Anal Cancer—Diagnosis, Treatment and Follow-Up

Abstract

Background:

The number of anal cancer diagnoses has been rising steadily, so that the incidence has doubled in the past 20 years. Almost all anal cancers are induced by persistent infection with human papillomaviruses. Hitherto the care of patients with anal cancer has been heterogeneous and little experience exists with the primary management of anal cancer.

Methods

The guideline was developed in accordance with the requirements of the German Guideline Program in Oncology. In line with the GRADE approach, the certainty of the evidence was assessed on the outcome level following a systematic literature search. Interdisciplinary working groups were set up to compile suggestions for recommendations, which were discussed and agreed upon in a formal consensus conference.

Results

Ninety-three recommendations and statements were developed. No high-quality evidence was available to support recommendations for or against the treatment of stage I anal cancer with local excision alone as an alternative to chemoradiotherapy. Chemoradiotherapy is the gold standard in the treatment of stages II–III. Among other aspects regarding the timing and extent of response evaluation after chemoradiotherapy, the guideline panel recommended against obtaining a biopsy in the event of complete clinical response. Owing to lack of confidence in the available evidence, only open recommendations were given for treatment of stage IV.

Conclusion

This evidence-based clinical practice guideline provides a sound basis for optimizing the interdisciplinary, cross-sector care of anal cancer patients. Among other areas, gaps in research were identified with respect to the care of patients with early-stage or metastatic anal cancer. Approaches such as chemoradiotherapy combined with regional deep hyperthermia require further investigation. The role for immunotherapy in the management of metastasized anal cancer has also been insufficiently explored to date.

In October 2020, the first evidence- and consensus-based German-language guideline for anal squamous cell carcinoma was published (1). Although anal cancer is relatively rare, with an incidence of 2–3 per 100 000 (2– 5), the number of new cases is steadily rising. The incidence of cancer of the anal canal alone doubled between 1999 and 2016 (4), with an average annual percentage rise in the incidence rate of 2.8 in men and 3.1 in women (5). Women are approximately 1.6 times more likely to develop cancer of the anal canal compared to men, with an average age of onset of 65 and 64 years, respectively (5). The 5-year overall survival rate in Germany is 65% for women and 61% for men (5). Due to its relatively low incidence, there is little experience nationwide in the diagnosis, treatment, and follow-up of anal cancer. Given the nonspecific symptoms it causes and the delay in diagnosis due to patients’ embarrassment, anal cancer is often detected late.

The majority of anal cancers (89–100%) are induced by persistent infection with human papillomaviruses (HPV) (6). Persistent HPV infections, and thus also the development of anal cancer, are promoted by increased exposure to anal HPV infections and/or immunodeficiency (7– 16). This is also reflected in a sometimes significantly increased incidence of anal cancer in certain subpopulations compared to the general population (17), particularly in HIV-positive individuals, men who have sex with men (MSM), women diagnosed with gynecological cancers and precancerous lesions, as well as in the case of iatrogenic immunosuppression (table 1). Therefore, the guideline recommends the screening of at-risk patients and draws the reader’s attention to the recommendations of the Standing Commission on Vaccination at the Robert Koch Institute for prophylactic HPV vaccination of all girls and boys (18).

Table 1. Incidence rates of anal cancer in different population groups.

Population group	Incidence (new diagnoses per 100 000 per year) [95% CI]
General population in Germany *1
Women	3.2
Men	2.0
HIV-positive individuals *2
MSM	85 [82; 89], 7 Studies, 2,229,234 PY, I2 = 93%
Heterosexual men	32 [30; 35], 5 Studies, 1,626,448 PY, I2 = 63%
Women	22 [19; 24], 6 Studies, 1,472,173 PY, I2 = 76%
HIV-negative MSM *2	19 [10; 36], 2 Studies, 48,135 PY, I2 = 0%
After HPV-related gynecological diseases *2
Vulvar intraepithelial neoplasia, grade 3	42 [33; 52], 1 Study, 195,136 PY
Vaginal intraepithelial neoplasia, grade 3	19 [9; 43],1 Study, 30,816 PY
Cervical intraepithelial neoplasias (predominantly grade 3)	6 [5; 7], 8 Studies, 7,839,421 PY, I2 = 74%
Vulvar cancer	48 [38; 61], 4 Studies, 145,147 PY, I2 = 0%
Vaginal cancer	10 [3; 30], 4 Studies, 32,671 PY, I2 = 0%
Cervical cancer	9 [8; 12], 4 Studies, 779,098 PY, I2 = 0%
Iatrogenic immunosuppression, chronic inflammatory diseases *2
Organ transplantation	13 [12; 15], 5 Studies, 1,946,206 PY, I2 = 37%
Lupus erythematosus	10 [5; 19], 4 Studies, 97,816 PY, I2 = 0%
Ulcerative colitis	6 [3; 11], 2 Studies, 276,167 PY, I2 = 92%
Crohn’s disease	3 [2; 4], 2 Studies, 614,830 PY, I2 = 74%

