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Treatment of anal cancer

Treatment of anal cancer
Literature review current through: Jan 2024.
This topic last updated: Jul 24, 2023.

INTRODUCTION — The term "anal cancer" usually refers to a squamous cell cancer (SCC) of the anal canal, which represents the majority of cancers arising in the anal region. However, SCCs can also arise in the perianal skin and in the rectum, and SCCs arising at these sites are generally treated in the same manner as anal canal SCCs. On the other hand, the treatment paradigm for anal adenocarcinomas, which are much less common than anal SCCs, is similar to that for rectal adenocarcinomas, with resection representing an important component of multimodality therapy for most patients.

This topic review will cover the treatment of all of these types of anal cancers. The classification, histology, epidemiology, clinical features and staging of anal cancers, as well as the diagnosis and management of anal intraepithelial neoplasia are presented separately. (See "Classification and epidemiology of anal cancer" and "Clinical features and staging of anal cancer" and "Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment".)

ANATOMY AND TYPES OF TUMORS — The anus consists of a glandular mucosa-lined anal canal and the epidermis-lined perianal "margin" (figure 1). The anus encompasses mucosa of three different histologic types: glandular (mucosa-lined), transitional, and squamous, proximal to distal, respectively. Distally, the squamous mucosa (which is devoid of the epidermal appendages, hair follicles, apocrine glands, and sweat glands) merges with the hair-bearing perianal skin (true epidermis). This mucocutaneous junction has been referred to as the anal "verge" or margin. (See "Classification and epidemiology of anal cancer".)

Four distinct categories of tumors arise in the anal region:

Tumors that develop from any of the three types of mucosa and that cannot be visualized in their entirety while gentle traction is placed on the buttocks are termed anal canal cancers [1]:

Tumors arising in the transitional or squamous mucosa are squamous cell cancers (SCCs) and appear to behave similarly, despite their sometimes variable morphologic appearance. By convention, most series that report outcomes of "anal cancer" refer exclusively to these tumors. The term "anal cancer" by common definition refers to SCCs arising within the mucosa of the anal canal, and the two terms will be used interchangeably throughout this review. These tumors are mainly treated with radiation therapy (RT) plus concurrent chemotherapy. (See 'Squamous cell cancer of the anal canal' below.)

Basaloid (also termed junctional or cloacogenic) carcinoma is a variant of SCC that arises from epithelial transitional zone. However, these terms have largely been abandoned because these tumors are now recognized as nonkeratinizing types of SCC. Tumors arising within the anal canal above the dentate line are termed nonkeratinizing SCCs, while those arising within the anal canal distal to the pectinate (dentate) line are termed keratinizing SCCs.

Adenocarcinomas arising from glandular elements within the anal canal are rare. They appear to share a similar natural history with rectal adenocarcinomas and are treated similarly. (See 'Anal adenocarcinoma' below.)

Tumors arising within the hair-bearing skin at or distal to the squamous mucocutaneous junction have been referred to as anal margin cancers. However, the most recent (eighth) edition of the American Joint Committee on Cancer (AJCC) cancer staging manual and the fifth edition of the World Health Organization (WHO) classification of tumors of the digestive tract specifically defines tumors that arise within the skin at or distal to the squamous mucocutaneous junction that can be seen in their entirety with gentle traction placed on the buttocks and are within 5 cm of the anus as perianal cancers [1,2]. Like most clinicians, we treat SCC lesions of the perianal skin the same as anal canal cancers, using RT and concurrent chemotherapy. (See 'Squamous cell cancer of the anal canal' below.)

Local treatment, surgery, or local RT (electrons) is used only when the lesion is very separate from the anal verge and is a discrete skin lesion. (See 'True perianal skin cancers' below.)

Primary rectal SCCs, which are very rare, can be difficult to distinguish from anal cancers, but they are treated according to the same approach as anal cancer. (See 'Rectal squamous cell cancers' below.)

An algorithmic approach to selecting initial treatment based on the tumor location and histology is provided (algorithm 1).

TREATMENT OF LOCALIZED DISEASE

Squamous cell cancer of the anal canal — We suggest initial concurrent chemoradiotherapy rather than upfront surgery for most patients with anal canal squamous cell cancers (SCCs), even those with T1-2N0M0 tumors. Despite the absence of randomized trials directly comparing upfront chemoradiotherapy versus surgery, chemoradiotherapy has emerged as the preferred method of treatment for anal canal SCC because it can cure many patients while preserving the anal sphincter in approximately 70 to 85 percent. Local excision may be an option for carefully selected patients with very favorable, small (<1 cm) superficially invasive tumors that are completely excised and have ≤3 mm of basement membrane invasion and a maximal horizontal spread of ≤7 mm. However, local excision has never been compared with radiation therapy (RT) or chemoradiation, which are considered the standards of care in this patient population. If this approach is selected, vigilant follow-up is mandatory, with the prompt initiation of chemoradiotherapy for recurrent disease. (See 'Local excision for small T1 tumors' below.)

Initial chemoradiotherapy — We suggest concurrent use of fluorouracil (FU) plus mitomycin during RT rather than FU alone or FU plus cisplatin for most patients, including those with cT1N0 tumors. Because poor compliance to chemotherapy and RT are associated with inferior local failure-free survival and overall survival, treatment interruptions should be minimized, and overall treatment time and total dose maintained as much as possible. (See 'Management of recurrent or persistent disease' below.)

Although the original regimen, described as the "Wayne State or Nigro regimen," used infusional FU 1000 mg/m2 on days 1 to 4 and 29 to 32 (plus mitomycin 10 to 15 mg/m2 on day 1 only) concurrent with RT [3], consensus-based National Comprehensive Cancer Network (NCCN) guidelines suggest a modified regimen as was used in the Radiation Therapy Oncology Group (RTOG) 98-11 trial [4,5]. The chemotherapy consists of infusional FU 1000 mg/m2 on days 1 to 4 and 29 to 32 plus mitomycin 10 mg/m2 on days 1 and 29, maximum 20 mg per dose. European guidelines also suggest the infusional FU plus mitomycin regimen, but offer the option of utilizing mitomycin 12 mg/m2 on day 1 only (maximum 20 mg single dose), as was used in the ACT II trial [6]. In our view, either approach is acceptable. (See 'Replacement of mitomycin by cisplatin' below.)

Evolution of sphincter-sparing treatment — In the past, abdominoperineal resection (APR) was routinely performed for tumors arising in the anal canal. This radical procedure required removal of the anorectum with creation of a permanent colostomy. In early series, the overall probability of five-year survival was 40 to 70 percent, with a perioperative mortality of 3 percent [7-12].

Extending prior observations of a radiation-potentiating effect of concomitant fluoropyrimidines in a variety of gastrointestinal malignancies, investigators at Wayne State initially devised a protocol of preoperative treatment with chemotherapy plus RT as a means of decreasing the surgical failure rate for patients with anal canal cancer [3]. The "Nigro" regimen consisted of FU (1000 mg/m2 per day by continuous infusion days 1 through 4 and 29 through 32), mitomycin (10 to 15 mg/m2 on day 1 only), and intermediate dose RT (30 Gy). The finding that the first three patients had complete pathologic responses led to the development of strategies that were directed at preservation of the anal sphincter.

In a follow-up series, patients with anal canal cancer were initially treated with chemoradiotherapy (same regimen) and subjected to subsequent surgery (typically an APR) only if there was residual tumor in a postradiation biopsy [13]. The majority of patients treated with chemoradiotherapy were cured (five-year overall survival 67 percent) without an APR (five-year colostomy-free survival 59 percent).

These findings were subsequently confirmed by multiple investigators using a variety of regimens. Taken together, the use of combined chemoradiotherapy results in local failure rates of 14 to 37 percent, five-year overall survival rates of 72 to 89 percent, and five-year colostomy-free survival rates of 70 to 86 percent [13-19]. As a result of these data, the use of concurrent RT with infusional FU and mitomycin has become the standard of care for patients with SCC of the anal canal, replacing surgery, even for those with T1-2N0 disease.

It should be noted that the use of local excision alone for T1N0 disease is increasing over time, especially for tumors that are <1 cm in size. Overall survival data appear to be comparable with chemoradiation, although local recurrence, colostomy-free survival, and tolerability are lacking. (See 'Local excision for small T1 tumors' below.)

Chemoradiotherapy versus radiation therapy alone — The necessity of including chemotherapy in the nonoperative treatment regimen for anal cancer has been addressed in at least two randomized trials:

The Anal Cancer Trial Working Party of the United Kingdom Coordination Committee on Cancer Research (UKCCCR) randomly assigned 585 patients with T1 to T4 SCC of the anal canal or margin to receive either RT alone (45 Gy external beam in 20 or 25 fractions over four to five weeks plus a 15 Gy external beam or 25 Gy brachytherapy boost), or RT plus concurrent infusional FU (1000 mg/m2 for four days or 750 mg/m2 for five days during the first and the final weeks of RT) and mitomycin (12 mg/m2 on day 1 only) [20]. Chemoradiotherapy was associated with significant reductions in local failure (59 versus 36 percent) and cause-related mortality (28 versus 39 percent). More acute morbidity, including six deaths, occurred with combined modality therapy; late morbidity was similar.

Overall survival was similar between the two groups, and this was attributed to an early increase in non-anal cancer deaths in the first five years, which disappeared by year 10 [21]. Only 11 patients in the chemoradiotherapy group suffered a locoregional relapse as a first event after five years.

In a second trial, The European Organisation for the Research and Treatment of Cancer (EORTC) randomly assigned 110 patients with locally advanced (T3-4 or N1-3) anal cancer to receive RT (45 Gy with a 15 or 30 Gy boost) with or without concurrent infusional FU (750 mg/m2 per day on days 1 through 5 and 29 through 33) plus mitomycin (15 mg/m2 day 1 only) [22]. Chemoradiotherapy was associated with a significantly higher pathologic complete remission rate (80 versus 54 percent), an 18 percent higher five-year locoregional control rate, a 32 percent higher colostomy-free rate, and higher event-free and progression-free survival. Overall survival was not significantly different, and in contrast to the UKCCCR trial, the incidence of acute and late side effects and treatment-related mortality did not differ between the groups.

The role of RT alone for early-stage tumors is discussed below. (See 'Elderly or extensive comorbidity' below.)

Role of mitomycin — The need for mitomycin has been questioned since it does not sensitize tumor cells to the effects of RT, has only modest antitumor activity against SCCs, and is associated with renal, pulmonary, and bone marrow toxicity [23,24]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)" and "Mitomycin pulmonary toxicity".)

The need for mitomycin in curative treatment of anal cancer was addressed in a joint trial from the Radiation Therapy Oncology Group (RTOG) and the Eastern Cooperative Oncology Group (ECOG) in which 310 patients with anal cancer of any tumor or nodal stage were randomly assigned to combined modality therapy with or without mitomycin (using the Wayne State regimen) [4]. Patients who received mitomycin had significantly better four-year colostomy-free survival (71 versus 59 percent) and disease-free survival (73 versus 51 percent), but pathologic complete response rates and overall survival were similar. Grade 4 toxicity (23 versus 7 percent) and fatal neutropenic sepsis (4 versus 1 patient) were significantly more common in the mitomycin group.

The authors concluded that, despite greater toxicity, the use of mitomycin in a definitive complete response regimen for anal cancer was justified.

Replacement of mitomycin by cisplatin — Cisplatin is more active in the treatment of SCCs in general than is mitomycin. Early uncontrolled studies suggested encouraging colostomy-free and overall survival rates with the substitution of cisplatin for mitomycin in the treatment of anal cancer [14-16,25]. This issue has been addressed in two large controlled studies, with conflicting results [26,27]:

The substitution of cisplatin for mitomycin in the treatment of anal canal cancer was not supported by the results of the United States Intergroup trial (RTOG 98-11) [26,28]. Induction chemotherapy plus concurrent chemoradiotherapy using cisplatin and FU (with RT begun on day 57 after two courses of cisplatin and FU) was directly compared with the standard regimen of mitomycin, FU, and RT. The chemotherapy drugs in both arms were given during weeks 1 and 5 of RT. The trial enrolled 682 non-HIV-infected patients with SCC of the anal canal, 27 percent >5 cm, and 26 percent clinically node positive.

In the latest update, there were significant differences favoring FU plus mitomycin in five-year disease-free survival (68 versus 58 percent, p = 0.006), overall survival (78 versus 71 percent, p = 0.026), and colostomy-free survival (72 versus 65 percent, p = 0.05) [28]. FU plus mitomycin was also associated with a statistically nonsignificant trend toward fewer locoregional failures (LRFs; 20 versus 26 percent) and fewer colostomies (cumulative rate of colostomy failure 12 versus 17 percent). Hematologic toxicity was worse in the mitomycin group, but nonhematologic toxicity and late RT-related toxicity were similar in the two groups.

On the other hand, the therapeutic equivalence of cisplatin and mitomycin when used in combination with infusional FU concurrent with RT was suggested in the ACT II randomized trial of 940 non-HIV-infected patients with anal SCC (30 percent node positive, 43 percent T3/4) [29]. Treatment consisted of RT in both arms (50.4 Gy in 28 fractions) with concurrent infusional FU (1000 mg/m2 per day on days 1 to 4 and 29 to 32) and either cisplatin (60 mg/m2 on days 1 and 29) or mitomycin (12 mg/m2 day 1 only). There was a second randomization to receive or not receive maintenance chemotherapy starting four weeks after chemoradiotherapy (two courses of cisplatin plus FU, administered four weeks apart).

