Approach Considerations
For the majority of patients diagnosed with anal squamous cell carcinoma, treatment will consist of radiation therapy combined with radiosensitizing chemotherapeutic agents. [30, 31, 40] This treatment method has remained remarkably unchanged since its advent as the so-called Nigro Protocol in 1974. [41]
Surgery plays a limited role in the treatment for anal cancer. National Comprehensive Cancer Network (NCCN) guidelines recommend that lesions in the anal margin, which starts at the anal verge and includes the perianal skin over a 5- to 6-cm radius from the squamous mucocutaneous junction, can be evaluated for local excision with adequate margins and subsequent observation, with no additional cancer-specific treatments. [31] However, this approach is reserved for patients with locally advanced disease, refractory disease, pretreatment incontinence, or other specific factors.
Medical Care
Symptom control
Symptom management is critical during the entire process of discovery, diagnosis, and treatment phases for the anal cancer patient. Anal and fecal incontinence can be alleviated or minimized by slowing of stool passage with bulking agents such as psyllium husk powder and, in the case of diarrhea, with antidiarrheal agents.
Hygiene issues and moisture-related skin breakdown are very common in anal cancer patients. Maintaining excellent post–bowel movement cleansing by means of sitz baths or showers can be of great benefit to patients. Dressings or clothing that wick moisture away from the skin can also provide great comfort. Barrier creams and off-loading strategies should be considered in the case of skin breakdown. Symptom control will require the design of a bowel and lifestyle regimen specific to the particular patient’s needs and goals.
Cancer treatment
For localized disease, National Comprehensive Cancer Network (NCCN) guidelines recommend 5-fluorouracil (5-FU), mitomycin, and radiotherapy. [31] 5-FU is infused continuously during days 1-4 and days 29-32. Mitomycin is administered on days 1 and 29 as a bolus infusion. Alternatively, oral capecitabine (eg, 825 mg/m2 twice daily on days 1–5 weekly for 6 weeks) can be substituted for 5-FU.
In a randomized study, the RTOG 98-11 trial, that attempted to improve on the above regimen with substitution of cisplatin for mitomycin in non-metastatic disease, the mitomycin regimen proved superior. The primary endpoint of the study, 5-year disease-free survival, was 67.8% with 5-FU/mitomycin versus 57.8% with 5-FU/cisplatin (P= 0.006); 5-year overall survival also favored the mitomycin-containing regimen (78.3% vs 70.7%, respectively; P = 0.026). [42] The NCCN considers 5-FU/cisplatin plus radiation therapy as a category 2B recommendation. [31] Similarly, the ACCORD 03 trial, which evaluated the utility of induction chemotherapy prior to the chemoradiation regimen or additional radiation boost, showed no advantage to either alteration in protocol. [43]
Concurrent multifocal radiotherapy progresses 5 days per week for the full 32 days of treatment, with a total minimum dose of 45 Gy in 25 fractions of 1.8 Gy to the primary cancer, plus additional radiation to the inguinal nodal basins. Additional radiation is recommended for more advanced lesions or known nodal spread. An increased total radiation dose, even up to 65 Gy, and avoiding prolonged breaks are recommended based on limited but compelling data, [30] although increased dose is associated with increased toxicity.
Radiation therapy for anal cancer has historically involved two- or three-dimensional conformal (3DCRT techniques, but intensity-modulated radiation therapy.(IMRT) has become the most widely utilized radiation therapy technique for anal cancer, with 3DCRT used in a very small minority of patients. [44] The NCCN currently recommends IMRT over 3DCRT for radiation therapy in anal cancer. [31]
Compared with non-IMRT radiation therapy, IMRT delivers significantly less radiation to normal tissue, leading to reduced rates of toxicity-related treatment interruption. [45] Analysis of 8,108 patients diagnosed with non-metastatic anal cancer from 2004 to 2013 found that overall survival (OS) was longer with IMRT than with non-IMRT (hazard ratio [HR] 0.83, 95% CI: 0.74-0.94; P=0.002); 5-year OS rates were 74.6% vs 70.5%, respectively (P=0.0022). [46] MRT does require specialized equipment and expertise and careful target design, however, and therefore may increase the cost of treatment.
At the conclusion of the chemoradiation regimen, a re-evaluation by the surgeon is conducted at 8-12 weeks. Subsequent management depends on whether the patient has remission of disease, persistent disease, or progression of disease.
Patients with complete remission of visible disease require surveillance with serial digital rectal examinations, inguinal examinations, and (if T3/4 or inguinal N+) annual computed tomography (CT) scans of the chest, abdomen, and pelvis (see Treatment/Long-Term Monitoring). Patients with local recurrence require surgical treatment with abdominoperineal resection (APR). If inguinal recurrence is found, inguinal dissection with possible chemotherapy is indicated. If distant metastasis is found after treatment, a cisplatin-based chemotherapeutic regimen is recommended.
If the patient has persistent disease, re-evaluation is indicated after 4 additional weeks, to allow completion of the effects of radiation therapy. If regression is then evident, serial examinations and CT scans are indicated.