*¹ Crude case rate in Germany in 2016, from (5)

*² Meta-analysis of international study data (17)

HPV, human papillomaviruses; CI, confidence interval; MSM, men who have sex with men; PY, person years

The S3 guideline is aimed at all healthcare professionals who initiate the necessary diagnostic steps upon first contact in the case of suspected anal cancer or refer patients to specialists, who implement curative or palliative therapy concepts, and who are involved in diagnosis, treatment, or support. In addition to that, the guideline can serve as a guide on the subject for health care payers and decision-makers.

Methods

The S3 guideline was developed according to the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) Guidance Manual and Rules for Guideline Development (19) and under the methodological auspices of the German Guideline Program in Oncology. A consensus was reached on the key questions during the kick-off conference. To answer the evidence-based key questions (treatment of anal margin and anal canal cancer in stages I–III, as well as of residual/recurrent and metastatic anal cancer; response assessment after combined chemoradiation), a systematic review of the primary literature was conducted (PROSPERO registry: CRD42019140829). The search was carried out in the MEDLINE, Embase, and Cochrane databases; the search date was 25 October 2018, while the update search was on 18 July 2019 (figure).

Figure.

PRISMA flowchart: overview of study identification and selection

Studies were included hierarchically according to design (randomized controlled trials, non-randomized controlled trials, prospective cohort studies). Case reports and case series with fewer than 10 participants for whom follow-up results were reported were not included. In total, 75 publications were included in order to answer the evidence-based guideline questions.

The systematic appraisal, analysis, and presentation of evidence were performed according to the GRADE system (GRADE, Grading of Recommendations Assessment, Development, and Evaluation) (20, 21). An overview of the assessment of confidence in the estimates of effect and their interpretation can be found in eTable 1.

eTable 1. GRADE evaluation of the confidence in the effect estimates (modified from Balshem et al. [e78] and Meerpohl et al. [e79]).

Confidence in the effect estimates	Symbolic representation				Interpretation/implications
High					We are very confident that the true effect is close to the estimate of effect.
Moderate					We are reasonably confident in the estimate of effect: the true effect is probably close to the estimate of effect; however, there is a possibility that it is substantially different.
Low					We have limited confidence in the estimate of effect: the true effect may be substantially differ from the estimate of effect.
Very low					We have very little confidence in the estimate of effect: the true effect is likely to be substantially different from the estimate of effect.

GRADE, Grading of Recommendations Assessment, Development and Evaluation

The relevance of the outcomes considered (22) was assessed by means of a survey of the nominated experts in the guideline development group and of anal cancer patients; the results of this survey were published separately (23) and were taken into consideration during the consensus process for recommendations.

Consensus on recommendations was reached during a structured consensus conference. Standardized grades of recommendation (GR) were used to formulate recommendations (etable 2). Strong consensus was sought for all recommendations considered during the consensus process.

eTable 2. Grades of recommendation used and their interpretation, modified from Kaminski-Hartenthaler et al. (e80) and the Association of the Scientific Medical Societies in Germany (AWMF) Guidance Manual and Rules for Guideline Development (20).

