Summary
The anus is the canal that connects the lower part of the large intestine (the rectum) to the outside of the body. Anal cancer is fairly rare. Different cancers can develop in different parts of the anus, part of which is inside the body and part of which is outside. Sometimes abnormal changes of the anus are harmless in their early stages but may later develop into cancer. Some anal warts, for example, contain precancerous areas and can develop into cancer. The most common type of anal cancer is squamous cell carcinoma of the anus.
Causes
The disease is more common in people who have anal intercourse and there is an association with human papilloma virus infection as well HIV, although a causative link has not firmly been established. There are many types of human papilloma virus and only a few of these types seem to be linked to the development of anal cancer. Those that are linked to these viruses have a similar prognosis to those that are not.
Long term immunosuppression, eg in those who have had organ transplants, also increases the risk of developing anal cancer
Smoking increases the risk of developing Anal Cancer by between 2- and 5- fold.
The development of anal cancer does not seem to be linked to haemorrhoids (piles), anal fissures or fistulae. The link with inflammatory bowel disease (Crohn’s Disease or Ulcerative Colitis) is controversial.
Incidence
Anal cancer is rare tumour and only 300 new cases arise each year in the UK. It is therefore a less serious health problem than colorectal cancer.
Symptoms & diagnosis: Anal cancer
The symptoms of anal cancer may be:
- Bleeding
- Pain
- Discomfort
- The sensation of a lump
- Itching of the skin around the anus
- Changes in existing anal warts
Many of these symptoms may be caused by benign conditions e.g. haemorrhoids or and anal fissure, so thorough examination is important.
Diagnosis
The diagnosis is confirmed by taking a sample of the lump or suspicious region, and having this examined under a microscope by a specialist. The biopsy may be taken in the outpatient clinic, but usually a full examination of the area is undertaken whilst the patient is under anaesthetic. This allows a much more thorough examination to be done. The biopsy can be taken during this procedure.
Other tests that are done include a CT scan of the chest, abdomen and pelvis, and an MRI scan of the pelvis.
Stages
The ‘stage’ of the cancer defines whether the tumour is localised to the anus or whether it has spread to the local lymph nodes (usually the groin nodes or pelvic nodes) or whether it has spread to other organs. The treating oncologist needs to know the stage to decide the most suitable treatment.
The information needed to decide the stage is gathered from both clinical examination and scanning. An examination under anaesthetic is often done to obtain the most accurate stage.
The stage is usually classified using a system called the ‘TNM Staging System’, where T stands for tumour, N for ‘nodes’ (ie lymph nodes), and M for ‘metastases’ (ie whether other organs are involved). Each letter is followed by a number that defines the extent of the cancer eg T2N1M0.
Treatment & outcomes: Anal cancer
Treatment for anal cancer is dependent on the stage of the disease and on the aim of the treatment. When the disease is localised it is potentially curable.
Treatment options include surgery to remove the anus, or a combination of radiotherapy and chemotherapy given simultaneously (leaving the patient with a colostomy bag). Specialised locally delivered radiotherapy (brachytherapy) has been used for very small anal tumours as well.
The usual treatment that is chosen is combination of chemotherapy and radiotherapy, called chemoradiotherapy. This treatment has a major advantage over surgery in that most patients do not require a colostomy bag permanently. When surgery is performed with the aim of curing anal cancer, the anus itself is removed as well. With chemoradiotherapy, the organ is preserved. Another advantage of using chemo-radiotherapy as the first treatment is that, surgery is still available as a curative treatment if the disease returns in the anus. In a large trail, chemo-radiotherapy was demonstrated to be as effective in curing the disease as surgery.
The radiotherapy is usually given on a daily basis, Monday to Friday, in a specialist department. It will involve lying still on a couch in a treatment room, whilst a treatment machine, gives the radiotherapy. The treatment does not hurt and is invisible. It does not make patients radioactive. Each treatment lasts about fifteen minutes. Often, the bladder is kept full during the treatment to minimise the amount of radiotherapy given to the small bowel.
Before radiotherapy starts, there are a number of sessions that are undertaken to work out how to aim the radiotherapy to the areas that need to be treated. Often the first visit is to make sure the position is correct (sometimes lying on the front), and a specialised CT scan done with the patient in that position. The scans are then worked on by the radiotherapy department, using sophisticated computer software, so as to get the best ‘plan’ for the treatment and optimise the best treatment beam orientation. This can take 2 to 3 weeks to do. After a series of checks, the patient is given another appointment for a ‘dummy run’ of the treatment to make sure everything lines up accurately. The actual treatment then starts shortly afterwards.