Patients receiving mitomycin had more acute grade 3 or 4 hematologic toxicity (26 versus 16 percent), but no higher rates of febrile neutropenia (3 percent in both groups) during chemoradiotherapy. Rates of grade 3 or 4 nonhematologic toxicity were similar (62 versus 68 percent). The complete response rate at six months (the primary endpoint) was 90.5 versus 89.6 percent with mitomycin and cisplatin, respectively, and the three-year colostomy-free survival rate was similar in patients treated with mitomycin or cisplatin and those treated with and without maintenance treatment (72 to 75 percent in all groups). At a median follow-up of 5.1 years, three-year progression-free survival was similar with cisplatin versus mitomycin, and overall survival was also similar (hazard ratio [HR] for death with cisplatin versus mitomycin 1.05, 95% CI 0.80-1.38). Overall survival was also comparable with and without the use of maintenance therapy (HR 1.07, 95% CI 0.81-1.41).

Taken together, these data suggest that FU plus mitomycin remains the standard of care, but that FU and cisplatin could be considered a reasonable approach as well. Both options are included in European guidelines although they state that FU plus mitomycin is generally recommended [6]. Importantly, any marginal benefit for cisplatin over mitomycin in terms of less hematologic toxicity is likely to be offset by the extra resources needed to administer cisplatin.

There appears to be no role for induction chemotherapy or a continuation of chemotherapy beyond concurrent chemoradiotherapy.

Capecitabine as an alternative to infusional fluorouracil — At least some data suggest that substituting daily oral capecitabine for infusional FU in conjunction with intravenous (IV) mitomycin during RT is well tolerated with minimal toxicity [30-32]. In a phase II trial of 31 patients, 77 percent had a complete clinical response (cCR) four weeks after completion of therapy [30]. At a median follow-up of 14 months, there were three locoregional recurrences. In our view, the combination of capecitabine and mitomycin is an acceptable substitute for infusional FU plus mitomycin for chemoradiotherapy.

Radiation therapy dose and schedule — Patients are typically treated with external beam RT using fields that initially encompass the pelvis from the S1-S2 level, inguinal lymph nodes (even if palpably negative), and anus. Chemotherapy (typically infusional FU plus mitomycin) is administered concurrently with the first and fifth weeks of RT. Treatment interruptions should be minimized, and overall treatment time and total dose maintained as much as possible.

Compared with historical series of APR and inguinal lymph node dissection, this strategy has significantly reduced the rates of locoregional recurrence and led to markedly improved control of gross nodal disease [33-35]. Rates of inguinal node recurrence are <5 percent [34,36]; rates are higher when elective inguinal node irradiation (for those with no palpable or radiographic evidence of inguinal nodal disease) is omitted [35,37].

The optimal dose of external beam RT for the treatment of anal canal cancer is the subject of considerable debate. Total doses, including boost doses, vary considerably between countries, from 50.4 Gy as was used in the ACT II trial, to 55 to 59 Gy for T3-4 or node-positive disease (as was used in the RTOG 98-11 trial),and up to 60 Gy used in some Nordic series [26,29,38].

Even lower doses have been used. At least two retrospective studies suggest that 30 Gy of RT with concurrent chemotherapy after an excisional biopsy might be adequate for selected patients with early-stage disease [39,40]. In the larger report, the entire group of 25 patients had a five-year colostomy-free survival of 91 percent [39]. However, other retrospective reports suggest that total dose is a significant prognostic factor for both local control and survival [41-43], particularly for more advanced tumors, such as T3 or 4 or node-positive disease. As an example, in a series of 50 patients with non-metastatic anal cancer, RT doses of ≥54 Gy were associated with significantly better overall survival (84 versus 47 percent), disease-free survival (74 versus 56 percent), and local control (77 versus 61 percent) compared with lower doses [42]. Most of these patients also received concurrent FU and mitomycin. European [44] and NCCN guidelines [5] recommend a minimum dose of 45 Gy for all patients.

Two trials have evaluated the potential benefit of doses of external beam RT above 54 Gy, both of which are flawed by the use of a split-dose course of RT [45,46]:

In an RTOG study, 47 patients with anal cancers ≥2 cm received 59.4 Gy RT in a "split dose" schedule (two-week delay after 36 Gy) plus concurrent FU and mitomycin [45], and the results compared with those of a previous RTOG trial in which patients were treated with 45 Gy in a continuous schedule plus the same chemotherapy regimen [4]. Although cross-trial comparisons such as these can be misleading, local control did not seem better with the higher RT doses, and although patients receiving 59.4 Gy had comparable toxicity, the two-year colostomy rate was much higher than expected (30 versus 9 percent in the previous trial). The split course schedule may have influenced treatment-related toxicity.

A similar split-course schedule of RT was studied in an ECOG trial in which 19 patients received 59.4 Gy concurrent with two courses of infusional FU and cisplatin [46]. Although the response rate was 95 percent, toxicity, particularly hematologic, was prohibitive.

Radiotherapy techniques have also evolved over the past decade. Intensity-modulated RT (IMRT) is now a preferred approach over other RT techniques, including three-dimensional conformal RT (3D-CRT) [47,48]. IMRT uses three-dimensional radiation treatment planning, and there are variable, computer-controlled intensities within each RT beam, in contrast to the uniform doses within each 3D-CRT beam. Compared with most other treatment techniques, IMRT can achieve a higher degree of accuracy in conforming the radiation to the planned target while sparing normal tissue. The advantages of IMRT are particularly evident when the target volumes have complex shapes or concave regions. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

Several retrospective reports and prospective cohort studies support the safety of IMRT in conjunction with concurrent chemotherapy for anal SCC, with promising early efficacy results [49-54] and emerging data on long-term outcomes [55]. A confirmatory phase II study was conducted by the RTOG (RTOG 0529); in the final report, outcomes with IMRT in conjunction with FU and mitomycin C were compared with those from the FU/mitomycin control arm of the RTOG 98-11 trial [56]. (See 'Replacement of mitomycin by cisplatin' above.)

The following were noted:

The primary endpoint (reduction of grade 2+ combined acute gastrointestinal/genitourinary toxicity by at least 15 percent compared with the conventional RT/FU/mitomycin arm from RTOG 9811) was not met; the rate with IMRT (77 percent) was identical to that reported in RTOG 98-11.

However, there were lower than expected rates of acute grade 3 or higher dermatologic (23 versus 49 percent in RTOG 98-11) and gastrointestinal (21 versus 36 percent) toxicity with IMRT, and there was also less grade 2 or higher hematologic toxicity (73 versus 83 percent).

Importantly, 81 percent of the patients enrolled in this trial required a change in the radiation treatment plan following pretreatment central review, illustrating the learning curve for practitioners using this treatment method.

With IMRT treatment planning radiation doses are typically prescribed to PTVs (Planning Target Volumes). The dose of radiation required to control disease is extrapolated from historical studies that show excellent rates of control with concurrent radiation and chemotherapy. Typically prescribed dose varies by size of the tumor and risk of microscopic spread in elective nodal areas. One approach with "shrinking field technique" is that the low risk elective nodal PTV volume is typically prescribed to 30.6 Gy in 1.8 Gy daily fractions. The high-risk elective nodal PTV is sequentially prescribed an additional 14.4 Gy in 1.8 Gy daily fractions for a total prescribed dose of 45 Gy. Finally, for T1–2 lesions with residual disease after 45 Gy, T3–4 lesions, or N1 lesions, an additional 5.4 to 14.4 Gy in 1.8 to 2 Gy daily fractions is again sequentially prescribed to the gross disease PTV volume (total dose, 50.4 to 59.4 Gy). In RTOG-0529, the prescription parameters are different due to the use of only a single elective nodal volume and slightly different dose prescriptions depending on tumor stage. Furthermore, delivery of escalating dose to different target volumes was performed using a simultaneous integrated boost (SIB) dose painting technique with a maximum dose of 1.8 Gy per fraction to the primary tumor and large volume gross nodal involvement and 1.5 Gy per daily fraction to elective nodal areas. Table 1 outlines dose prescriptions by TNM stage according to the RTOG-0529 protocol (table 1). The SIB approach offers the convenience of developing a single treatment plan with reduced planning complexity, albeit with a lower biological dose delivered to the elective nodal areas.

Brachytherapy provides another means of dose intensification, sparing the surrounding normal structures. In several series, the addition of brachytherapy provided a complete pathologic response rate of 83 percent (range 73 to 91 percent), a local control rate of 81 percent (range 73 to 89 percent), and a five-year survival rate of 70 percent (range 60 to 84 percent) [15,16,57-62]. However, anal necrosis range developed in 2 to 76 percent [15,16,59,61], and many patients required surgical therapy (APR) for complications.

The incidence of late toxicity from RT, such as anal ulcers, stenosis, and necrosis, is also dose-dependent [57]. The development of such toxicities may necessitate a colostomy in 6 to 12 percent of patients who are otherwise free of disease [33,36,58]. In a review of late radiation complications in 144 patients with anal cancer who were treated with either RT alone or with chemotherapy, after five years, 10 percent required an APR for late treatment-related complications [57]. The serious complication rate was much higher in those patients who had at least 39 Gy of external beam RT to the pelvis before the boost to the tumor (23 versus 7 percent in those who received less than 39 Gy). (See 'Toxicity and quality of life issues' below.)

Special populations

Patients living with HIV — Anal SCC in people living with HIV (PLWH) is potentially curable with combined modality therapy, and in general these patients are treated similarly to those who do not have HIV. A low CD4 count does not necessarily predict for greater treatment-related toxicity. However, patients with active HIV/AIDS-related complications or a history of complications (eg, opportunistic infections, other malignancies) may not tolerate full-dose therapy or may require dose adjustment. (See "Clinical features and staging of anal cancer".)

Most data suggest that response to therapy, local control, and survival are as good in PLWH who as in non-HIV-infected patients, particularly in the era of potent antiretroviral therapy (ART; previously called highly active antiretroviral therapy) [63-71]. In some series, acute treatment-related toxicity has been worse than expected, particularly with RT doses >30 Gy [63,71,72], but this has not been a universal finding, and it does not appear to compromise long-term outcomes. Diverting colostomy or APR is required for toxicity management in 6 to 12 percent of cases [36,57].

The relationship between treatment tolerance and CD4 counts has been directly addressed only in small observational studies:

An early report of 17 patients seen before the era of modern ART found that no patient with a pretreatment CD4 count ≥200 cells/microL required hospitalization during treatment [72]. By contrast, four of the eight with counts <200 cells/microL needed hospitalization for myelosuppression, diarrhea, or moist desquamation, and four required a colostomy for a therapy-related complication or persisting/recurrent disease. Similar findings have been noted by others [73].

Three later series totaling 59 patients treated in the era of modern ART did not find a significant relationship between the CD4 count and treatment-related toxicity, even if the CD4 counts were <200 to 300 cells/microL [64,66,74].

In general, PLWH should be treated similarly to non-HIV positive individuals, although those with active HIV/AIDS-related complications or a history of opportunistic infections, or other HIV-related malignancies may not tolerate full-dose therapy, or may not tolerate mitomycin, and require either dose adjustment or treatment without mitomycin [75]. There is no evidence that the addition of cetuximab, which enhances the effect of RT in human papillomavirus (HPV)-related oropharyngeal SCC, improves outcomes in HIV related anal SCC when added to conventional chemoradiotherapy [76].

Patients with locally advanced disease — We approach patients with T3/4 primary tumors or N1b/c (table 2) disease similarly to those with less-advanced-stage disease (ie, using the same regimen of RT plus concomitant FU and mitomycin (table 3)). However, patients with T3, T4, or node-positive disease receive an additional RT boost of 10 to 14 Gy in 2 Gy fractions (total dose 55 to 59 Gy versus the usual 45 Gy for earlier stage disease). (See 'Radiation therapy dose and schedule' above.)

Patients with large (T3/4) primary tumors or advanced (ie, N1b or N1c (table 2)) nodal metastases have a cure rate of approximately 50 to 60 percent with standard chemoradiotherapy [77]. Several studies have attempted to escalate treatment in order to improve outcomes, with mixed results [26,78-80].

Taken together, there is no consistent demonstration of better outcomes when patients with locally advanced anal SCCs are treated with an intensified approach. We treat these patients similarly to those with earlier stage disease, an approach that is also recommended by the NCCN [5] and the European Society for Medical Oncology (ESMO) [6].

Patients with para-aortic nodal involvement — Isolated para-aortic lymph node involvement is rare and considered M1 (stage IV) disease (table 2). The optimal management of these patients is undefined. Definitive chemoradiotherapy with the inclusion of the para-aortic nodes in the radiation field is a reasonable approach; however, these patients remain at high risk for the development of additional metastatic disease.

Limited data suggest that definitive combined chemoradiotherapy is a potentially curative treatment option for these patients [81,82]. One report described outcomes in 30 patients with SCC and distant metastases limited to the para-aortic lymph nodes [82]. The primary tumor and involved nodes were treated to a median dose of 51 Gy, while uninvolved nodal regions were treated with a median dose of 45 Gy; all patients received concomitant chemotherapy. Grade 3 or 4 gastrointestinal, dermatologic, and hematologic adverse events occurred in 30, 27, and 20 percent of patients during therapy, respectively. After a median follow-up of three years, the overall and disease-free survival rates were 67 and 42 percent, respectively. Fifteen patients had experienced a recurrence at a median of 0.9 years (range 0.5 to 3.5 years), and the predominant site of recurrence was distant metastases.

While these data provide support for definitive chemoradiotherapy in the setting of isolated para-aortic nodal metastases, these patients remain at high risk for the development of additional metastatic disease. Whether additional courses of adjuvant chemotherapy might be beneficial is unknown.

Elderly or extensive comorbidity — Concomitant chemoradiotherapy using conventional doses of FU plus mitomycin is the standard approach for most patients with localized anal SCCs (table 3). For the extremely aged population with T1N0 tumors, or those with significant comorbidities, enrollment on clinical trials testing the feasibility of lower RT and chemotherapy doses (eg, ) is preferred. If protocol therapy is not available, reduction of mitomycin and FU doses during RT could be considered, although this is not a standard approach.