Direction of recommendation and strength	Wording	Symbolic representation	Interpretation/implications
Strong recommendation for an approach	“… shall …”	A	We believe that all or almost all informed individuals would reach this decision. Clinicians need to spend less time on the decision-making process with their patients. In most clinical situations, the recommendation can be adopted as a general approach.
Weak recommendation for an approach	“… should …”	B	We believe that the majority of informed individuals would—but a substantial proportion would not—reach this decision. Clinicians and other healthcare providers need to spend more time ensuring that the choice of procedure, together with the consequences potentially associated with it, reflects the values and preferences of the individual patient. Decision-making processes in the healthcare system require in-depth discussion and the involvement of numerous stakeholders.
Open recommendation/ no recommendation	“… can be considered …”	0	It is currently not possible to make a recommendation for or against a particular procedure as a result of certain circumstances (for example, unclear or balanced benefit–risk ratio, no evidence available, etc.).
Weak recommendation against an approach	“… should not …”	B	We believe that the majority of informed individuals would—but a substantial proportion would not—reach this decision.
Strong recommendation against an approach	“… shall not …”	A	We believe that all or almost all informed individuals would reach this decision.

The long and short versions of the guideline, the evidence report, and the guideline methods report are available for reading at www.awmf.org and www.leitlinienprogramm-onkologie.de/leitlinien/ (1). The patient guideline will be published in mid-2021.

Results

A total of 93 recommendations and statements were formulated, the most important of which are summarized below. In addition, consensus was reached on 13 quality indicators.

Definitions and terminology

The current American Joint Committee on Cancer (AJCC) classification (24) shall be used for staging (Tables 2 and 3). Carcinomas of the anal margin can be fully visualized when the nates are retracted, and the predominant portion of their tissue lies within a 5-cm radius of the anal verge. Carcinomas of the anal canal are, at least partially, located so far inside the anal canal that they cannot be visualized, or not fully, when the nates are retracted.

Table 2. TNM classification of anal cancer according to AJCC 2017 (24).

TNM	Definition
Definition of the primary tumor (T)
TX	Primary tumor not assessed
T0	No evidence of primary tumor
Tis	High-grade squamous intraepithelial lesion (HSIL) (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia [AIN] II–III, high-grade AIN)
T1	Tumor ≤ 2 cm
T2	Tumor > 2 and ≤ 5 cm
T3	Tumor > 5 cm
T4	Tumor of any size invading adjacent organs, such as the vagina, urethra, or bladder
Definition of regional lymph nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in inguinal, mesorectal, internal iliac, or external iliac nodes
N1a	Metastasis in inguinal, mesorectal, or internal iliac lymph nodes
N1b	Metastasis in external iliac lymph nodes
N1c	Metastasis in external iliac lymph nodes as well as N1a lymph nodes
Definition of distant metastasis (M)
M0	No distant metastasis
M1	Distant metastasis

AJCC, American Joint Committee on Cancer

Table 3. Anal cancer staging according to AJCC 2017 (24).

Stage	Primary tumor (T)	Regional lymph nodes (N)	Distant metastasis (M)
0	Tis	N0	M0
I	T1	N0	M0
IIA	T2	N0	M0
IIB	T3	N0	M0
IIIA	T1, T2	N1	M0
IIIB	T4	N0	M0
IIIC	T3, T4	N1	M0
IV	Any T	Any N	M1

AJCC, American Joint Committee on Cancer; Tis, tumor in situ

Prevention and screening

In HIV-positive patients, screening for the detection of incidental anal carcinomas and precancerous lesions shall be performed annually according to the recommendations of the guideline “Anal dysplasia and anal cancer in HIV-positive individuals” (25, 26). HIV-negative individuals at increased risk for developing anal cancer shall also be offered regular screening examinations (at least every 36 months). The methods available for screening, in addition to inspection and digital rectal examination, include anal cytology, HR-HPV detection (HR, high risk), and proctoscopy or high-resolution anoscopy, including biopsy sampling where required.

Primary diagnostic work-up in suspected anal cancer and pretreatment diagnostic imaging

The mostly non-specific symptoms such as bleeding, itching, pain, non-healing wounds/ulcers, and (urge) incontinence can delay diagnosis. In addition to taking a detailed patient history and identifying risk factors (immunodeficiency including HIV infection [7, 8, 17, 27], receptive anal intercourse [28], prior history of HPV-related anogenital lesions [17, 28–31], nicotine abuse [28] [Table 1]), a physical examination focusing on the inguinal lymph nodes, a proctological examination including digital rectal examination and proctoscopy shall be performed, as well as rectoscopy, anal endosonography, and colposcopy where required.