The chemotherapy is usually given in the first and last week of the 5 and a half weeks of daily radiotherapy treatment. The chemotherapy may be given as an in-patient and will usually include two of the following anti-cancer drugs: 5-fluorouracil, mitomycin or cis-platin. A trial that looked at whether the continuation of chemotherapy, after the end of radiotherapy, increased the cure rate – came to the conclusion that such extra chemotherapy did not improve on chemoradiotherapy alone. This remains standard of care.
Chemoradiotherapy is a complex treatment and has many side effects. Most side effects disappear a few weeks after the treatment is completed, but some may last many months or be permanent.
The side effects of radiotherapy include:
- Tiredness
- Sore skin, and peeling of the skin near the anal area and in the groins
- Diarrhoea
- Pain around and in the anus
The combination of the diarrhoea and the sore skin around the anus means that a temporary colostomy is occasionally recommended to make these side effects easier to manage.
These effects usually improve in the weeks after the treatment is completed, although the way the bowel works may not return to normal completely.
Side effects that may be long term or permanent include:
- Vaginal narrowing and dryness: this can affect sexual function after treatment. It is important to see a specialist nurse before and during treatment who may advise using a vaginal dilator to minimise the risk of this side effect as much as possible.
- Infertility: this should be discussed with the oncologist if it is an issue.
- All the potential risks and side effects should be discussed by the oncologist.
Side effects of chemotherapy include:
- Tiredness
- nausea and vomiting: this can be reduced by anti-sickness medication given with the chemotherapy
- sore mouth: mouthwashes can be given to help this
- loss of appetite
- a low blood count: if this happens, the body’s defences against infection can be reduced, which in turn means any infection may become more serious.
Having said all this, the chemoradiotherapy saves many hundreds of people the need to have an operation at the end of which they are left with a colostomy for life and most retain a continent and decent functioning anal sphincter.
Outcomes
The outcome of treatment depends on the stage of the disease and the response to treatment, but the majority of those with early disease stand a very good chance of cure. It is quite probable that the presence of HPV (quite apart from its etiological role in the disease) confers some of the radio sensitivity of this disease.
The advantage of the chemo-radiotherapy programme is that it allows the patient to keep the normal anatomy of the rectum and anus; in the majority of cases (where the sphincter has not been destroyed by the cancer) the patient keeps an intact sphincter (and hence remains continent of faeces).
If the disease returns locally after chemoradiotherapy, then surgery may be possible with the aim of cure. In this eventuality, the patient will have removal of the ano(rectum) and be left with a colostomy.
What to do if there is metastatic relapse after the foregoing therapy?
Alternative chemotherapy should be trialled but it is also worthwhile considering other options.
Genomic analysis by next generation sequencing of a new tissue biopsy of by analysis of blood for cell-free DNA (which is often released from the turning-over cancer cells into the bloodstream and can be analysed by NGS to give the mean of the cancer genomics (i.e. not constrained by the genomics of a single site biopsy that may not be representative of the whole cancer). This is will occasionally be useful in directing the oncologist towards an activating oncogene that can be inhibited (the Americans say: ‘Druggable’).
Immunotherapy has an emerging role in metastatic anal cancer and this tumour may carry enough mutations to be sensitive to immunotherapy drugs such as the checkpoint inhibitors: pembrolizumab an nivolumab in particular. Indeed, immunotherapy may well be optimal therapy for the patient with metastatic relapse.
NGS on the tissue biopsy of the metastases or cfDNA will inform the Oncologist as to whether the cancer has mismatch repair (MMR) deficiency (which implies that the cancer is hypermutated and likely to be antigenic enough to respond to immunotherapy).
The expression of PDL1 will also help to predict if immunotherapy will cause a response in this metastatic disease as the PDL1 expression , if high, predicts that cancer cell expression of PDL1 is preventing the immune attack on the cancer and that either a PD1 or PDL1 inhibitor may release the immune attack and cause a remission of the metastatic cancer. Immunotherapy has yet to be proven for this type of cancer.
Outcomes:
The majority of patients with early anal cancer are cured with intact anorectal function (i.e. no incontinence and a fairly normally functioning ano-rectum). For those who later relapse, there is more hope than a decade ago for a durable remission.
Screening:
There is no routine screening programme for this disease which is rare, but it should be noted that those with HIV and HPV are higher risk.
All solid lumps developing in this region should be regarded with suspicion.
Although the majority of anal lesions will be either haemorrhoidal in origin or painful fissures, neither of these should have a solid lump component.
CREDIT: P N Plowman MD, The Oncology Clinic, 20 Harley Street, London W1G 9PH. (Advanced Genomics).