RT alone – Randomized trials demonstrate the superiority of chemoradiotherapy over RT alone in terms of disease-free survival, local relapse, and colostomy-free survival, but whether these benefits apply to early-stage disease (T1-2N0 (table 2)) is unclear. Only one of the two randomized trials described above enrolled patients with T1 or 2 tumors, and results were not analyzed according to primary tumor stage [20].

Several retrospective series report excellent outcomes for patients with T1-2N0M0 disease RT alone [83-85]. However, not all reports are favorable:

A retrospective series of 146 patients with T1-2N0M0 anal SCC treated with RT alone (n = 71) or chemoradiotherapy (n = 75) reported a twofold higher rate of LRF with RT alone (five-year locoregional control 76 versus 87 percent) [86].

A preliminary report of an analysis derived from the National Cancer Database (NCDB) and presented at the 2021 American Society of Clinical Oncology GI Cancer Symposium also noted inferior outcomes for patients with cT1N0 anal SCC who were treated with RT alone without multiagent chemotherapy [87]. Of the 2959 patients with cT1N0 disease reported to the NCDB from 2004 to 2016 who were treated nonoperatively who had at least two months of follow-up, 92 percent had multiagent chemotherapy, but 237 were treated without chemotherapy. Predictors of omission of chemotherapy were older age, comorbidity, Black American race, and more remote year of treatment. The use of multiagent chemotherapy was a significant predictor of survival (HR for death 0.48, 95% CI 0.38-0.62), as was female biologic sex, younger age, higher income, and private insurance. After propensity matching, overall survival at 120 months for patients treated with and without chemotherapy was 86 and 65 percent, respectively.

RT with reduced dose chemotherapy – RT using lower chemotherapy doses has been used for older adult patients with anal canal SCC [40,88-92]. One report evaluated 58 patients ≥75 years of age who received RT (39.6 Gy followed by a delayed boost of 20 Gy) with or without infusional FU (median dose 600 mg/m2 per day, days 1 through 4, and 29 through 32) plus mitomycin (median dose 9.5 mg/m2 on day 1 only) [88]. The toxicity of this regimen was comparable with that seen in younger patients treated with higher chemotherapy doses, and efficacy was preserved (five-year survival and local control rates were 54 and 79 percent, respectively). Others note poorer outcomes than could be achieved using standard chemoradiotherapy [93].

Notably, NCCN guidelines recommend definitive chemoradiotherapy using standard dose FU and mitomycin for all patients with anal canal SCC, even those with T1-2N0M0 tumors [5].

Local excision for small T1 tumors — Local excision is an option for patients with T1 tumors less than 1 cm in size, although this approach has never been compared with RT or chemoradiotherapy, which are considered the standards of care in this patient population. We reserve this approach for superficially invasive cancers (ie, a completely excised lesion with ≤3 mm of basement membrane invasion and a maximal horizontal spread of ≤7 mm) without lymphovascular invasion. These are the definitions for superficially invasive tumors from the Lower Anogenital Squamous Terminology (LAST) Project of the College of American Pathologists (CAP) [94]. If this approach is selected, vigilant follow-up is mandatory, with the prompt initiation of chemoradiotherapy for recurrent disease.

The use of local excision for T1 tumors has been increasing over time [95], and the available evidence suggests that it is appropriate in selected patients. Updated guidelines from the NCCN suggest that this approach be limited to superficially invasive squamous cell anal cancers, defined as a completely excised lesion with ≤3 mm of basement membrane invasion and a maximal horizontal spread of ≤7 mm, adopting the definition of the CAP [96]. In one retrospective analysis of 17 patients with completely excised T1 anal SCC treated with local excision, 7 of whom met the criteria for a superficially invasive lesion, 12 received adjuvant RT for a positive margin, and the remainder were treated with local excision alone [97]. After a median follow-up of 45 months, five-year overall survival in the entire cohort was 100 percent, and there was no difference in five-year cancer recurrence-free survival between the superficially invasive and invasive cancers.

Prognosis — The main prognostic factors are tumor diameter and nodal status, as reflected by Tumor, Node, Metastasis (TNM) stage [98]. In data derived from the United States Intergroup RTOG 98-11 trial of chemoradiotherapy for squamous cell anal cancer [99] and using the most recent 2017 American Joint Committee on Cancer (AJCC) staging system for anal cancer (table 2) [1], the following rates of five-year survival and LRF were reported:

T2N0 – 82 percent survival; 17 percent LRF

T3N0 – 74 percent survival; 18 percent LRF

T4N0 – 57 percent survival; 37 percent LRF

T2N+ – 70 percent survival; 26 percent LRF

T3N+ – 57 percent survival; 44 percent LRF

T4N+ – 42 percent survival; 60 percent LRF

Palpable, clinically positive lymph nodes and male sex are also poor prognostic factors for LRF and overall survival [22,98,100].

Over the past three decades, the percentage of cases with positive lymph nodes has increased significantly, largely attributed to enhanced detection with newer imaging modalities. As an example, in one analysis of 62 studies including 10,569 patients with anal SCC, the lymph node positivity proportions increased from a mean estimate of 15 percent in 1980 to 37 percent in 2012 [101].

Despite this finding, the relative differences in overall survival for node-positive versus node-negative disease have decreased over time [101,102]. The apparently reduced ability of nodal status to predict outcomes is likely related to misclassification of true disease stage, caused by the introduction of new staging technologies.

However, reclassification has also facilitated more accurate treatment with CRT, which has probably contributed to the more favorable contemporary outcomes for patients with non-metastatic anal cancer treated with chemoradiotherapy compared with historical trials (along with incremental improvements in chemoradiotherapy driven by randomized trials). In one analysis of 560 such patients treated over a 25-year period at a single large British medical institute, comparing individuals treated from 1990 to 1994 with those treated most recently (2010 to 2014), three-year locoregional failure rates declined from 33 to 16 percent, and five-year overall survival increased from 62 to 80 percent [102]. This is despite striking increases in the rate of pretreatment nodal positivity from 17 percent in 1990 to 1994 to 41 percent in 2010 to 2014.

Colostomy rates — Colostomy-free survival is a measure of anal sphincter preservation after treatment with RT or chemoradiotherapy. Multiple investigators using a variety of regimens report five-year colostomy-free survival rates of 65 to 86 percent [13-19,103]. (See 'Evolution of sphincter-sparing treatment' above.)

Failure to control anal cancer and complications of treatment are alternative indications for a colostomy, but in most cases, colostomy is required for recurrent tumor:

In a review of 235 patients diagnosed with anal cancer between 1995 and 2003 and treated with curative-intent RT or chemoradiotherapy at four different Danish centers, the five-year cumulative incidences of tumor-related and treatment-related colostomy were 26 and 8 percent, respectively [104]. Large tumor size (>6 cm) was associated with a higher risk of tumor-related colostomy, while a history of prior excision was a risk factor for therapy-related colostomy.

Similarly, in an analysis of data from RTOG trial 98-11 (discussed above), five-year colostomy rates among patients treated initially with chemoradiotherapy were 9 percent for those with node-positive disease, and 19 percent for tumors >5 cm in diameter, regardless of nodal status [105]. Overall, 78 percent of the colostomies were performed for persistent or recurrent disease. (See 'Management of recurrent or persistent disease' below.)

Toxicity and quality of life issues

Early toxicity – In the two trials comparing conventional RT with and without chemotherapy described above, significant acute gastrointestinal toxicity occurred in 33 to 45 of patients treated with chemoradiotherapy, while 49 to 76 percent of patients had significant acute dermatologic toxicity, and rates of grade 3 or 4 hematologic toxicity were as high as 50 percent [20,22]. Modern RT techniques such as IMRT have been associated with lower rates of acute toxicities during CRT, including grade ≥3 hematologic (range 20 to 40 percent), dermatologic (range 10 to 40 percent), gastrointestinal (range 7 to 21 percent), and genitourinary (range 0 to 7 percent) toxicities [52,53,56]. The majority of patients report anorectal discomfort which tends to be worse at the end of treatment and improves thereafter [53]. Rates of hematologic toxicity tend to be lower with a single rather than two cycles of mitomycin. (See 'Role of mitomycin' above.)

Managing hematologic toxicity during therapy is paramount to avoid life-threatening infections and treatment delays.

Late toxicity – Pelvic RT can cause late toxicity, including altered bowel, urinary, and sexual function, potentially impacting quality of life (QOL) [106-112]. The following data are available on long-term QOL in patients undergoing chemoradiotherapy for invasive anal cancer:

In a national cohort of 199 anal cancer survivors treated with curative chemoradiotherapy between 2000 and 2007, 128 returned questionnaires addressing symptoms and QOL; the same questionnaires were answered by an age- and sex-matched reference group of volunteers (n = 269) not treated for pelvic cancer [110]. The median time since diagnosis was 66 months. Global QOL was significantly reduced among survivors (difference 15 points, p <0.001). Survivors had markedly worse scores for fatigue, dyspnea, insomnia, and diarrhea; significantly increased stool frequency; more buttock pain, flatulence, fecal incontinence, impotence (males), dyspareunia, and reduced sexual interest (females). In a later analysis of this same cohort compared with an expanded group of 1211 volunteers, stool incontinence of any degree was reported in 43 versus 5 percent of the survivors and volunteers, respectively, while rates of rectal urgency were 64 versus 6 percent [111].

Sexual dysfunction may occur in both men and women. The majority of male survivors report inability to achieve or sustain an erection, difficulty with climaxing, lack of interest in sex, and less energy [107]. A trial of a phosphodiesterase type 5 (PDE5) inhibitor such as sildenafil is reasonable, although the data on efficacy of these drugs in men with erectile dysfunction due to pelvic chemoradiotherapy are only anecdotal.

A large proportion of women report dyspareunia (which may be related to vaginal stenosis [113]), fatigue, loss of sexual desire, and/or emotional changes that affect sexual functioning. These findings are consistent with other reports noting late effects of RT for other pelvic malignancies. For women, proactive approaches, including early and ongoing use of dilators, moisturizers, and lubricants, should be encouraged. Unless contraindicated, topical estrogen (one to three times weekly) applied in the first six months following radiation may reduce dyspareunia and improve vaginal caliber. (See "Overview of sexual dysfunction in female cancer survivors", section on 'Vaginal stenosis' and "Treatment-related toxicity from the use of radiation therapy for gynecologic malignancies", section on 'Vaginal stenosis' and "Management of intra-abdominal, pelvic, and genitourinary complications of colorectal surgery", section on 'Genitourinary complications'.)

Post-treatment surveillance and assessing the local response to primary chemoradiotherapy — SCCs regress slowly and continue to decrease in size for up to 26 weeks following therapy. We perform a clinical assessment of response by physical examination (digital rectal examination [DRE], palpation of the inguinal regions) from 8 to 12 weeks following the completion of therapy. For patients with a clinical complete response, re-evaluation at three- to six-month intervals with DRE, anoscopy, and inguinal node palpation is recommended for five years, with contrast-enhanced computed tomography (CT) of the chest, abdomen, and pelvis or contrast-enhanced magnetic resonance imaging (MRI) performed annually for three years.

Patients with clinical suspicion for persistent disease on the initial post-treatment physical examination can be watched for up to six months following completion of RT and chemotherapy as long as there is no progressive disease during this period of follow-up. Progression of disease at any time or a clinical suspicion for persisting disease six months or more after completion of chemoradiotherapy should prompt a biopsy, with salvage therapy (typically APR) offered to those with biopsy-proven disease persistence/recurrence.

There are no prospective trials to guide the post-treatment surveillance strategy for patients treated for anal cancer. In general, LRFs predominate after primary chemoradiotherapy, and early identification of those with persistent or recurrent locoregional disease who need salvage therapy (typically an abdominoperineal resection) is an important goal of the post-treatment surveillance strategy. The majority of recurrences develop within three years [114], providing justification for more intensive surveillance during this period.

The first post-treatment assessment by physical examination is typically carried out at 8 to 12 weeks after the completion of all treatments. Early assessment of response by MRI is unhelpful and not recommended [115].

Clinical suspicion of persistent disease at this early time point should not necessarily prompt a biopsy or referral for APR. SCCs regress slowly and continue to decrease in size for up to 26 weeks following therapy [33,116]. This was shown in an analysis of data from the ACT II trial, in which 940 patients were randomly assigned to FU plus either mitomycin or cisplatin during concurrent RT, and then were further randomized to receive or not receive maintenance chemotherapy [116]. (See 'Replacement of mitomycin by cisplatin' above.)

The protocol required three response assessments at 11 and 18 weeks (with DRE, with or without examination under anesthesia) and at 26 weeks (DRE, examination under anesthesia, abdomen and pelvis CT, and chest radiograph). Biopsies were not routinely performed. The cCR rate increased over time in both chemoradiotherapy groups (52, 71, and 78 percent at 11, 18, and 26 weeks, respectively). Importantly, 72 percent of those not in a cCR at 11 weeks achieved it at 26 weeks. Furthermore, the greatest separation in outcomes between complete responders and those who did not achieve a cCR occurred when the assessment took place at 26 weeks (progression-free survival 80 versus 33 percent, HR for progression 0.16, 95% CI 0.12-0.21; overall survival 87 versus 46 percent, HR for death 0.17, 95% CI 0.12-0.23). These data support the view that anal SCCs continue to regress for up to 26 weeks after the completion of chemoradiotherapy and that the decision to pursue APR for persisting disease is best deferred until at least 26 weeks.

In keeping with these data, updated NCCN guidelines recommend post-treatment re-evaluation with DRE examination at 8 to 12 weeks after chemoradiotherapy, with the response classified clinically as a complete response, persistent disease, or progressive disease [5]:

For patients with a cCR, re-evaluation every three to six months with DRE, anoscopy, and inguinal node palpation is recommended for five years. In addition, contrast-enhanced CT of the chest abdomen and pelvis or contrast-enhanced MRI is recommended annually for three years.