If anal cancer is suspected, histopathological confirmation shall be sought once the abovementioned examinations have been performed and documented. If a cancer of the anal margin measuring up to 2 cm in diameter is suspected and the sphincter apparatus and adjacent organs have not been infiltrated, the entire lesion should be removed—already at the time of confirmation of the diagnosis—as an excisional biopsy with a safety margin of 0.5 cm.

An MRI scan of the pelvis shall be performed to determine tumor stage (32). This should include a multiparametric MRI angulated to the anal canal. For the detection of locoregional lymph node metastasis, MRI of the pelvis shall be performed (33, 34), as should PET/CT (cost not necessarily covered by statutory health insurances) (35– 39, e1– e3). PET/CT improves staging (by demonstrating additional lymph node metastasis) and, as a result, can potentially lead to changes in the therapeutic approach (alterations in radiation planning in terms of dose distribution and field boundary). If locoregional lymph node metastasis is suspected on the basis of imaging, neither histo- nor cytopathological confirmation of suspicious lymph nodes shall be carried out if chemoradiation is planned. Since the lymphatic drainage pathways are included in the radiation volume as standard, this would be of no therapeutic consequence, representing instead an additional burden and increasing the risk of morbidity as a result of the procedure. For the detection of distant metastasis, chest and abdominal CT shall be performed. Alternatively, PET/CT can be considered (cost not necessarily covered by statutory health insurances) (e4– e9).

Other diagnostic methods and supportive measures before and during specific cancer therapy

Anal cancer is associated with a history of HPV-related anogenital disease, including anogenital warts, as well as gynecological intraepithelial neoplasias and cancer (17, 28– 31, e10). Therefore, a thorough examination of the anogenital region shall be performed in anal cancer patients, including cervical cancer screening in women.

Individuals living with HIV have a higher risk for developing anal cancer (7– 9, 17). Since anal cancer is one of the HIV indicator conditions, HIV testing is recommended if HIV status is unknown (e11).

According to the experience of the experts, colostomy is rarely necessary prior to treatment initiation. There was strong consensus for the recommendation that the indication for stoma creation prior to curative-intent radiochemotherapy be made with caution. The decision on pretreatment protective stoma creation shall be made in an interdisciplinary manner within the tumor board. Stoma creation may be necessary in patients with malignant intestinal obstruction, symptomatic ano-/rectovaginal fistula, or severe fecal incontinence and resulting distress. The position of the stoma shall be marked preoperatively.

Treatment of stages I–III anal cancer

Only retrospective comparative, and in some cases registry-based, cohort studies are available on the basis of which a recommendation can be formulated for or against local excision alone as an alternative to chemoradiation for patients with early-stage anal cancer (e12– e15). A registry-based comparative cohort study revealed no significant differences between excision alone and chemoradiation for primary tumors both ≤1 cm and >1–2 cm in diameter with regard to 5-year overall survival (diameter ≤ 1 cm: 88.5% versus 91.6%, diameter >1–2 cm: 86.6% versus 86.4%) (e12). Therefore, the following recommendations were formulated: Cancer of the anal margin <2 cm in diameter without regional or distant metastases (stage I) shall be excised locally while ensuring an adequate safety margin (0.5 cm) (grade of recommendation [GR]: A; GRADE: very low). Cancer of the anal canal measuring <2 cm in diameter without regional or distant metastases (stage I) should be treated with primary combined chemoradiation (GR: B; GRADE: very low). Alternatively, in the case of cancer of the anal canal measuring <2 cm in diameter without regional metastases or distant metastases, R0 excision alone can be considered (stage I) (GR: 0; GRADE: very low).

For patients with stage II–III disease, combined chemoradiation is the gold standard: Stage II–III anal cancer shall be treated with combined chemoradiation (GR: A; GRADE: low to moderate [e16–e18]). There are no studies comparing surgical versus radiation oncology treatment for cancer of the anal margin; however, there is consensus among the guideline group that performing excision alone with an adequate safety margin (0.5 cm) can be considered for stage IIA cancer of the anal margin (T2N0M0) (expert consensus [EC]).

