Squamous Cell Carcinoma of the Anal Canal
Management has changed from abdomino-perineal resection (APR) to organ-preserving therapy (radiotherapy or chemoradiotherapy) with APR reserved for cases of local failure. Anal cancer is typically a loco-regional disease, and distant metastasis is rare (~ 10% of patients at presentation and another 10% after treatment has completed). This makes local control the most important target for treatment. Systemic therapy has not been shown to decrease the rates of distant metastasis (as opposed to rectal cancer).
Surgery Alone
Surgery with APR had survival rates of about 50% for all comers, and < 20% for those with inguinal metastases at presentation. Failures often occured locally or in regional nodes. The success of sphincter preserving therapies has relegated surgery to a secondary role for patients with local recurrence.
Radiotherapy Alone
Radiotherapy alone may be an alternative to surgery for T1 tumours (< 2 cm) with no lymph node involvement. 5-year survival of 100% has been reported in several non-randomised series. The dose varies from 45 to 60 Gy. The only randomised data comparing radiotherapy to chemoradiotherapy included patients with T1-T4 tumours but did not perform subanalysis on outcomes for different stages. Therefore, chemoradiotherapy is typically considered 'standard of care' for all stages of chemothera
Chemoradiotherapy (Sphincter-preserving surgery)
Chemoradiotherapy is the standard of care for all anal malignancies. It was established as the mainstay of treatment after several studies demonstrated similar outcomes to abdomino-perineal resection. The usual protocol includes:
- Radiotherapy:
- 36 Gy to tumour, peri-rectal, inguinal, external and internal iliac lymph nodes
- 45 Gy to tumour, involved lymph node regions
- 9 Gy / 5 fractions to tumour for T3, T4, and T2 tumours with metastases
- 5.4 Gy / 3# to tumour for T2 N0 tumour
- Concurrent Chemotherapy
- 5-fluorouracil 750-1000 mg/m2 Days 1-4 and Days 29-32
- Mitomycin C 10 mg/m2 Day 1 and Day 29
Multiple series have demonstrated:
- Local control of ~ 75%
- 5-year survival of ~ 80%
- 5-year stoma-free survival of ~70-75%
Early toxicity is frequently a problem with this treatment. Skin reaction is particularly florid and involves the vulva in women. Patients complain of pain passing bowel motions and dysuria. Chemotherapy toxicity is not uncommon and is due to the mitomycin C, usually haemotological (neutropenia, thrombocytopenia). Late toxicities can include loss of function of the anal sphincter (often necessitating stoma) in 5-10% of patients, cosmetic skin changes, bladder or rectal bleeding, impotence or vaginal stenosis.
In general:
- 5FU and MMC are 'gold standard' chemotherapy agents. Cisplatin/5FU have been explored but seem to be slightly less effective
- Trials excluding mitomycin C have shown inferior results for sphincter preservation (75% vs 50%) but higher rates of grade 4 toxicities
- Lower radiotherapy doses are sometimes used but there is no randomised evidence (eg. 30 Gy for early stage disease)
- Split course treatments are associated with higher colostomy rates; two studies have evaluated using split-course treatment to elevate the total radiotherapy dose but this has not been associated with improved outcomes or late toxicity. Split course has the advantage of reducing early toxicities and may be considered (or occur unintentionally) in patients unable to tolerate standard therapy.
Radiotherapy Techniques
There is retrospective data supporting the use of modern radiotherapy techniques (3D conformal and IMRT). Patients appear to suffer less toxicity and require fewer treatment breaks, with similar survival outcomes to previously reported data. Careful contouring of the nodal groups is essential for successful treatment with these modern therapies which would singificantly impact on the time needed to treat these patients.
Follow Up
Patients need a full evaluation 6-8 weeks after therapy to determine their response:
- Patients with complete response need 3-6 monthly examination of the anal canal and inguinal nodes
- Patients with persistent disease need assessments every 4 weeks to ensure ongoign regression
- Patients with progressive disease need salvage surgery
Special Situations
Advanced Disease
Locally advanced disease (T3-T4, N2-3) has been explored in several randomised studies. Novel approaches include using induction chemotherapy (eg. 5-FU + cisplatin); these approaches have not been consistently shown to be superior to the standard treatment described above and are not mainstream. These patients may need a diverting stoma prior to treatment as they are at high risk of obstructive or painful symptoms.
Metastatic anal cancer is associated with poor outcomes (5 year survival < 10%). Chemotherapy with 5-FU and cisplatin is mainstream.
Isolated liver metastasis presents an interesting dilemma. There is significantly less data relating to treament of oligometastases for anal cancer than rectal cancer. There is a suggestion that local treatment of oligometastases may improve survival but randomised data will likely never be available; this should be approached on a case by case basis.
HIV Positive Patients
Anal cancer may occur more frequently in patients with HIV, often in homosexual men who are co-infected with HPV. Before the widespread availability of anti-retroviral medications, these patients were thought to be at higher risk of complications from chemoradiotherapy due to the extensive desquamation that can occur. This has not been seen in more recent studies. Patients who are HIV generally receive identical treatment to HIV negative patients. Patients with severe AIDS that is poorly controlled may suffer increased toxicity; these patients may need to have mitomycin C withheld due to toxicity concerns.
Other Tumours of the Anal Region
Anal Intraepithelial Neoplasia (AIN)
This lesion is similar to CIN of the cervical transitional zone. It is thought to progress to anal cancer, particularly high grade lesions with full thickness dysplasia (AIN 3). Although usually an incidental finding, patients may present with discomfort and the lesions may form plaques or polyps.
Small and localised lesions are effectively treated with topical trichloroacetic acid. Larger localised lesions may be treated with electrocautery. Extensive AIN may not respond to any treatment and should be observed; there seems to be no role for prophylactic chemoradiotherapy or APR.
Adenocarcinoma of the Anal Canal
These tumours are rare and many are thought to be rectal cancers that are infiltrating the anal canal. Treatment of these tumours follows the guidelines for rectal cancer - neoadjuvant chemoradiotherapy with continuous infusional 5-FU followed by APR.
Perianal Squamous Cell Carcinoma
These are skin cancers that arise outside of the anal canal (ie. in the perianal skin). The squamous epithelium of this skin is similar to skin elsewhere, as opposed to the frequently non-keratinised squamous epithelium of the distal anal canal. These tumours are managed as skin cancers (local excision and adjuvant radiotherapy if required).