Patients with clinical suspicion for persistent disease can be watched for up to six months following completion of RT and chemotherapy as long as there is no progressive disease during this period of follow-up.

Patients who appear to have progressive disease require histologic confirmation.

European guidelines for management of anal canal cancer also suggest 26 weeks may be the optimal time to assess complete response to chemoradiotherapy if surgical salvage is being discussed [6].

Consensus-based guidelines from ESMO are comparable [6]:

Clinical examination including DRE and palpation of the inguinal nodes every three to six months for two years, then every 6 to 12 months until year 5.

Suspicious lesions should be assessed by MRI and/or PET, and biopsied, if possible.

Once tumor regression is confirmed at 3 and 6 months, annual CT scans for surveillance at 12, 24, and 36 months are recommended. Given the very low relapse rate (<1 percent after three year as in the ACT-II study), extended imaging surveillance after this time is not warranted.

Role of FDG/PET — There is insufficient evidence to recommend integrated fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT in the assessment of treatment response or follow-up of treated anal canal [117-119]. Its ability to impact earlier salvage compared with clinical evaluation remains inconclusive. Consistent with guidelines from the NCCN, ESMO, and the American Society of Colon and Rectal Surgeons, we do not routinely order it, unless there is an equivocal finding on cross-sectional imaging [5,6,120].

Management of recurrent or persistent disease

Risk factors — Risk factors for disease recurrence/persistence include primary tumor size >5 cm and nodal-positivity [99]. In addition, poor treatment adherence, unnecessary chemotherapy dose reductions, and treatment delays also increase the risk for locoregional failure [121].

Persistent or locally recurrent disease following chemoradiotherapy can be successfully salvaged with surgery (typically APR); however, locally recurrent anal SCC can be a difficult clinical problem that is associated with profound morbidity and long-term disease control in only approximately 25 to 40 percent of cases.

Abdominoperineal resection — APR is the treatment of choice for locally recurrent anal cancer following chemoradiotherapy; long-term disease control is achieved in 25 to 40 percent of cases [43,122-129]. Outcomes of locally recurrent anal cancer can be illustrated by a series of 185 consecutive patients with anal cancer treated with either RT alone or chemoradiotherapy, in which 42 developed local failure requiring salvage therapy [126]. Twenty-six patients (62 percent) underwent potentially curative surgery, including 23 APRs and 3 local excisions. The five-year rates of overall survival, secondary local control, and locoregional control were 45, 53, and 43 percent, respectively.

APR is also the treatment of choice for patients who have persisting disease after completion of combined modality therapy, as noted above; based on data from the ACT II trial, patients with clinical suspicion for persistent disease on the initial post-treatment physical examination at 8 to 12 weeks can be watched for up to six months following completion of RT and chemotherapy as long as there is no progressive disease during this period of follow-up. Progression of disease at any time or a clinical suspicion for persisting disease six months or more after completion of chemoradiotherapy should prompt a biopsy, with salvage therapy (typically APR) offered to those with biopsy-proven disease persistence/recurrence. (See 'Post-treatment surveillance and assessing the local response to primary chemoradiotherapy' above.)

The results of surgical salvage for persistent anal cancer are similar to those for patients with locally recurrent disease. This was shown in a series of 111 patients with anal cancer who were treated with chemoradiotherapy or RT alone, followed by APR for persistent (n = 61) or recurrent (n = 50) disease [124]. The estimated five-year survival rate disease free was 30 percent. In univariate analysis, outcomes were similar for patients with persistent versus recurrent disease. In multivariate analysis, only three factors significantly influenced prognosis: the status of the surgical margin, perineural and/or lymphatic invasion, and whether or not the nodes in the resected specimen were involved with tumor.

Sphincter-sparing salvage therapy — The relative efficacy of nonsurgical salvage in patients with persistent disease is not known. However, at least some of these patients may be successfully salvaged with further sphincter-sparing therapy. As an example, the RTOG/ECOG treated 22 patients who had persistent disease following primary chemoradiotherapy; they received FU, cisplatin, and RT (9 Gy boost) as a salvage regimen [4]. Twelve (55 percent) were rendered disease free after chemoradiotherapy; among these, four required subsequent APR and are free of disease, four died (three with recurrent disease), and four remain disease free. Of the 10 patients who had unsuccessful nonoperative salvage therapy, nine underwent APR. After four years, three were alive without disease and seven had died, six with recurrent disease. However, it is important to note that this trial mandated a post-treatment biopsy at 60 to 74 days after completing treatment, and if the biopsy was positive, the patient received further RT plus chemotherapy. Modern treatment plans emphasize the continued regression up to 26 weeks. (See 'Post-treatment surveillance and assessing the local response to primary chemoradiotherapy' above.)

In our view, the decision to pursue sphincter saving treatment for persistent/recurrent disease is a difficult one, and should entail a multidisciplinary discussion and consideration of the biopsy results and clinical course of the individual lesion.

Anal adenocarcinoma — For patients with adenocarcinoma of the anal canal, we suggest treatment according to a rectal cancer paradigm rather than initial FU and mitomycin-containing chemoradiotherapy, as is used for anal SCCs. For most patients this will include surgery (typically APR) and either preoperative or postoperative fluoropyrimidine-based chemoradiotherapy. The selection of patients for neoadjuvant chemoradiotherapy rather than initial resection followed by adjuvant therapy is discussed elsewhere. (See "Neoadjuvant therapy for rectal adenocarcinoma".)

Primary adenocarcinoma of the anal canal is rare (representing 5 to 19 percent of anal canal cancers [130-132]), and many of these tumors represent rectal cancer with downward spread. Determination of the anatomic site of origin of carcinomas that overlap the anorectal junction can be problematic. For staging purposes, such tumors are classified as rectal cancers if their epicenter is located more than 2 cm proximal to the dentate line or proximal to the anorectal ring on digital examination, and as anal canal cancers if their epicenter is 2 cm or less from the dentate line [8].

Prognosis of anal adenocarcinomas is worse than it is with either anal squamous cell cancer or distal rectal adenocarcinoma [133-136]. (See 'Prognosis' above and "Overview of the management of rectal adenocarcinoma", section on 'Prognosis'.)

There are scarce data to guide management recommendations for anal adenocarcinomas. There are no randomized trials. However, treatment using the same chemoradiotherapy regimens as are used for anal SCC has been associated with high rates of both local and distant failure [137,138], and in many (but not all [139]) retrospective series, survival rates are better in patients receiving multimodality management akin to that used for rectal cancer, that includes radical surgery, with chemotherapy and RT given as preoperative or postoperative therapy to improve local and systemic control [131,134,140-144].

The primary importance of resection in the initial management of adenocarcinomas arising in the anal canal can be illustrated by the following reports:

A National Cancer Database (NCDB) series of 1747 anal adenocarcinomas diagnosed in 2004 to 2015 included 1005 who received surgery as a component of treatment; the remainder had chemoradiotherapy alone [131]. At a median follow-up of 3.5 years, the five-year survival in those who received surgery as a component of initial therapy was 61 percent, compared with 40 percent for those receiving chemoradiotherapy alone. Predictors of receipt of surgery were age <65, having private insurance, overlapping involvement of the anus and rectum, clinical node-negative disease, and RT dose ≥40 Gy. However, the survival benefit of surgical treatment persisted when the analysis was restricted to a propensity score-matched cohort.

The importance of radical surgery rather than just local excision is illustrated by a series of 28 patients with anal adenocarcinoma who were treated with curative intent at MD Anderson Cancer Center between 1983 and 2004, including 13 who had only local excision followed by either chemoradiotherapy or RT, and 15 who had radical resection and either preoperative or postoperative chemoradiotherapy [144]. At a median follow-up of 37 months, five-year overall survival for those who had local excision was 43 percent, compared with 63 percent of those treated with radical surgery.

Given these data, the management of adenocarcinomas arising in the anal canal should follow the same principles as those applied to the treatment of rectal cancer. For most patients this will include resection and either preoperative or postoperative fluoropyrimidine-based chemoradiotherapy. This recommendation is consistent with guidelines from the NCCN [5]. There are no European guidelines that are specific to management of anal adenocarcinoma [6]. Others prefer an approach that includes preoperative chemoradiotherapy plus 12 to 16 weeks of oxaliplatin-based chemotherapy prior to surgery, which is termed "total neoadjuvant therapy" [145]. The principles of preoperative staging and management of rectal adenocarcinoma, including a discussion of the merits of total neoadjuvant therapy are discussed in detail elsewhere. (See "Overview of the management of rectal adenocarcinoma" and "Pretreatment local staging evaluation for rectal cancer" and "Neoadjuvant therapy for rectal adenocarcinoma" and "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Total neoadjuvant therapy for locally advanced tumors' and "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy" and "Radical resection of rectal cancer".)

True perianal skin cancers — For the rare patient with a T1N0 well-differentiated cancer of the perianal skin that forms a discrete skin lesion that is clearly separate from the anal canal, wide local excision alone is adequate if negative margins can be achieved without compromise of the sphincter muscles. For patients with high-risk histologic features (eg, poorly differentiated histology, perineural invasion), postoperative RT is an option. For T2 or higher disease, if sphincter function could be compromised by surgery, if there is evidence of nodal involvement, or if it is not clear where the tumor originated, we suggest chemoradiotherapy, with surgery reserved for persistent or recurrent disease.

SCC of the perianal skin is relatively rare, occurring three to five times less frequently than anal canal SCC. These tumors differ in natural history from cancers of the anal canal and usually have a more favorable outcome. The main prognostic factors are histologic differentiation, T stage, and lymph node involvement at diagnosis [146,147]. (See "Clinical features and staging of anal cancer", section on 'Staging'.)

There is a lack of prospective data regarding optimal treatment of true perianal skin cancers. For a localized lesion, surgery is often performed as long as sphincteric muscles are not compromised. The role of sentinel lymph node biopsy in this setting is unclear [148,149]. After excision of a perianal skin cancer with high-risk histologic features (eg, poorly differentiated histology, perineural invasion), postoperative RT is often pursued, but there are no trials proving benefit.

If sphincter function could be compromised by surgery, if there is evidence of nodal involvement, or for more extensive primary lesions, chemoradiation is a more effective alternative [147,150,151].

Rectal squamous cell cancers — For patients with primary rectal squamous cell cancer, we suggest chemoradiotherapy using FU and mitomycin as is used for SCC of the anal canal rather than treatment according to a rectal cancer paradigm.

Primary rectal SCC, which are very rare (0.3 percent of all rectal cancers [152]), can be difficult to distinguish from anal cancers, and they should be staged [153] according to the same approach as anal SCC. The majority represent anal SCCs with extension into the rectum, although primary SCCs of rectal origin are described [154].

The optimal treatment for rectal SCC is not well established due to its rarity. Historically, these patients were treated like rectal adenocarcinoma, and the main treatment was surgical resection. However, more recently, several retrospective single institutional cases series demonstrate that good results can be obtained using definitive chemoradiotherapy is used for anal canal SCC [153,155-163]. In the largest single institution series of 23 patients, five-year overall survival was 86 percent, local control was achieved in 83 percent, and the five-year colostomy-free survival rate was 65 percent [162].

The optimal chemotherapy regimen to be used during concurrent chemoradiotherapy is not established. Most series have utilized a combination of a fluoropyrimidine with either mitomycin or cisplatin. We prefer fluoropyrimidine plus mitomycin in this setting.

TREATMENT OF METASTATIC ANAL SQUAMOUS CELL CANCER — Systemic therapy is the usual approach for treatment of metastatic anal squamous cell cancer (SCC). There may be a small subset of patients with isolated hepatic metastases who stand to benefit from resection, but selection criteria are undefined.

The liver is the most frequent site of distant metastases [11,18,164]. However, the development of distant metastases has been infrequent overall in patients with SCC of the anal canal [20,22,29]:

In the United Kingdom Coordination Committee on Cancer Research (UKCCCR) and the European Organisation for the Research and Treatment of Cancer (EORTC) trials described above, for example, distant metastases developed following combined modality therapy in 10 and 17 percent, respectively [20,22]. (See 'Chemoradiotherapy versus radiation therapy alone' above.)

In the ACT II trial, only 22 percent of the 209 patients who relapsed had distant metastases [29]. (See 'Replacement of mitomycin by cisplatin' above.)

This may be changing. Epidemiologic data suggest that at least in the United States, the incidence of distant-stage SCC tripled between 2001 and 2015, with an average annual percentage change of 8.6 percent in men and 7.5 percent in women [165]. (See "Classification and epidemiology of anal cancer", section on 'Epidemiology and risk factors'.)

Systemic chemotherapy — For most patients with metastatic anal canal SCC, we recommend paclitaxel plus carboplatin, rather than cisplatin plus fluorouracil (FU), as our preferred regimen for first-line therapy. This recommendation is consistent with updated guidelines from ESMO [6] and NCCN [5].

Paclitaxel plus carboplatin — Paclitaxel plus carboplatin is an effective chemotherapy regimen for anal SCC [166-168]. In the InterAACT trial, 91 patients with previously untreated advanced anal SCC were randomly assigned to carboplatin (area under the curve of concentration x time [AUC] 5 on day 1 every 28 days) plus weekly paclitaxel (80 mg/m2 on days 1, 8, and 15 every 28 days) or to cisplatin (60 mg/m2 on day 1 every 21 days) plus infusional FU (1000 mg/m2 per 24 hours on days 1 through 4 every 21 days) [168]. The primary outcome was response rate. Carboplatin plus weekly paclitaxel had similar response rates to cisplatin plus FU (59 versus 57 percent), but it had better median overall survival (20 versus 12.3 months) and a more favorable toxicity profile (serious adverse events in 36 versus 62 percent).