However, if biopsy after this observation period demonstrates progression of disease, then restaging should be completed. Local disease is managed surgically with APR, and followed up with subsequent examinations and CT scans. If evidence of metastatic disease is found after the above radiation/chemotherapy regimen, then the 5-FU/cisplatin chemotherapy regimen described below is indicated.
For metastatic disease at presentation, 5-FU is infused on a continuous basis for 5 days, along with cisplatin infusion on day 2. This regimen is repeated every 4 weeks.
In refractory metastatic anal cancer, immune checkpoint inhibitors (eg. pembrolizumab, nivolumab) have demonstrated promising efficacy. Research into the use of these agents for refractory cases is ongoing, and clinicians should consider enrolling patients with refractory metastatic anal cancer in one of these clinical trials. [47]
Pembrolizumab was also granted accelerated approval for unresectable or metastatic tumor mutational burden–high (TMB-H; ≥10 mutations/megabase) solid tumors in patients who have progressive disease despite treatment and who have no alternative treatment options. Approval was based on results of an analysis of 10 cohorts of previously treated patients with various unresectable or metastatic TMB-H solid tumors enrolled in the KEYNOTE-158 trial. Among the 13% of patients identified as TMB-H, the objective response rate was 29%, with a 4% complete response rate and 25% partial response rate. The median duration of response was not reached, with response durations of ≥12 months in 57% of patients and of ≥24 months in 50%. [48]
For more information, see Anal Cancer Treatment Protocols.
Surgical Care
Surgery is indicated in anal cancer for T1, N0, well-differentiated lesions in the anal margin. If there is a reasonable expectation of adequate margins, then surgery can be attempted, as complete excision will eliminate the need for chemotherapy and radiation therapy. If the margins are inadequate, re-excision may be attempted or the above radiation/chemotherapy regimen should be initiated.
Historically, treatment of anal cancer was primarily surgical, with APR and permanent end-colostomy as the primary option. That treatment was associated with substantial morbidity and a relatively high recurrence rate.The 5-year survival was 40-70% after APR, [24] though those data represent studies dating back to the 1940s and may not serve as an accurate comparison to modern techniques.
Nevertheless, with the impressive results from nonsurgical treatment (chemoradiation) and its elimination of the need for end-colostomy, APR has become only sparingly used in the treatment of anal cancer. APR for anal cancer consists of removal of the anorectum as well as any affected perianal skin and any satellite lesions. Creation of anatomic flaps to fill the void left by this radical excision is often necessary and plastic surgery consultants are usually required to provide such specialized and individualized perineal wound closure. [49]
At the time of APR, all patients require end-colostomy to provide distal elimination of the digestive tract. This colostomy is preferably created in the left lower quadrant, using a muscle-splitting technique to help prevent or forestall the appearance of paracolostomy hernia. The issue of paracolostomy hernia is more significant in those patients with end-colostomy, as there is no hope for reversal of the stoma and it will be present life-long.
Some surgeons advocate the placement of peristomal mesh at the time of creation and small studies have suggested that this may be a useful strategy. [50, 51] Consensus on this subject does not yet exist and at least two large randomized controlled studies to determine its benefit are currently in progress. [52, 53]
APR is indicated in cases of locoregional disease that initially responds completely to chemoradiation but recurs, and also in cases that persist or progress through chemoradiation, as well as in select patients who have fecal incontinence. Groin dissection is indicated when inguinal nodes are known to contain metastasis. Sentinel lymph node biopsy is under investigation and shows high detection rates. [54, 55] However, forgoing inguinal radiation therapy in patients with negative sentinel nodes is not recommended. [30, 54]
Complications
A wide variety of complications can affect the anal cancer patient, including the short-term adverse effects of active chemotherapy and long-term risks of radiation exposure. Because chemotherapy combined with radiation is the current standard of care for most anal cancer patients, complications of radiation are more common.Technique, volume, total dose, fraction size, and timeframe are all factors that may have effects on radiation complications. [56]
Radiation exposure causes microvascular changes that alter the efficiency of the wound healing process and platelet function in exposed tissues and also increases angiogenesis by means of expression changes in the tissues themselves. [57] In the era of narrowed, multifocal fields and intensity-modulated radiation therapy (IMRT), radiation complications have decreased and are likely to continue to do so, [58, 59] although they still may occur, even years after treatment, in 1%-20% of patients. [60]
Inflammatory conditions, sexual dysfunction, and bowel dysfunction are the most common negative side effects of radiation therapy to the pelvis. Among the late inflammatory sequelae of radiation, the most common is proctitis of any kind, which most commonly manifests as rectal bleeding and other symptoms. Late rectal bleeding after pelvic radiation is fairly common, affecting 22% of 2D simulation and 7% of 3D simulation patients. [59]
Mild bleeding, urgency, frequency, and diarrhea are common manifestations of radiation proctitis in its milder forms. Most often, proctitis produces minimal complaints; however, bleeding from the rectum can be significant and difficult to control. The severity of early acute proctitis may possibly be a predictor of late chronic proctitis. [60]
Generally, short-course antibiotic therapy with a fluoroquinolone and metronidazole is an effective first choice for treatment. Other treatment modalities for bleeding in the rectum may include electrocautery and argon beam cautery of bleeding sites, topical applications of medications such as formalin in cases of more diffuse bleeding, hyperbaric oxygen, and even, rarely, surgical diversion or excision of the affected organ.