In the context of combined chemoradiation, stage II–III anal cancer shall be treated with a chemotherapy regimen comprising mitomycin and 5-fluorouracil (5-FU) (GR: A; GRADE: moderate to high [e19]). Alternatively, a chemotherapy regimen comprising cisplatin and 5-FU can be considered in the context of chemoradiation (EC: 0; GRADE: moderate to high [e20–e23]), or 5-FU substituted by capecitabine (GR: 0; GRADE: very low [e24–e27]). The radiotherapy dose shall not exceed 59.4 Gy (GR: A; GRADE: very low [e28]). Radiation therapy shall be performed as intensity-modulated radiotherapy (IMRT) (GR: A; GRADE: very low to moderate [e29–e37]).

In the context of combined chemoradiation, no induction chemotherapy (GR: A; GRADE: moderate [e38]) and no maintenance chemotherapy shall be performed (GR: A; GRADE: moderate [e22, e23]).

Further protocols are available for additional studies on a variety of therapeutic regimens, but no results have been published for these regimens as yet (e39– e41).

Response assessment following primary chemoradiation

Complete tumor regression often takes weeks to months after completing radiochemotherapy. Therefore, the following recommendations have been formulated: To evaluate response following chemoradiation, a clinical examination (digital rectal examination, proctoscopy) shall be performed 11 weeks, 18 weeks, and 26 weeks after the start of chemoradiation (GR: A; GRADE: moderate to high [e42]). If residual tumor is suspected (stable or reduced, but persistent local findings), the indication to perform further diagnostic evaluation (tissue sample, imaging) shall be established at the earliest 26 weeks after the start of combined chemoradiation (GR: A; GRADE: moderate to high [e42]). However, in the case of clinical progression (for example, progression in size), further diagnostic evaluation shall already be performed before the end of the abovementioned time period (EC).

In the case of complete remission 26 weeks following the start of chemoradiation, an MRI of the pelvis should be performed to confirm findings and establish a baseline for follow-up (e43). In the case of complete remission, biopsy for histopathological confirmation of response shall not be performed.

Follow-up

Follow-up should be performed over a 5-year period and shall begin following successful completion of treatment. Successful completion of treatment is defined as follows: histopathologically confirmed R0 resection or complete remission 26 weeks after the start of chemoradiation. The follow-up schedule shown in Table 4 can be used for follow-up examinations (EC).

Table 4. Follow-up investigations in anal cancer patients following successful completion of treatment with curative intent.

Investigation	Months following successful treatment completion
	3	6	9	12	15	18	21	24	30	36	42	48	54	60
Patient’s history	X	X	X	X	(X)	X	(X)	X	(X)	X	(X)	X	(X)	X
Clinical examination including inguinal palpation and digital rectal examination	X	X	X	X	(X)	X	(X)	X	(X)	X	(X)	X	(X)	X
Proctoscopy and, where appropriate, rectoscopy	X	X	X	X	(X)	X	(X)	X	(X)	X	(X)	X	(X)	X
Magnetic resonance imaging of the pelvis		(X)		X				X		(X)		(X)
CT of the chest and abdomen with contrast medium *1		X				(X)			(X)
Optional PET/CT *2		(X)				(X)			(X)

Examinations in parentheses are recommended for patients at increased risk.

This includes all patients with anal cancer in stage IIB or higher, as well as all HIV-positive and otherwise immunocompromised patients irrespective of stage.

*¹ This applies to stage IIA and higher, cancer of the anal margin following chemoradiation, and cancer of the anal canal irrespective of primary treatment.

*² CAVEAT: PET scans do not belong to the catalog of services offered by statutory health insurances as part of the diagnostic work-up for anal cancer (cost not necessarily covered).

CT, computed tomography; PET, positron emission tomography

Treatment of residual or recurrent anal cancer

In the case of residual or recurrent cancer following primary treatment, further treatment planning shall be carried out within the interdisciplinary tumor board. Since up to 30% of anal cancer patients do not experience complete remission or have locoregional recurrence (e44), identifying an effective treatment in this setting is of major relevance. However, no comparative studies were available.