Whether treatment-related toxicity is better using weekly paclitaxel in this regimen as compared with other regimens in which both carboplatin and paclitaxel are administered on day 1 every three weeks (table 4) is not established. In our view, either regimen is acceptable. (See "Treatment protocols for anal cancer".)

Cisplatin/fluorouracil — The most widely published active regimen for the treatment of metastatic disease is cisplatin plus FU (table 5) [166,169-175]. However, while response rates of up to 60 to 65 percent are reported [169,175], they are seldom sustained. The best outcomes appear to be in patients who undergo multidisciplinary management for their metastatic disease; in one report, median survival for patients who underwent multidisciplinary management was 53 months compared with 17 months for those undergoing palliative systemic chemotherapy alone [166].

Docetaxel, cisplatin, and fluorouracil — Combinations of docetaxel, cisplatin, and FU (DCF) are also active but can be toxic [176,177]. In the largest phase II study, 66 patients received DCF in one of two combinations (standard and modified) depending on age and performance status [177]:

For patients younger than 75 with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, six cycles of a standard DCF regimen (table 6)were recommended, although not mandatory.

Older patients and those with an ECOG performance status of 1 were offered eight cycles of a modified DCF regimen (table 7).

All patients received granulocyte colony-stimulating factor (G-CSF) support for primary prophylaxis of febrile neutropenia.

Of the 66 patients who received treatment, 36 received standard DCF, and 30 received modified DCF. The primary endpoint, progression-free survival at 12 months, was achieved by 47 percent of the entire cohort, and a similar percentage of patients with standard and modified DCF had disease progression at 12 months (61 versus 60 percent, respectively); the objective response rates (89 versus 83 percent), complete response rates (42 versus 47 percent), and median progression-free survival durations (11 months each) were also similar. Not surprisingly, toxicity was worse with standard DCF, including anemia, diarrhea, fatigue, nausea, and febrile neutropenia. Notably, only 2 of the 66 patients enrolled in this trial were HIV positive, and 62 percent had only locoregional and not metastatic disease.

In our view, modified DCF (table 7) is an option for patients with advanced disease, but more data are needed before it can be concluded that this is the appropriate first-step regimen for all individuals with metastatic disease.

Other combinations — The role of other combinations, such as mitomycin/doxorubicin/cisplatin or a taxane/carboplatin/FU, is uncertain, particularly for second-line therapy; few data are available, but objective responses are reported [174,176,178,179]. Single case reports and small series describe activity for single-agent carboplatin [180], doxorubicin [181], irinotecan [182], and paclitaxel [174,183], as well as for some combinations, including paclitaxel plus ifosfamide and cisplatin, paclitaxel plus carboplatin and FU, and cetuximab with or without irinotecan (in patients whose tumors do not carry RAS mutations) [167,184-188]. (See "Systemic therapy for metastatic colorectal cancer: General principles", section on 'RAS'.)

Eligible patients should be encouraged to enroll in clinical trials testing new strategies.

Immunotherapy — Immunotherapy monotherapy using agents that target the programmed cell death receptor 1 (PD-1) pathway is an option for patients who have progressed on first-line chemotherapy for metastatic SCC of the anus. The optimal selection of patients who are most likely to benefit from immunotherapy is not established. In our view, overexpression of programmed cell death ligand-1 (PD-L1) should not be used to select patients with advanced anal SCC for treatments targeting the PD-1 pathway. Combinations of immunotherapy plus cytotoxic chemotherapy are beginning to be studied for first-line therapy; however, until further information is available, this cannot yet be considered a standard approach outside of the context of a clinical trial.

Immunotherapy differs from traditional chemotherapy, which primarily targets rapidly dividing cells, and from targeted therapies, which interfere with key molecular events in tumor cells that drive tumor growth and invasion. Immunotherapeutic approaches to cancer treatment are based on the premise that the immune system plays a key role in the surveillance and eradication of malignancy, and that tumors evolve ways to elude the immune system. The general principles and rationale of immunotherapy are discussed separately. (See "Principles of cancer immunotherapy".)

Several immune checkpoints exist to dampen the immune response in order to protect against detrimental inflammation and autoimmunity. In the setting of malignancy, these immune checkpoints can be co-opted by tumors, resulting in immune tolerance and subsequent progression of malignancy. One well-characterized checkpoint being targeted in melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer is PD-1, which is expressed on activated T-cells. PD-1 binds to its ligands PD1-L1 and PD1-L2, which are expressed on tumor cells, thereby preventing the immune system from rejecting the tumor. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Initial management of advanced non-small cell lung cancer lacking a driver mutation" and "Systemic therapy of advanced clear cell renal carcinoma".)

Promising results with two immune checkpoint inhibitors that inhibit the PD-1 pathway, nivolumab and pembrolizumab, have been reported in advanced anal SCC:

Nivolumab is a monoclonal antibody that targets PD-1. In a small, prospective, phase II trial conducted in patients with chemorefractory metastatic anal canal SCC, nivolumab was administered at a dose of 3 mg/kg intravenous (IV) every two weeks; programmed cell death ligand 1 (PD-L1) expression was not required [189]. Of the 39 enrolled patients, 37 were evaluable for toxicity and intent to treat (ITT) analysis. The median number of cycles delivered was six (interquartile range 3 to 10). There were nine objective responses (24 percent), two complete responses, and an additional 17 (46 percent) had stable disease as best response. Median progression-free survival was 4.1 months, and median overall survival was 11.5 months. Although the data were very limited (n = 13 patients), overexpression of PD-1 and PD-L1 seemed to correlate with responses. The side effect profile was as expected and consisted of one grade 2 pneumonitis, grade 3 anemia in 5 percent, and grade 3 fatigue, rash, and hypothyroidism in 3 percent each. (See "Toxicities associated with immune checkpoint inhibitors".)

Dosing is variable. Some clinicians still use 3 mg/kg every two weeks, but others have transitioned to flat dosing of 240 mg once every two weeks or 480 mg every four weeks, which are both approved schedules.

The KEYNOTE-028 trial of pembrolizumab, another anti-PD-1 monoclonal antibody, included 25 patients with PD-L1-positive anal cancer [190]. Pembrolizumab was administered IV at a dose of 10 mg/kg every two weeks for up to two years. Among the 24 with SCC histology, there were four confirmed partial responses (overall response rate 17 percent), and an additional 10 had stable disease as the best response (42 percent). The most common treatment-related adverse events were diarrhea, fatigue, and nausea.

Additional information on the efficacy of pembrolizumab is available from the phase II KEYNOTE-158 trial, which administered pembrolizumab (200 mg IV every three weeks) to a cohort of 112 patients with metastatic or unresectable anal SCC that had progressed following frontline therapy [191]. Treatment continued for two years, or until disease progression, unacceptable toxicity, or withdrawal of consent. Study enrollment was not limited by the level of tumoral PD-L1 expression, although 67 percent of the patients had a PD-L1-positive tumor. At a median time from first dose to data cutoff of 34.7 months, there were 12 objective responses (11 percent) and 6 were complete. When analyzed according to PD-L1 expression, responses were more frequent in those with a combined positive score of 1 or higher (15 versus 3 percent). Median duration of response was not reached at the time of data cutoff (range 6.0+ to 33.9+ months) but by Kaplan-Meier estimation, 90 percent of the responders had response duration ≥24 months. Although median progression-free survival was only 2.1 months, median overall survival in the entire cohort was 11.9 months. Toxicity was manageable; although approximately 61 percent had a treatment-related adverse event, and 22 percent of patients experienced at least one immune-mediated adverse effect, only five discontinued the drug for side effects.

If pembrolizumab is chosen, an alternative dosing schedule of 400 mg every six weeks, as is used in other settings, is acceptable.

Is there benefit in patients living with HIV? — Preclinical data suggest that the local tumor immune microenvironment is not different in people living with HIV (PLWH) as compared with HIV negative individuals with anal SCC, supporting clinical use of immunotherapy irrespective of HIV status [192].

We prefer that eligible patients be encouraged to enroll in available clinical trials. As examples:

A trial of nivolumab in combination with ipilimumab, a monoclonal antibody that targets a different immune checkpoint, the cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), is underway in PLWH who have solid tumors.

In addition, a trial of pembrolizumab to treat HIV positive patients with a range of solid and hematologic malignancies (including anal cancer) is also accruing patients.

Combined approaches — Combinations of immunotherapy plus cytotoxic chemotherapy are beginning to be studied for first-line therapy; however, until further information is available, this cannot yet be considered a standard approach outside of the context of a clinical trial.

Modified DCF (mDCF, (table 7)) is an effective and reasonably well tolerated regimen for advanced anal SCC, and at least some data suggest that it might stimulate antigen-specific T-cell responses [177], providing the rationale for studying the combination of mDCF with immune checkpoint inhibitor immunotherapy. (See 'Docetaxel, cisplatin, and fluorouracil' above.)

Unfortunately, benefit for combined therapy could not be shown in the randomized phase II SCARCE-PRODIGE 60 trial, in which 97 patients with previously untreated locally advanced or metastatic anal SCC were randomly assigned to mDCF alone or combined with the anti-PD-L1 monoclonal antibody atezolizumab [193]. In a preliminary report presented at the 2022 annual American Society of Clinical Oncology meeting, at a median follow-up of 22 months, the addition of atezolizumab did not improve the objective response rate (75 versus 78 percent), 12-month progression-free survival rate (44 versus 43 percent), or 12 month overall survival (78 versus 81 percent), and it was more toxic.

Role of regional therapy for liver metastases — The role of regional therapy for patients with limited, isolated hepatic metastases is incompletely defined and must be addressed on a case-by-case basis.

Given that the liver is the most common site of metastatic disease, regional therapy is an option for patients with limited, isolated hepatic metastases. However, there is far less experience with resection or nonsurgical local ablative procedures for anal SCC than there is with isolated liver colorectal adenocarcinoma or neuroendocrine cancer liver metastases, and selection criteria are undefined. (See "Potentially resectable colorectal cancer liver metastases: Integration of surgery and chemotherapy" and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring".)

Scant published data [194-196] suggest that there may be a small subset of patients with isolated hepatic metastases who stand to benefit from resection or other regional treatments. In the largest experience, the role of regional therapy was addressed in a multicenter analysis of 52 patients who underwent hepatic resection (n = 47), radiofrequency ablation (n = 3), or both (n = 2) for metastatic SCC at eight major cancer centers; 27 for metastatic anal cancer [194]. The majority had received some form of systemic therapy prior to resection. At a median follow-up of 18 months, 33 patients had recurred, 21 in the liver. The actuarial disease-free survival rates at three and five years were each 19 percent. When the analysis was restricted to the 27 patients with metastatic anal cancer, the median disease-free and overall survival durations were 9.6 and 22.3 months. In multivariate analysis, hepatic metastasis size >5 cm and positive surgical resections margins were both associated with a twofold higher risk of recurrence.

DRUG SHORTAGES — There may be any number of cancer therapies in short supply at various times. Guidance in the setting of drug shortages has been provided by the American Society of Clinical Oncology (table 8).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anal cancer".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Anal cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

Anatomy and tumor types – Four categories of tumors arise in the anal region: anal canal squamous cell cancers (SCCs), anal canal adenocarcinomas, perianal skin cancers, and SCCs with an epicenter in the distal rectum. An algorithmic approach to selecting initial treatment for localized disease based on tumor location and histology is provided (algorithm 1). (See 'Anatomy and types of tumors' above.)

Anal canal SCC

Localized disease

-We suggest initial concurrent chemoradiotherapy (CRT) rather than surgery for most patients even T1-2N0M0 tumors (table 2) (Grade 2B). (See 'Initial chemoradiotherapy' above.)

Local excision may be an option for carefully selected patients with <1 cm, superficially invasive tumors that are completely excised and have ≤3 mm of basement membrane invasion and a horizontal spread of ≤7 mm. (See 'Local excision for small T1 tumors' above.)

-During RT, for most patients, we suggest concurrent use of standard dose fluorouracil (FU) plus mitomycin (table 3) rather than FU alone or FU plus cisplatin (Grade 2B). The substitution of capecitabine for FU is acceptable (table 9). Treatment interruptions should be minimized during CRT, and overall treatment time and total dose maintained as much as possible. (See 'Role of mitomycin' above and 'Replacement of mitomycin by cisplatin' above and 'Capecitabine as an alternative to infusional fluorouracil' above.)

For the extremely aged population with T1N0 (table 2) tumors, or those with significant comorbidities, reduction of mitomycin and FU doses during CRT may be considered, although this is not a standard approach. (See 'Elderly or extensive comorbidity' above.)

-We treat anal SCC in people living with HIV similarly to those without HIV. However, patients with active or a prior history of HIV/AIDS-related complications may not tolerate full-dose therapy or require chemotherapy dose adjustment. (See 'Patients living with HIV' above.)

-We assess treatment response clinically 8 to 12 weeks after completion of CRT. For patients with a clinical complete response, re-evaluation at three- to six-month intervals with digital rectal examination, anoscopy, and inguinal node palpation is recommended, with annual contrast-enhanced CT of the chest, abdomen, and pelvis or MRI for at least three years. Patients with clinical suspicion for persistent disease at 8 to 12 weeks can be watched for up to six months following completion of CRT. Biopsy is indicated for overt disease progression or a clinical suspicion for persisting disease ≥6 months after completion of CRT. (See 'Post-treatment surveillance and assessing the local response to primary chemoradiotherapy' above.)

Persistent or locally recurrent disease – Persistent or locally recurrent anal SCC following CRT can be successfully salvaged with surgery (typically APR), with long-term control in approximately 25 to 40 percent. (See 'Management of recurrent or persistent disease' above.)

Metastatic disease

-Systemic therapy is the usual approach for metastatic anal SCC.

For most patients, we recommend paclitaxel plus carboplatin (table 4) rather than cisplatin plus FU, because of better survival and tolerability (Grade 1B). (See 'Paclitaxel plus carboplatin' above and "Treatment protocols for anal cancer".)

