 57 %) and progression-free survival (84 % vs. 57 %) [39]. The results of a prospective study, RTOG 0529, are awaited. A recent analysis of sites of locoregional failure from Memorial Sloan-Kettering Cancer Center concludes that inguinal and all pelvic nodal regions should be included in the PTV for IMRT, including the external iliac, internal iliac and presacral regions. The authors also recommend that common iliac nodes should be included in the radiation fields of patients with advanced T and N stage disease, based on 4 of 58 (7 %) common iliac node recurrences, three of which were not “in-field” in this subset of patients [26].

If the inguinal lymph nodes are found to be positive on physical exam or imaging and FNA confirms the finding, these nodes are then included in the radiation field. Many have advocated for routine prophylactic inguinal irradiation regardless of T stage, citing a 2 % 5-year inguinal lymph node recurrence rate for the prophylactic group compared to 16 % in those who did not get upfront inguinal radiation [40]. In patients who did not receive inguinal radiation, there was a 12 % rate of inguinal lymph node recurrence in those with T1 or T2 lesions and 30 % rate for T3 or T4 lesions. Many of the radiation treatment protocols used in the randomised trials include the inguinal nodes in all patients [5, 35, 38, 41].

The current guidelines for follow-up of patients with anal cancer after definitive CRT include serial digital rectal examination, with biopsy of suspicious lesions every 3 months beginning 8–12 weeks after completing CRT [42]. Cell death may continue up to 12 weeks after completion of CRT [43]. In addition, treatment-related ulcers may persist for 3–6 months [44]. Differentiation of treatment effect versus residual tumour can be challenging, and liberal use of biopsies is recommended. The Tru-Cut core biopsy needle can be used for sampling of deeper tissues in the ischiorectal fossa [3]. Most local recurrences, however, are apparent on physical exam, and a biopsy is obtained to confirm the diagnosis [35].

The role of ultrasound in the follow-up of treated anal cancer is controversial. It is difficult to distinguish oedema and scar from persistent tumour on EAUS. In addition, this can be painful for patients with a relative anal stenosis. Some authors have recommended that waiting 16–20 weeks after radiation is sufficient to allow for resolution of oedema and improves the accuracy of the ultrasound imaging [45]. Serial exams can monitor for changes in the size of the scar, and this modality may add to routine clinical follow-up [46].

FDG-PET/CT, a non-invasive technique, has been studied to both determine residual disease and predict recurrence and survival. During posttreatment follow-up, FDG-PET/CT had, on a per examination basis, sensitivity for the detection of persistent or recurrent disease of 93 % and specificity of 81 % [18]. The 2-year cancer-specific survival was 94 % for those with a complete metabolic response (CMR) and 39 % for those with persistent FDG uptake post-CRT on PET/CT scan at a median of 2 months after completion of CRT, (p = 0.0008) [42]. CMR was associated with significantly improved progression-free and cause-specific survival compared with partial metabolic response. In fact, the results of the posttreatment FDG-PET/CT were more predictive of survival outcome than the pretreatment T stage. A similar predictive power of the PET response to radiation therapy has also been shown in a prospective study on 92 women with cervical cancer by the same researchers from Washington University in St. Louis, Missouri [47]. Another retrospective study of 48 patients with anal cancer showed a 5-year overall survival difference of 88 % in those with a CMR, 69 % for those with a partial metabolic response and 0 % in those with no metabolic response (p < 0.0001) [48]. This study noted that 20 % of patients had coincident FDG-avid abnormalities that were not related to anal carcinoma—in three patients, separate primary malignancies were diagnosed. Studies on post-therapy PET/CT show that this modality is promising as a surveillance technique, but further confirmatory prospective data is needed to justify its routine use. Additionally, the timing of post-CRT PET/CT is thought to impact the specificity of this test, but at this point there is no data to clarify when PET/CT should be performed.

MRI has also been a part of follow-up but is reported in only a few studies. Stabilisation of the T2-weighted SI and scar size more than 1 year after CRT is associated with good outcomes in one small study of 15 patients [15]. With this modality it is important to establish a base line and look for stability of the images [14].

With varying CRT protocols using 5-FU/MMC and XRT, the complete response rates range from 72 to 95 %, with local failure of 25–39 % and overall 5-year survival of 58–84 % (Table 7.2). In multivariate analysis in the RTOG 98-11 trial, male sex (p = 0.02), clinically positive nodes (p < 0.001) and tumour size greater than 5 cm (p = 0.004) were independent prognostic factors for worse survival. With the mitomycin-based treatment, local failure occurred in 13 %, regional failure rate was 7, and 25 % had distant metastasis at 5 years. Overall survival rates were less than 50 % at 4 years in those with tumour >5 cm and clinically positive lymph nodes [5].

Colostomy rate has been used as an end point for trials. Few studies distinguish the indication for the colostomy—whether it is created for tumour or treatment-related factors. Cumulative colostomy rates range from 4 to 23 % with standard CRT [5, 35, 37]. As many as 20 % of colostomies are created to deal with treatment-related effects [5, 35], and up to 10 % are created to deal with the presenting symptoms [37].

As mentioned above, radiation is associated with haematological toxicity in 60 % of patients that may interrupt treatment. Non-haematological toxicity rates may be reduced with the intensity-modulated radiotherapy technique [39]. Irradiation of the inguinofemoral region can lead to serious complications with acute and late toxicity. Acute toxicity includes epidermolysis with ulceration and superinfection of the skin, while late toxicity includes inguinal fibrosis, external genitalia oedema, neurogenic bladder, lower limb lymphedema, osteonecrosis of the femoral head, artery stenosis and soft tissue sarcomas. There was no difference in late toxicity rates observed between those receiving radiation alone and with the addition of 5-FU and MMC in both the EORTC and the UKCCR trials.