In the case of local residual or recurrent tumor following primary chemoradiation without distant metastasis, surgical resection with curative intent shall be performed (EC). Abdominoperineal resection is the standard procedure for local recurrence or residual cancer of the anal canal following primary chemoradiation (e45– e49). If R0 resection of residual or recurrent tumor is not possible, an individualized palliative treatment plan shall be offered.

Patients with locoregional recurrent disease following primary surgical resection shall be treated as treatment-naive patients.

A more recent randomized trial demonstrated that combination therapy with avelumab and cetuximab may also be an option for the treatment of residual or recurrent disease following primary chemoradiation (e50). These results were not available at the time of guideline development.

Treatment of metastatic anal cancer

For stage IV disease (distant metastasis), further treatment planning shall take place within the interdisciplinary tumor board. Predominantly retrospective non-comparative case series and cohort studies (e51– e64) and only a handful of retrospective comparative observational studies (e65– e70) were available on the treatment approach to metastatic anal cancer (hence effect estimates were not calculated and no GRADE assessment was performed; due to insufficient confidence in the evidence, no determination of strength has been applied for the recommendations [GR: 0]). For metastatic stage IV anal cancer, platinum-based chemotherapy can be considered (GR: 0).

Depending on tumor burden and symptoms, additive local treatment can be considered for the primary tumor in the case of synchronous metastatic anal cancer (GR: 0). Likewise in oligometastatic anal cancer, local treatment of metastasis can be performed as part of a multimodal approach (GR: 0). A more recent randomized trial revealed that combination therapy with carboplatin and paclitaxel may be an option for metastatic and/or unresectable anal cancer (e71). These results were not available at the time of guideline development.

Immunotherapies for the treatment of metastatic anal cancer have only been investigated to date in uncontrolled studies (e72– e74). No results have been published as yet for other trials (some of which are randomized) in metastatic and/or unresectable anal cancer (e75, e76).

Palliative treatment

The general and specialized palliative care for patients with anal cancer shall be provided in accordance with the recommendations of the S3 guideline “Palliative care for patients with incurable cancer” (e77).

Incurability remains a prognostic estimate that needs to be formulated on a case-by-case basis. The following situations render it likely that anal cancer is incurable: stage IV, progression or recurrence following salvage rectal resection, as well as progression or recurrence following inguinal lymph node resection or lymphadenectomy. All patients shall be offered palliative treatment following the diagnosis of incurable anal cancer, irrespective of whether tumor-specific therapy is performed (guideline adaptation, GR: A, evidence level 1-).

Rehabilitation

an oncological rehabilitation during the course of their cancer-specific treatment.The rehabilitation starts after completing primary therapy, but chemotherapy does not need to have been completed and can be continued during rehabilitation.

Conclusion

Recommendations on the diagnosis, treatment, and follow-up of anal cancer were formulated on the basis of a systematic review of the evidence and expert consensus. Research is lacking on, among other aspects, the treatment of early-stage disease, metastatic stages, as well as on recurrent and residual disease following chemoradiation. Promising approaches, such as the use of regional deep hyperthermia in combination with chemoradiation, require further investigation before they can be conclusively evaluated. The role of new immunotherapies, for example checkpoint inhibitors, in the treatment of metastatic anal cancer have not been sufficiently investigated to date; however, further results are expected from studies currently underway. Future health services research concepts should use quality indicators to investigate the extent to which guideline recommendations are taken into consideration and contribute to improving quality of life and cancer-free survival.

eTable 4. Methodological coordination.

Person	Function
Dr. med. Ricardo N. Werner	Clinical and methodological coordination in the guideline office, drawing up of guideline documents, assisting working group leaders in the drafting of recommendations and background texts, as well as drawing up of the evidence report: including the systematic search, selection, and evaluation of the literature, elaboration of evidence tables, narrative abstracts
Matthew Gaskins, MPH	Among other tasks, second reviewer in the systematic review, selection, and evaluation of the literature, elaboration of evidence tables, narrative abstracts
Gabriela L. Avila Valle, M.Sc.	Among other tasks, second reviewer in the systematic review, selection, and evaluation of the literature, elaboration of evidence tables, narrative abstracts
Martin Dittmann	Organizational preparation of kick-off meeting and consensus conferences, technical support, communication, administrative support