Immunotherapy using agents that target the programmed cell death receptor 1 (PD-1) pathway is an option for patients who have progressed on first-line therapy. (See 'Immunotherapy' above.)

Combinations of immunotherapy plus cytotoxic chemotherapy are beginning to be studied for first-line therapy; however, until further information is available, this cannot yet be considered a standard approach outside of the context of a clinical trial. (See 'Combined approaches' above.)

-The role of regional therapy for patients with limited, isolated hepatic metastases is incompletely defined and must be addressed on a case-by-case basis. (See 'Role of regional therapy for liver metastases' above.)

Anal adenocarcinoma – For patients with adenocarcinoma of the anal canal, we suggest treatment according to a rectal cancer paradigm rather than initial FU and mitomycin-containing CRT, as is used for anal SCCs (Grade 2C). For most patients this will include surgery (typically APR) plus fluoropyrimidine-based CRT. (See 'Anal adenocarcinoma' above.)

Perianal skin cancer – For patients with T1N0 well-differentiated cancers of the perianal skin forming a discrete skin lesion that is clearly separate from the anal canal, we suggest wide local excision alone if negative margins can be achieved without compromising the sphincter muscles (Grade 2C). If the tumor is ≥T2 or node-positive (table 2), if sphincter function is at risk with surgery, or if it is not clear whether the tumor arose in the perianal skin or anal canal, we suggest CRT rather than initial surgery (Grade 2C). (See 'True perianal skin cancers' above.)

Rectal SCC – Primary rectal SCCs, which are very rare, can be difficult to distinguish from anal cancers, and they should be treated according to the same approach as anal SCC. (See 'Rectal squamous cell cancers' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David P Ryan, MD, who contributed to earlier versions of this topic review.