Overall quality of life has been found to be good at a median of 51 months after CRT using the EORTC QLQ-CR29 and the global QLQ-C30 questionnaires in those who had a complete response [49]. Increased urinary frequency in 40 % of patients and some degree of faecal incontinence in 47 % of patients has been reported. More than half maintained an interest in having sexual relations, but 100 % of male patients had difficulty maintaining an erection. For women who maintained an interest in having sexual relations, 50 % reported having pain or discomfort during intercourse, and 100 % of men had difficulty maintaining an erection [49]. Another study that used EORTC questionnaires found that fatigue was the strongest predictor of impaired function-related quality of life [50].

Salvage surgery is a curative approach to recurrent anal cancer after radiotherapy or chemoradiation. Almost always, an abdominoperineal resection (APR) is required, although scattered reports of local excision or low anterior resection can be found in the literature [51]. Between 17 % and 39 % of patients diagnosed with curable anal cancer will eventually require consideration of salvage APR for local control [2, 52, 53]. Not all patients with isolated local recurrence can be salvaged, as some will be unresectable when the recurrence is detected. In a large comprehensive series of anal cancer patients from a tertiary referral centre, Christie NHS hospital in Manchester, England, the surgical salvage rate for local recurrence was 82.7 % in those who had undergone chemoradiation and 71.4 % in those who had undergone radiation alone. Upon occasion, APR is performed because of the toxicity of radiation therapy [7]. In some cases recurrent or persistent disease cannot be ruled out, and these patients undergo APR [54].

Early detection of local recurrence can improve the chance for offering salvage surgery to the patient. Patients are examined carefully 3–6 months after chemoradiation or radiotherapy. Liberal use of examination under anaesthesia with biopsy is helpful as recurrences in the anal canal may be difficult to detect in patients who are often tender from treatment and whose examination findings can be confounded by radiation injury. Reported time to local recurrence after chemoradiation ranges from 12 to 21 months [55–58]. The recurrence is usually detected as a mass in 45–95 % of cases, and patients may complain of new anal pain or bleeding. The UKCCCR study found that recurrences were nearly always digitally palpable. In reported series of salvage APR for anal cancer, persistent disease comprises one-third to half of patients in nearly all series.

Preoperative planning is poorly described in published case series but is essential in planning an R0 resection. Renehan indicates that CT imaging, and more recently MRI, is used for preoperative planning. Preoperative planning is critical because many patients require a multivisceral resection (MVR) as part of salvage surgery. Most series report that 40–60 % of salvage patients require MVR [51–53, 56]. In one of the largest series (n = 95) from France, Lefevre et al. report that 86 % of APRs for anal cancer included MVR, with the majority (70 %) comprising posterior colpectomy.

Salvage APR for anal cancer can be difficult and laborious due to bulky disease and fibrosis resulting from chemoradiation. The median blood loss ranges from 400 cc [57] to 1,000 cc [56], and operative duration has been reported as a mean of 4.6 [59] to 6 h [56]. In one series of 62 patients, three (8.5 %) patients developed profound bleeding during the resection that resulted in closing the abdomen with packs and reoperation the subsequent day [52].

Given the size of the soft tissue defect after APR and the difficulties with wound healing in an intensely radiated field, many authors describe myocutaneous flap closures of the perineal wound. The flap commonly used is the vertical rectus abdominis flap (VRAM). In many series, nearly half of patients had a flap closure of the perineal wound [53, 56, 59]. Renehan et al. reported that nearly all cases are closed with a flap. Flaps do not completely prevent perineal wound complications, and in one series, all patients who had myocutaneous flap procedures developed perineal wound breakdown [58]. Lefevre et al. report no differences in perineal complications in the flap versus no flap groups, with a reoperation rate of 17 % in the VRAM group and 26 % in the group without VRAM. The benefit of VRAM was the decrease in time to perineal wound healing with a median time to healing of 19 days compared to 95 days in the group without a VRAM. There was a statistically significant difference in perineal hernia rates between groups, with no perineal hernias in patients with VRAM reconstruction.

Post-operative complication rates vary substantially. High rates (~70 %) are reported by Schiller et al. from Canada, Ferenschild et al. from the Netherlands and Lefevre et al. from France. Stewart et al. from the United States report an 18 % rate of late (>30 days) complications. These are predominantly perineal wound complications with rates of infection or dehiscence between 35 and 80 %. Renehan et al. describe that 66 % of perineal wound problems require over 3 months to heal, and Stewart et al. report a median time to perineal wound healing in all patients of 7 months.

Obtaining an R0 resection poses some challenges when performing salvage resection of recurrent or persistent anal cancer. Renehan et al. found that a positive resection margin was a risk factor for decreased overall survival in their report of 73 patients. R1 or R2 resections are reported in 8.5 [53] to 32 % [57] of cases, with many authors reporting rates close to 20 % [54, 56, 60]. Lefevre et al. argue that liberal use of the VRAM flap allows the surgeon to obtain wider margins on the tumour. The location of positive margins is not described in any of the literature.

Reported survival rates after salvage surgery range from around 30 [51, 60] to 64 % [53]. Survival rates are not improved with more recently published series suggesting that modern surgical practices are not improving outcomes. Predictors of survival are not consistent amongst reports, likely reflecting the small size of series—all include fewer than 100 patients and most include 40 or fewer patients (Table 7.3). Nilsson et al. found T3 or T4 tumours, persistent cancer, node-positive disease and older age associated with worse overall survival. Patients with persistent cancer had a 5-year overall survival of 33 % compared with 82 % in patients with recurrent cancer.