Surgery for these high-risk individuals in the setting of proctitis comes with high morbidity and mortality and should be avoided if possible. If surgery is required, it should be performed at a tertiary care center. [61]
Stricture, fistula, and perforation are also complications of pelvic radiation related to poor healing and are unlikely to resolve without surgical intervention. Case reports of colorectal cancers in previous radiation fields have also been documented [62] and are thought to be related to chronic inflammation in the field.
Prevention
Prevention begins with recognition of the risk factors for anal cancer, which are as follows [16, 19] :
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Anal human papillomavirus (HPV) infection
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In women, a history of vulvar, cervical, or vaginal cancer or precancerous lesions
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HIV infection
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Immunosuppression (eg, in organ transplant recipients, individuals with autoimmune diseases)
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Certain sexual practices (receptive anal intercourse, having many sexual partners, sex between men)
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Cigarette smoking
Strategies for prevention of anal squamous cell carcinoma consist of vaccination against HPV and management of anal intraepithelial neoplasia (AIN). In the United States, 91% of anal cancers have been found to be positive for HPV, with HPV subtype 16 most commonly detected. [63] A systematic review and meta-analysis concluded that HPV16 is by far the most carcinogenic HPV type in the anus that may contribute to the progression of HSIL to anal cancer. HPV16 may prove to be a priority target for anal cancer screening and prevention. [64]
Initially approved in 2014, the 9-valent HPV vaccine (Gardasil 9 [9vHPV]) is the only HPV vaccine available in the US. The 9vHPV vaccine covers HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. It is indicated for males and females aged 9 through 45 years to prevent anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58. Additionally, it is indicated for prevention of precancerous AIN grades 1, 2, and 3 caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. [65]
In HIV-positive men who have sex with men (MSM), screening for anal cancer has been proposed as a cost-effective measure. [66] Possible screening methods could include anal Pap smears or anoscopy on an annual basis, or targeted anoscopy 5 years after the CD4 count drops below 200 cells/μL. [67]
Women, regardless of HIV status, with a history of high-grade lesion or cancer of the cervix, vulva, or vagina are another at-risk population that may benefit from screening. A 2019 systematic review and meta-analysis with paired anal and cervical samples demonstrated a strong association between anal HPV16 and high-grade lesions with cervical HPV16. Additional considerations include a history of anogenital warts and cigarette smoking, although these by themselves are not an indication for anal dysplasia screening. [68]
The use of topical creams in the setting of close long-term follow-up is considered appropriate for AIN lesions. Topical 5% imiquimod cream is considered appropriate for anal margin AIN lesions, as is 5% 5-fluorouracil (5-FU) cream. Good responses are reported; adverse effects are common but typically of low severity. [30]
Topical therapy may be especially useful in HIV-positive patients, who have a higher rate of conversion from AIN to cancer. The ANCHOR trial demonstrated a 57% reduced rate of progression to anal cancer in HIV-positive individuals with high-grade squamous intra-epithelial lesions (HSIL) receiving treatment versus active monitoring. [69] A large randomized phase III trial comparing ablative and topical treatment with observation for prevention of anal cancer in HIV-positive patients with high-grade AIN is in progress. Completion of the study is expected in 2027. [70]
A study in HIV-positive MSM by Richel et al reported a higher complete response rate in AIN treated with electrocautery than with imiquimod or topical 5-FU. Recurrence rates were high with all treatments. [71]
Targeted biopsy and destruction of the lesions, when visible, are considered the preferred methods of control for AIN. Anal mapping (ie, perianal mapping biopsies in advance of formal wide excision), while once routine, is generally not required, but is still used. [30]
Long-Term Monitoring
Follow-up in patients with a history of anal cancer should include the following:
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Digital rectal examinations (DRE) and inguinal palpation every 3-6 months for 5 years
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Anoscopy every 6-12 months for 3 years
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Chest/abdomen/pelvis computed tomography (CT) scan annually for 3 years
In patients who have undergone abdominoperineal resection and colostomy placement, DRE and anoscopy are obviously eliminated from the regimen. CT scanning can also be avoided in cases of complete remission and when the original staging was not T3, T4, or inguinal lymph node positive. [31]
Use of the following additional imaging techniques has been recommended for detection of recurrent disease, although supporting data are currently limited:
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Anal cancer with typical mass. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
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Paget disease. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
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Anal cancer. Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
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Anal cancer in the setting of condyloma (anal warts). Courtesy of Luay Ailabouni, MD, FACS, FASCRS.
Tables
Stage |
T |
N |
M |
0 |
Tis | N0 | M0 |
| I | T1 | N0 | M0 |
| IIA | T2 | N0 | M0 |
| IIB | T3 | N0 | M0 |
| IIIA | T1-2 | N1 | M0 |
| IIIB | T4 | N0 | M0 |
| IIIC | T3-4 | N1 | M0 |
| IV | Any T | Any N | M1 |