  1. Welton ML, Steele SR, Goodman KA, et al. Anus. In: AJCC Cancer Staging Manual, 8th ed, Amin MB (Ed), AJCC, Chicago 2017. p.275.
  2. Lam AK, Goldblum JR. Tumours of the anal canal: Introduction. In: WHO Classification of Tumours: Digestive System Tumours, 5th ed, WHO Classification of Tumours Editorial Board (Ed), International Agency for Research on Cancer, Lyon 2019.
  3. Nigro ND, Vaitkevicius VK, Considine B Jr. Combined therapy for cancer of the anal canal: a preliminary report. Dis Colon Rectum 1974; 17:354.
  4. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol 1996; 14:2527.
  5. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Available at: https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf (Accessed on July 25, 2023).
  6. Rao S, Guren MG, Khan K, et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up☆. Ann Oncol 2021; 32:1087.
  7. Schraut WH, Wang CH, Dawson PJ, Block GE. Depth of invasion, location, and size of cancer of the anus dictate operative treatment. Cancer 1983; 51:1291.
  8. American Joint Committee on Cancer Staging Manual, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.165.
  9. Boman BM, Moertel CG, O'Connell MJ, et al. Carcinoma of the anal canal. A clinical and pathologic study of 188 cases. Cancer 1984; 54:114.
  10. American Joint Committee on Cancer Staging Manual, 7th ed, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.301.
  11. Greenall MJ, Quan SH, Stearns MW, et al. Epidermoid cancer of the anal margin. Pathologic features, treatment, and clinical results. Am J Surg 1985; 149:95.
  12. Cotter SE, Grigsby PW, Siegel BA, et al. FDG-PET/CT in the evaluation of anal carcinoma. Int J Radiat Oncol Biol Phys 2006; 65:720.
  13. Leichman L, Nigro N, Vaitkevicius VK, et al. Cancer of the anal canal. Model for preoperative adjuvant combined modality therapy. Am J Med 1985; 78:211.
  14. Doci R, Zucali R, La Monica G, et al. Primary chemoradiation therapy with fluorouracil and cisplatin for cancer of the anus: results in 35 consecutive patients. J Clin Oncol 1996; 14:3121.
  15. Peiffert D, Seitz JF, Rougier P, et al. Preliminary results of a phase II study of high-dose radiation therapy and neoadjuvant plus concomitant 5-fluorouracil with CDDP chemotherapy for patients with anal canal cancer: a French cooperative study. Ann Oncol 1997; 8:575.
  16. Gerard JP, Ayzac L, Hun D, et al. Treatment of anal canal carcinoma with high dose radiation therapy and concomitant fluorouracil-cisplatinum. Long-term results in 95 patients. Radiother Oncol 1998; 46:249.
  17. Sischy B, Doggett RL, Krall JM, et al. Definitive irradiation and chemotherapy for radiosensitization in management of anal carcinoma: interim report on Radiation Therapy Oncology Group study no. 8314. J Natl Cancer Inst 1989; 81:850.
  18. Allal A, Kurtz JM, Pipard G, et al. Chemoradiotherapy versus radiotherapy alone for anal cancer: a retrospective comparison. Int J Radiat Oncol Biol Phys 1993; 27:59.
  19. Martenson JA, Lipsitz SR, Lefkopoulou M, et al. Results of combined modality therapy for patients with anal cancer (E7283). An Eastern Cooperative Oncology Group study. Cancer 1995; 76:1731.
  20. Epidermoid anal cancer: results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. UKCCCR Anal Cancer Trial Working Party. UK Co-ordinating Committee on Cancer Research. Lancet 1996; 348:1049.
  21. Northover J, Glynne-Jones R, Sebag-Montefiore D, et al. Chemoradiation for the treatment of epidermoid anal cancer: 13-year follow-up of the first randomised UKCCCR Anal Cancer Trial (ACT I). Br J Cancer 2010; 102:1123.
  22. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol 1997; 15:2040.
  23. Kantarjian HM, Keating MJ, Walters RS, et al. Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic, and prognostic features. J Clin Oncol 1986; 4:1748.
  24. Pedersen-Bjergaard J, Philip P, Larsen SO, et al. Therapy-related myelodysplasia and acute myeloid leukemia. Cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series. Leukemia 1993; 7:1975.
  25. Hung A, Crane C, Delclos M, et al. Cisplatin-based combined modality therapy for anal carcinoma: a wider therapeutic index. Cancer 2003; 97:1195.
  26. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA 2008; 299:1914.
  27. James R, Wan S, Glynne-Jones R, et al. A randomized trial of chemoradiation using mitomycin or cisplatin, with or without maintenance cisplatin/5FU in squamous cell carcinoma of the anus (ACT II). J Clin Oncol 2009; 27S:ASCO #LBA4009.
  28. 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; 30:4344.
  29. James RD, Glynne-Jones R, Meadows HM, et al. Mitomycin or cisplatin chemoradiation with or without maintenance chemotherapy for treatment of squamous-cell carcinoma of the anus (ACT II): a randomised, phase 3, open-label, 2 × 2 factorial trial. Lancet Oncol 2013; 14:516.
  30. Glynne-Jones R, Meadows H, Wan S, et al. EXTRA--a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. Int J Radiat Oncol Biol Phys 2008; 72:119.
  31. Meulendijks D, Dewit L, Tomasoa NB, et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: an alternative treatment option. Br J Cancer 2014; 111:1726.
  32. Goodman KA, Julie D, Cercek A, et al. Capecitabine With Mitomycin Reduces Acute Hematologic Toxicity and Treatment Delays in Patients Undergoing Definitive Chemoradiation Using Intensity Modulated Radiation Therapy for Anal Cancer. Int J Radiat Oncol Biol Phys 2017; 98:1087.
  33. Cummings BJ, Keane TJ, O'Sullivan B, et al. Epidermoid anal cancer: treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. Int J Radiat Oncol Biol Phys 1991; 21:1115.
  34. Myerson RJ, Kong F, Birnbaum EH, et al. Radiation therapy for epidermoid carcinoma of the anal canal, clinical and treatment factors associated with outcome. Radiother Oncol 2001; 61:15.
  35. Ortholan C, Resbeut M, Hannoun-Levi JM, et al. Anal canal cancer: management of inguinal nodes and benefit of prophylactic inguinal irradiation (CORS-03 Study). Int J Radiat Oncol Biol Phys 2012; 82:1988.
  36. Touboul E, Schlienger M, Buffat L, et al. Epidermoid carcinoma of the anal canal. Results of curative-intent radiation therapy in a series of 270 patients. Cancer 1994; 73:1569.
  37. Matthews JH, Burmeister BH, Borg M, et al. T1-2 anal carcinoma requires elective inguinal radiation treatment--the results of Trans Tasman Radiation Oncology Group study TROG 99.02. Radiother Oncol 2011; 98:93.
  38. Leon O, Guren M, Hagberg O, et al. Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines. Radiother Oncol 2014; 113:352.
  39. Hu K, Minsky BD, Cohen AM, et al. 30 Gy may be an adequate dose in patients with anal cancer treated with excisional biopsy followed by combined-modality therapy. J Surg Oncol 1999; 70:71.
  40. Hatfield P, Cooper R, Sebag-Montefiore D. Involved-field, low-dose chemoradiotherapy for early-stage anal carcinoma. Int J Radiat Oncol Biol Phys 2008; 70:419.
  41. Hughes LL, Rich TA, Delclos L, et al. Radiotherapy for anal cancer: experience from 1979-1987. Int J Radiat Oncol Biol Phys 1989; 17:1153.
  42. Constantinou EC, Daly W, Fung CY, et al. Time-dose considerations in the treatment of anal cancer. Int J Radiat Oncol Biol Phys 1997; 39:651.
  43. Renehan AG, Saunders MP, Schofield PF, O'Dwyer ST. Patterns of local disease failure and outcome after salvage surgery in patients with anal cancer. Br J Surg 2005; 92:605.
  44. Glynne-Jones R, Nilsson PJ, Aschele C, et al. Anal cancer: ESMO-ESSO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25 Suppl 3:iii10.
  45. John M, Pajak T, Flam M, et al. Dose escalation in chemoradiation for anal cancer: preliminary results of RTOG 92-08. Cancer J Sci Am 1996; 2:205.
  46. Martenson JA, Lipsitz SR, Wagner H Jr, et al. Initial results of a phase II trial of high dose radiation therapy, 5-fluorouracil, and cisplatin for patients with anal cancer (E4292): an Eastern Cooperative Oncology Group study. Int J Radiat Oncol Biol Phys 1996; 35:745.
  47. Glynne-Jones R, Tan D, Hughes R, Hoskin P. Squamous-cell carcinoma of the anus: progress in radiotherapy treatment. Nat Rev Clin Oncol 2016; 13:447.
  48. Eng C, Ciombor KK, Cho M, et al. Anal Cancer: Emerging Standards in a Rare Disease. J Clin Oncol 2022; 40:2774.
  49. Salama JK, Mell LK, Schomas DA, et al. Concurrent chemotherapy and intensity-modulated radiation therapy for anal canal cancer patients: a multicenter experience. J Clin Oncol 2007; 25:4581.
  50. Pepek JM, Willett CG, Wu QJ, et al. Intensity-modulated radiation therapy for anal malignancies: a preliminary toxicity and disease outcomes analysis. Int J Radiat Oncol Biol Phys 2010; 78:1413.
  51. Bazan JG, Hara W, Hsu A, et al. Intensity-modulated radiation therapy versus conventional radiation therapy for squamous cell carcinoma of the anal canal. Cancer 2011; 117:3342.
  52. Kachnic LA, Tsai HK, Coen JJ, et al. Dose-painted intensity-modulated radiation therapy for anal cancer: a multi-institutional report of acute toxicity and response to therapy. Int J Radiat Oncol Biol Phys 2012; 82:153.
  53. Han K, Cummings BJ, Lindsay P, et al. Prospective evaluation of acute toxicity and quality of life after IMRT and concurrent chemotherapy for anal canal and perianal cancer. Int J Radiat Oncol Biol Phys 2014; 90:587.
  54. Elson JK, Kachnic LA, Kharofa JR. Intensity-modulated radiotherapy improves survival and reduces treatment time in squamous cell carcinoma of the anus: A National Cancer Data Base study. Cancer 2018; 124:4383.
  55. de Meric de Bellefon M, Lemanski C, Castan F, et al. Long-term follow-up experience in anal canal cancer treated with Intensity-Modulated Radiation Therapy: Clinical outcomes, patterns of relapse and predictors of failure. Radiother Oncol 2020; 144:141.
  56. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013; 86:27.
  57. Allal AS, Mermillod B, Roth AD, et al. Impact of clinical and therapeutic factors on major late complications after radiotherapy with or without concomitant chemotherapy for anal carcinoma. Int J Radiat Oncol Biol Phys 1997; 39:1099.
  58. Wagner JP, Mahe MA, Romestaing P, et al. Radiation therapy in the conservative treatment of carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 1994; 29:17.
  59. Papillon J, Montbarbon JF. Epidermoid carcinoma of the anal canal. A series of 276 cases. Dis Colon Rectum 1987; 30:324.
  60. Sandhu AP, Symonds RP, Robertson AG, et al. Interstitial iridium-192 implantation combined with external radiotherapy in anal cancer: ten years experience. Int J Radiat Oncol Biol Phys 1998; 40:575.
  61. Roed H, Engelholm SA, Svendsen LB, et al. Pulsed dose rate (PDR) brachytherapy of anal carcinoma. Radiother Oncol 1996; 41:131.
  62. Löhnert M, Doniec JM, Kovács G, et al. New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy. Dis Colon Rectum 1998; 41:169.
  63. Oehler-Jänne C, Huguet F, Provencher S, et al. HIV-specific differences in outcome of squamous cell carcinoma of the anal canal: a multicentric cohort study of HIV-positive patients receiving highly active antiretroviral therapy. J Clin Oncol 2008; 26:2550.
  64. Edelman S, Johnstone PA. Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2006; 66:206.
  65. Chiao EY, Giordano TP, Richardson P, El-Serag HB. Human immunodeficiency virus-associated squamous cell cancer of the anus: epidemiology and outcomes in the highly active antiretroviral therapy era. J Clin Oncol 2008; 26:474.
  66. Seo Y, Kinsella MT, Reynolds HL, et al. Outcomes of chemoradiotherapy with 5-Fluorouracil and mitomycin C for anal cancer in immunocompetent versus immunodeficient patients. Int J Radiat Oncol Biol Phys 2009; 75:143.
  67. Fraunholz I, Rabeneck D, Gerstein J, et al. Concurrent chemoradiotherapy with 5-fluorouracil and mitomycin C for anal carcinoma: are there differences between HIV-positive and HIV-negative patients in the era of highly active antiretroviral therapy? Radiother Oncol 2011; 98:99.
  68. Wexler A, Berson AM, Goldstone SE, et al. Invasive anal squamous-cell carcinoma in the HIV-positive patient: outcome in the era of highly active antiretroviral therapy. Dis Colon Rectum 2008; 51:73.
  69. Martin D, Balermpas P, Fokas E, et al. Are there HIV-specific Differences for Anal Cancer Patients Treated with Standard Chemoradiotherapy in the Era of Combined Antiretroviral Therapy? Clin Oncol (R Coll Radiol) 2017; 29:248.
  70. White EC, Khodayari B, Erickson KT, et al. Comparison of Toxicity and Treatment Outcomes in HIV-positive Versus HIV-negative Patients With Squamous Cell Carcinoma of the Anal Canal. Am J Clin Oncol 2017; 40:386.
  71. Bryant AK, Huynh-Le MP, Simpson DR, et al. Association of HIV Status With Outcomes of Anal Squamous Cell Carcinoma in the Era of Highly Active Antiretroviral Therapy. JAMA Oncol 2018; 4:120.
  72. Hoffman R, Welton ML, Klencke B, et al. The significance of pretreatment CD4 count on the outcome and treatment tolerance of HIV-positive patients with anal cancer. Int J Radiat Oncol Biol Phys 1999; 44:127.
  73. Place RJ, Gregorcyk SG, Huber PJ, Simmang CL. Outcome analysis of HIV-positive patients with anal squamous cell carcinoma. Dis Colon Rectum 2001; 44:506.
  74. Stadler RF, Gregorcyk SG, Euhus DM, et al. Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy. Dis Colon Rectum 2004; 47:1305.
  75. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 2.2023. Available at: https://www.nccn.org/professionals/physician_gls/ https://www.nccn.org/professionals/physician_gls/ (Accessed on November 29, 2023).
  76. Sparano JA, Lee JY, Palefsky J, et al. Cetuximab Plus Chemoradiotherapy for HIV-Associated Anal Carcinoma: A Phase II AIDS Malignancy Consortium Trial. J Clin Oncol 2017; 35:727.
  77. Das P, Bhatia S, Eng C, et al. Predictors and patterns of recurrence after definitive chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys 2007; 68:794.
  78. Meropol NJ, Niedzwiecki D, Shank B, et al. Induction therapy for poor-prognosis anal canal carcinoma: a phase II study of the cancer and Leukemia Group B (CALGB 9281). J Clin Oncol 2008; 26:3229.
  79. Nilsson PJ, Svensson C, Goldman S, et al. Epidermoid anal cancer: a review of a population-based series of 308 consecutive patients treated according to prospective protocols. Int J Radiat Oncol Biol Phys 2005; 61:92.
  80. Peiffert D, Tournier-Rangeard L, Gérard JP, et al. Induction chemotherapy and dose intensification of the radiation boost in locally advanced anal canal carcinoma: final analysis of the randomized UNICANCER ACCORD 03 trial. J Clin Oncol 2012; 30:1941.
  81. Hodges JC, Das P, Eng C, et al. Intensity-modulated radiation therapy for the treatment of squamous cell anal cancer with para-aortic nodal involvement. Int J Radiat Oncol Biol Phys 2009; 75:791.
  82. Holliday EB, Lester SC, Harmsen WS, et al. Extended-Field Chemoradiation Therapy for Definitive Treatment of Anal Canal Squamous Cell Carcinoma Involving the Para-Aortic Lymph Nodes. Int J Radiat Oncol Biol Phys 2018; 102:102.
  83. Deniaud-Alexandre E, Touboul E, Tiret E, et al. Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal. Int J Radiat Oncol Biol Phys 2003; 56:1259.
  84. Newman G, Calverley DC, Acker BD, et al. The management of carcinoma of the anal canal by external beam radiotherapy, experience in Vancouver 1971-1988. Radiother Oncol 1992; 25:196.
  85. Martenson JA Jr, Gunderson LL. External radiation therapy without chemotherapy in the management of anal cancer. Cancer 1993; 71:1736.
  86. Zilli T, Schick U, Ozsahin M, et al. Node-negative T1-T2 anal cancer: radiotherapy alone or concomitant chemoradiotherapy? Radiother Oncol 2012; 102:62.
  87. Huffman D, Jayakrishnan TT, Wegner RE, et al. Chemotherapy use in early-stage anal canal squamous cell carcinoma and its impact on outcome. J Clin Oncol 2021; 39S:ASCO #2.
  88. Allal AS, Obradovic M, Laurencet F, et al. Treatment of anal carcinoma in the elderly: feasibility and outcome of radical radiotherapy with or without concomitant chemotherapy. Cancer 1999; 85:26.
  89. Ortholan C, Ramaioli A, Peiffert D, et al. Anal canal carcinoma: early-stage tumors < or =10 mm (T1 or Tis): therapeutic options and original pattern of local failure after radiotherapy. Int J Radiat Oncol Biol Phys 2005; 62:479.
  90. Smith DE, Shah KH, Rao AR, et al. Cancer of the anal canal: treatment with chemotherapy and low-dose radiation therapy. Radiology 1994; 191:569.
  91. Charnley N, Choudhury A, Chesser P, et al. Effective treatment of anal cancer in the elderly with low-dose chemoradiotherapy. Br J Cancer 2005; 92:1221.
  92. Peddada AV, Smith DE, Rao AR, et al. Chemotherapy and low-dose radiotherapy in the treatment of HIV-infected patients with carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 1997; 37:1101.
  93. Miller ED, Nalin AP, Diaz Pardo DA, et al. Disparate Use of Chemoradiation in Elderly Patients With Localized Anal Cancer. J Natl Compr Canc Netw 2021; 20:644.
  94. Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med 2012; 136:1266.
  95. Chai CY, Tran Cao HS, Awad S, Massarweh NN. Management of Stage I Squamous Cell Carcinoma of the Anal Canal. JAMA Surg 2018; 153:209.
  96. Benson AB, Venook AP, Al-Hawary MM, et al. Anal Carcinoma, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2018; 16:852.
  97. Arana R, Fléjou JF, Si-Mohamed A, et al. Clinicopathological and virological characteristics of superficially invasive squamous-cell carcinoma of the anus. Colorectal Dis 2015; 17:965.
  98. Ajani JA, Winter KA, Gunderson LL, et al. Prognostic factors derived from a prospective database dictate clinical biology of anal cancer: the intergroup trial (RTOG 98-11). Cancer 2010; 116:4007.
  99. Gunderson LL, Moughan J, Ajani JA, et al. Anal carcinoma: impact of TN category of disease on survival, disease relapse, and colostomy failure in US Gastrointestinal Intergroup RTOG 98-11 phase 3 trial. Int J Radiat Oncol Biol Phys 2013; 87:638.
  100. Glynne-Jones R, Sebag-Montefiore D, Adams R, et al. Prognostic factors for recurrence and survival in anal cancer: generating hypotheses from the mature outcomes of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I). Cancer 2013; 119:748.
  101. Sekhar H, Zwahlen M, Trelle S, et al. Nodal stage migration and prognosis in anal cancer: a systematic review, meta-regression, and simulation study. Lancet Oncol 2017; 18:1348.
  102. Sekhar H, Malcomson L, Kochhar R, et al. Temporal improvements in loco-regional failure and survival in patients with anal cancer treated with chemo-radiotherapy: treatment cohort study (1990-2014). Br J Cancer 2020; 122:749.
  103. Glynne-Jones R, Kadalayil L, Meadows HM, et al. Tumour- and treatment-related colostomy rates following mitomycin C or cisplatin chemoradiation with or without maintenance chemotherapy in squamous cell carcinoma of the anus in the ACT II trial. Ann Oncol 2014; 25:1616.
  104. Sunesen KG, Nørgaard M, Lundby L, et al. Cause-specific colostomy rates after radiotherapy for anal cancer: a Danish multicentre cohort study. J Clin Oncol 2011; 29:3535.
  105. Ajani JA, Winter KA, Gunderson LL, et al. US intergroup anal carcinoma trial: tumor diameter predicts for colostomy. J Clin Oncol 2009; 27:1116.
  106. Jephcott CR, Paltiel C, Hay J. Quality of life after non-surgical treatment of anal carcinoma: a case control study of long-term survivors. Clin Oncol (R Coll Radiol) 2004; 16:530.
  107. Allal AS, Sprangers MA, Laurencet F, et al. Assessment of long-term quality of life in patients with anal carcinomas treated by radiotherapy with or without chemotherapy. Br J Cancer 1999; 80:1588.
  108. Das P, Cantor SB, Parker CL, et al. Long-term quality of life after radiotherapy for the treatment of anal cancer. Cancer 2010; 116:822.
  109. Kachnic LA, Winter KA, Myerson RJ, et al. Long-Term Outcomes of NRG Oncology/RTOG 0529: A Phase 2 Evaluation of Dose-Painted Intensity Modulated Radiation Therapy in Combination With 5-Fluorouracil and Mitomycin-C for the Reduction of Acute Morbidity in Anal Canal Cancer. Int J Radiat Oncol Biol Phys 2022; 112:146.
  110. Bentzen AG, Balteskard L, Wanderås EH, et al. Impaired health-related quality of life after chemoradiotherapy for anal cancer: late effects in a national cohort of 128 survivors. Acta Oncol 2013; 52:736.
  111. Bentzen AG, Guren MG, Vonen B, et al. Faecal incontinence after chemoradiotherapy in anal cancer survivors: long-term results of a national cohort. Radiother Oncol 2013; 108:55.
  112. De B, Corrigan KL, Rooney MK, et al. Patient-Reported Bowel and Urinary Function in Long-Term Survivors of Squamous Cell Carcinoma of the Anus Treated With Definitive Intensity Modulated Radiation Therapy And Concurrent Chemotherapy. Int J Radiat Oncol Biol Phys 2022; 114:78.
  113. Mirabeau-Beale K, Hong TS, Niemierko A, et al. Clinical and treatment factors associated with vaginal stenosis after definitive chemoradiation for anal canal cancer. Pract Radiat Oncol 2015; 5:e113.
  114. Frazer ML, Yang G, Felder S, et al. Determining Optimal Follow-up for Patients With Anal Cancer Following Chemoradiation. Am J Clin Oncol 2020; 43:319.
  115. Goh V, Gollub FK, Liaw J, et al. Magnetic resonance imaging assessment of squamous cell carcinoma of the anal canal before and after chemoradiation: can MRI predict for eventual clinical outcome? Int J Radiat Oncol Biol Phys 2010; 78:715.
  116. Glynne-Jones R, Sebag-Montefiore D, Meadows HM, et al. Best time to assess complete clinical response after chemoradiotherapy in squamous cell carcinoma of the anus (ACT II): a post-hoc analysis of randomised controlled phase 3 trial. Lancet Oncol 2017; 18:347.
  117. Mahmud A, Poon R, Jonker D. PET imaging in anal canal cancer: a systematic review and meta-analysis. Br J Radiol 2017; 90:20170370.
  118. Jones M, Hruby G, Solomon M, et al. The Role of FDG-PET in the Initial Staging and Response Assessment of Anal Cancer: A Systematic Review and Meta-analysis. Ann Surg Oncol 2015; 22:3574.
  119. Jones MP, Hruby G, Metser U, et al. FDG-PET parameters predict for recurrence in anal cancer - results from a prospective, multicentre clinical trial. Radiat Oncol 2019; 14:140.
  120. Stewart DB, Gaertner WB, Glasgow SC, et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for Anal Squamous Cell Cancers (Revised 2018). Dis Colon Rectum 2018; 61:755.
  121. Glynne-Jones R, Meadows HM, Lopes A, et al. Impact of compliance to chemoradiation on long-term outcomes in squamous cell carcinoma of the anus: results of a post hoc analysis from the randomised phase III ACT II trial. Ann Oncol 2020; 31:1376.
  122. Eeson G, Foo M, Harrow S, et al. Outcomes of salvage surgery for epidermoid carcinoma of the anus following failed combined modality treatment. Am J Surg 2011; 201:628.
  123. Lefèvre JH, Corte H, Tiret E, et al. Abdominoperineal resection for squamous cell anal carcinoma: survival and risk factors for recurrence. Ann Surg Oncol 2012; 19:4186.
  124. Correa JH, Castro LS, Kesley R, et al. Salvage abdominoperineal resection for anal cancer following chemoradiation: a proposed scoring system for predicting postoperative survival. J Surg Oncol 2013; 107:486.
  125. Cunin L, Alfa-Wali M, Turner J, et al. Salvage surgery for residual primary and locally recurrent anal squamous cell carcinoma after chemoradiotherapy in HIV-positive individuals. Ann Surg Oncol 2014; 21:527.
  126. Allal AS, Laurencet FM, Reymond MA, et al. Effectiveness of surgical salvage therapy for patients with locally uncontrolled anal carcinoma after sphincter-conserving treatment. Cancer 1999; 86:405.
  127. Schiller DE, Cummings BJ, Rai S, et al. Outcomes of salvage surgery for squamous cell carcinoma of the anal canal. Ann Surg Oncol 2007; 14:2780.
  128. Mariani P, Ghanneme A, De la Rochefordière A, et al. Abdominoperineal resection for anal cancer. Dis Colon Rectum 2008; 51:1495.
  129. Hagemans JAW, Blinde SE, Nuyttens JJ, et al. Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience. Ann Surg Oncol 2018; 25:1970.
  130. Myerson RJ, Karnell LH, Menck HR. The National Cancer Data Base report on carcinoma of the anus. Cancer 1997; 80:805.
  131. Li R, Shinde A, Fakih M, et al. Impact of Surgical Resection on Survival Outcomes After Chemoradiotherapy in Anal Adenocarcinoma. J Natl Compr Canc Netw 2019; 17:1203.
  132. Tarazi R, Nelson RL. Anal adenocarcinoma: a comprehensive review. Semin Surg Oncol 1994; 10:235.
  133. Franklin RA, Giri S, Valasareddy P, et al. Comparative Survival of Patients With Anal Adenocarcinoma, Squamous Cell Carcinoma of the Anus, and Rectal Adenocarcinoma. Clin Colorectal Cancer 2016; 15:47.
  134. Lewis GD, Haque W, Butler EB, Teh BS. Survival Outcomes and Patterns of Management for Anal Adenocarcinoma. Ann Surg Oncol 2019; 26:1351.
  135. Bertelson N, Blumetti J, Cintron J, et al. Anal Adenocarcinoma: Outcomes in an Uncommon Malignancy. Am Surg 2015; 81:1114.
  136. Malakhov N, Kavi AM, Lee A, et al. Patterns of Care and Comparison of Outcomes Between Primary Anal Squamous Cell Carcinoma and Anal Adenocarcinoma. Dis Colon Rectum 2019; 62:1448.
  137. Papagikos M, Crane CH, Skibber J, et al. Chemoradiation for adenocarcinoma of the anus. Int J Radiat Oncol Biol Phys 2003; 55:669.
  138. Lukovic J, Kim JJ, Liu ZA, et al. Anal Adenocarcinoma: A Rare Entity in Need of Multidisciplinary Management. Dis Colon Rectum 2022; 65:189.
  139. Belkacémi Y, Berger C, Poortmans P, et al. Management of primary anal canal adenocarcinoma: a large retrospective study from the Rare Cancer Network. Int J Radiat Oncol Biol Phys 2003; 56:1274.
  140. Basik M, Rodriguez-Bigas MA, Penetrante R, Petrelli NJ. Prognosis and recurrence patterns of anal adenocarcinoma. Am J Surg 1995; 169:233.
  141. Klas JV, Rothenberger DA, Wong WD, Madoff RD. Malignant tumors of the anal canal: the spectrum of disease, treatment, and outcomes. Cancer 1999; 85:1686.
  142. Beal KP, Wong D, Guillem JG, et al. Primary adenocarcinoma of the anus treated with combined modality therapy. Dis Colon Rectum 2003; 46:1320.
  143. Kounalakis N, Artinyan A, Smith D, et al. Abdominal perineal resection improves survival for nonmetastatic adenocarcinoma of the anal canal. Ann Surg Oncol 2009; 16:1310.
  144. Chang GJ, Gonzalez RJ, Skibber JM, et al. A twenty-year experience with adenocarcinoma of the anal canal. Dis Colon Rectum 2009; 52:1375.
  145. Klute KA, Leinicke JA. Almost Everything I Know About Anal Adenocarcinoma I Learned From Rectal Cancer. JCO Oncol Pract 2020; 16:641.
  146. Chapet O, Gerard JP, Mornex F, et al. Prognostic factors of squamous cell carcinoma of the anal margin treated by radiotherapy: the Lyon experience. Int J Colorectal Dis 2007; 22:191.
  147. Khanfir K, Ozsahin M, Bieri S, et al. Patterns of failure and outcome in patients with carcinoma of the anal margin. Ann Surg Oncol 2008; 15:1092.
  148. de Jong JS, Beukema JC, van Dam GM, et al. Limited value of staging squamous cell carcinoma of the anal margin and canal using the sentinel lymph node procedure: a prospective study with long-term follow-up. Ann Surg Oncol 2010; 17:2656.
  149. 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; 108:527.
  150. Balamucki CJ, Zlotecki RA, Rout WR, et al. Squamous cell carcinoma of the anal margin: the university of Florida experience. Am J Clin Oncol 2011; 34:406.
  151. Bieri S, Allal AS, Kurtz JM. Sphincter-conserving treatment of carcinomas of the anal margin. Acta Oncol 2001; 40:29.
  152. Astaras C, Bornand A, Koessler T. Squamous rectal carcinoma: a rare malignancy, literature review and management recommendations. ESMO Open 2021; 6:100180.
  153. Goffredo P, Robinson TJ, Frakes JM, et al. Comparison of Anal Versus Rectal Staging in the Prognostication of Rectal Squamous Cell Carcinoma: A Population-Based Analysis. Dis Colon Rectum 2019; 62:302.
  154. Williams GT, Blackshaw AJ, Morson BC. Squamous carcinoma of the colorectum and its genesis. J Pathol 1979; 129:139.
  155. Péron J, Bylicki O, Laude C, et al. Nonoperative management of squamous-cell carcinoma of the rectum. Dis Colon Rectum 2015; 58:60.
  156. Clark J, Cleator S, Goldin R, et al. Treatment of primary rectal squamous cell carcinoma by primary chemoradiotherapy: should surgery still be considered a standard of care? Eur J Cancer 2008; 44:2340.
  157. Rasheed S, Yap T, Zia A, et al. Chemo-radiotherapy: an alternative to surgery for squamous cell carcinoma of the rectum--report of six patients and literature review. Colorectal Dis 2009; 11:191.
  158. Wang ML, Heriot A, Leong T, Ngan SY. Chemoradiotherapy in the management of primary squamous-cell carcinoma of the rectum. Colorectal Dis 2011; 13:296.
  159. Sturgeon JD, Crane CH, Krishnan S, et al. Definitive Chemoradiation for Squamous Cell Carcinoma of the Rectum. Am J Clin Oncol 2017; 40:163.
  160. Loganadane G, Servagi-Vernat S, Schernberg A, et al. Chemoradiation in rectal squamous cell carcinoma: Bi-institutional case series. Eur J Cancer 2016; 58:83.
  161. Nahas CS, Shia J, Joseph R, et al. Squamous-cell carcinoma of the rectum: a rare but curable tumor. Dis Colon Rectum 2007; 50:1393.
  162. Musio D, De Felice F, Manfrida S, et al. Squamous cell carcinoma of the rectum: The treatment paradigm. Eur J Surg Oncol 2015; 41:1054.
  163. Kulaylat AS, Hollenbeak CS, Stewart DB Sr. Squamous Cancers of the Rectum Demonstrate Poorer Survival and Increased Need for Salvage Surgery Compared With Squamous Cancers of the Anus. Dis Colon Rectum 2017; 60:922.
  164. Tanum G, Tveit K, Karlsen KO, Hauer-Jensen M. Chemotherapy and radiation therapy for anal carcinoma. Survival and late morbidity. Cancer 1991; 67:2462.
  165. Deshmukh AA, Suk R, Shiels MS, et al. Recent Trends in Squamous Cell Carcinoma of the Anus Incidence and Mortality in the United States, 2001-2015. J Natl Cancer Inst 2020; 112:829.
  166. Eng C, Chang GJ, You YN, et al. The role of systemic chemotherapy and multidisciplinary management in improving the overall survival of patients with metastatic squamous cell carcinoma of the anal canal. Oncotarget 2014; 5:11133.
  167. Kim R, Byer J, Fulp WJ, et al. Carboplatin and paclitaxel treatment is effective in advanced anal cancer. Oncology 2014; 87:125.
  168. Rao S, Sclafani F, Eng C, et al. International Rare Cancers Initiative Multicenter Randomized Phase II Trial of Cisplatin and Fluorouracil Versus Carboplatin and Paclitaxel in Advanced Anal Cancer: InterAAct. J Clin Oncol 2020; 38:2510.
  169. Faivre C, Rougier P, Ducreux M, et al. [5-fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer]. Bull Cancer 1999; 86:861.
  170. Jaiyesimi IA, Pazdur R. Cisplatin and 5-fluorouracil as salvage therapy for recurrent metastatic squamous cell carcinoma of the anal canal. Am J Clin Oncol 1993; 16:536.
  171. Tanum G. Treatment of relapsing anal carcinoma. Acta Oncol 1993; 32:33.
  172. Khater R, Frenay M, Bourry J, et al. Cisplatin plus 5-fluorouracil in the treatment of metastatic anal squamous cell carcinoma: a report of two cases. Cancer Treat Rep 1986; 70:1345.
  173. Ajani JA, Carrasco CH, Jackson DE, Wallace S. Combination of cisplatin plus fluoropyrimidine chemotherapy effective against liver metastases from carcinoma of the anal canal. Am J Med 1989; 87:221.
  174. Sclafani F, Morano F, Cunningham D, et al. Platinum-Fluoropyrimidine and Paclitaxel-Based Chemotherapy in the Treatment of Advanced Anal Cancer Patients. Oncologist 2017; 22:402.
  175. Evesque L, Benezery K, Follana P, et al. Multimodal Therapy of Squamous Cell Carcinoma of the Anus With Distant Metastasis: A Single-Institution Experience. Dis Colon Rectum 2017; 60:785.
  176. Kim S, Jary M, Mansi L, et al. DCF (docetaxel, cisplatin and 5-fluorouracil) chemotherapy is a promising treatment for recurrent advanced squamous cell anal carcinoma. Ann Oncol 2013; 24:3045.
  177. Kim S, François E, André T, et al. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study. Lancet Oncol 2018; 19:1094.
  178. Jhawer M, Mani S, Lefkopoulou M, et al. Phase II study of mitomycin-C, adriamycin, cisplatin (MAP) and Bleomycin-CCNU in patients with advanced cancer of the anal canal: An eastern cooperative oncology group study E7282. Invest New Drugs 2006; 24:447.
  179. Hainsworth JD, Burris HA 3rd, Meluch AA, et al. Paclitaxel, carboplatin, and long-term continuous infusion of 5-fluorouracil in the treatment of advanced squamous and other selected carcinomas: results of a Phase II trial. Cancer 2001; 92:642.
  180. Evans TR, Mansi JL, Glees JP. Response of metastatic anal carcinoma to single agent carboplatin. Clin Oncol (R Coll Radiol) 1993; 5:57.
  181. Fisher WB, Herbst KD, Sims JE, Critchfield CF. Metastatic cloacogenic carcinoma of the anus: sequential responses to adriamycin and cis-dichlorodiammineplatinum(II). Cancer Treat Rep 1978; 62:91.
  182. Grifaichi F, Padovani A, Romeo F, et al. Response of metastatic epidermoid anal cancer to single agent irinotecan: a case report. Tumori 2001; 87:58.
  183. Abbas A, Nehme E, Fakih M. Single-agent paclitaxel in advanced anal cancer after failure of cisplatin and 5-fluorouracil chemotherapy. Anticancer Res 2011; 31:4637.
  184. Phan LK, Hoff PM. Evidence of clinical activity for cetuximab combined with irinotecan in a patient with refractory anal canal squamous-cell carcinoma: report of a case. Dis Colon Rectum 2007; 50:395.
  185. Lukan N, Ströbel P, Willer A, et al. Cetuximab-based treatment of metastatic anal cancer: correlation of response with KRAS mutational status. Oncology 2009; 77:293.
  186. Saif MW, Kontny E, Syrigos KN, Shahrokni A. The Role of EGFR Inhibitors in the Treatment of Metastatic Anal Canal Carcinoma: A Case Series. J Oncol 2011; 2011:125467.
  187. Khawandanah M, Baxley A, Pant S. Recurrent metastatic anal cancer treated with modified paclitaxel, ifosfamide, and cisplatin and third-line mitomycin/cetuximab. J Oncol Pharm Pract 2015; 21:232.
  188. Golub DV, Civelek AC, Sharma VR. A regimen of taxol, Ifosfamide, and platinum for recurrent advanced squamous cell cancer of the anal canal. Chemother Res Pract 2011; 2011:163736.
  189. Morris VK, Salem ME, Nimeiri H, et al. Nivolumab for previously treated unresectable metastatic anal cancer (NCI9673): a multicentre, single-arm, phase 2 study. Lancet Oncol 2017; 18:446.
  190. Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol 2017; 28:1036.
  191. Marabelle A, Cassier PA, Fakih M, et al. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study. Lancet Gastroenterol Hepatol 2022; 7:446.
  192. Yanik EL, Kaunitz GJ, Cottrell TR, et al. Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma: Implications for Immunotherapy. JAMA Oncol 2017; 3:974.
  193. Kim S, Atezolizumab plus modified DCF (docetaxel, cisplatin, and 5-fluorouracil) as first-line treatment for metastatic or locally advanced squamous cell anal carcinoma: A SCARCE-PRODIGE 60 randomized phase II study (abstract). J Clin Oncol 40, 2022 (suppl 16; abstr 3508). Abstrct available online at https://meetings.asco.org/2022-asco-annual-meeting/14359?presentation=208330#208330 (Accessed on June 14, 2022).
  194. Pawlik TM, Gleisner AL, Bauer TW, et al. Liver-directed surgery for metastatic squamous cell carcinoma to the liver: results of a multi-center analysis. Ann Surg Oncol 2007; 14:2807.
  195. Sclafani F, Hesselberg G, Thompson SR, et al. Multimodality treatment of oligometastatic anal squamous cell carcinoma: A case series and literature review. J Surg Oncol 2019; 119:489.
  196. Hoffmann K, Bulut S, Tekbas A, et al. Is Hepatic Resection for Non-colorectal, Non-neuroendocrine Liver Metastases Justified? Ann Surg Oncol 2015; 22 Suppl 3:S1083.
Topic 123063 Version 27.0

References

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