The anus is the external opening farthest from the mouth at the end of the alimentary canal. Composed of skin or squamous cells, it is only one to two inches long and connects to the rectum. The junction of the rectum and the anus is known as the dentate line. The anal canal is lined by an internal sphincter muscle, which opens during defecation. Beneath the skin surrounding the outside of the anus is the external sphincter muscle. Cancer of the anus is much less common than other bowel or colorectal cancers and accounts for only 1 to 2 percent of all cancers of the large bowel and its outlet. The American Cancer Society estimates that 4,650 new cases of anal cancer will occur in the United States in 2007, 1,900 in men and 2,750 in women. However, the rate of anal cancer has steadily been climbing in recent decades, probably related to changes in sexual behavior. The rate of anal cancer is markedly higher in men who have sex with men (MSM) and particularly in people who are immunocompromised, such as those infected with HIV, but in others as well, such as organ transplant recipients.
Anal cancer is highly treatable and often curable, especially in the early stages. The first sign of the cancer is often bleeding, which may be mistaken for hemorrhoids or benign anal disease. Others may report a mass, an ulcer, or pain. But it is also quite common to have no particular symptoms at all; the cancer can be discovered when the doctor or other health care provider carefully examines the inside of the anus, feeling for abnormal lumps or hard areas in patients at risk or experiencing symptoms. Anal cancer may be discovered accidentally when the pathologist routinely examines a specimen from a surgical operation done for apparently benign disease, such as removal of hemorrhoids.
Types The vast majority of all primary cancers of the anus are called squamous cell (epidermoid) carcinomas. These cancers may arise in an area that is visible such as at the anal opening (anal verge) or in the skin around the anus (anal margin), but they most often arise inside the anal canal. In fact, most arise one to two inches internally near the border between the anus and the rectum at the anal transition zone. Squamous cell cancers include a subset of tumors that lack the microscopic features of classic squamous cells. These tumors, known as cloacogenic or basaloid cancers, arise in the anal lining at this transition zone. The biology and prognosis of these tumors appear to be similar to classic epidermoid carcinomas and are currently classified as squamous cell cancers. Well-differentiated tumors have a more favorable prognosis than poorly differentiated tumors.
Other cancer types that may be found in the anus include adenocarcinoma, small cell carcinoma, lymphoma, sarcoma, melanoma, and Paget’s disease of the mucous or sweat glands. Adenocarcinoma of the anal canal behaves like and is treated as rectal cancer.
How It Spreads Anal tumors remain confined to the pelvis throughout the disease course in over 80 percent of patients. As the tumor grows, it can extend directly into adjacent tissues, including the skin and sphincter muscle, or may involve adjacent organs such as the prostate, bladder, and vagina. Tumor cells can spread via the lymph system to lymph nodes in the groin (if the tumor is below the dentate line) or to pelvic lymph nodes (if the tumor is above the dentate line). Less commonly, tumor cells can also travel through the bloodstream (metastasize) to other locations in the body such as the lungs, liver, or bone.
What Causes It Human papillomavirus (HPV) causes the majority of anal cancers. HPV is also known to cause cervical, vaginal, vulvar, and penile cancers. HPV is the most common sexually transmitted infection, and up to 75 percent of sexually active adults have been exposed, but most are completely asymptomatic. Many women appear to clear the HPV infection from the cervix, but when it persists, it can lead to abnormal cellular changes known as dysplasia. Cancer develops only in a small proportion of those infected, and it can take years, generally decades, before cancer develops. Formerly, it was believed that cancers were due to chronic irritation of the anus (fistulas, fissures, and inflamed hemorrhoids). There is evidence for an increased risk of anal cancer in patients who have been treated for anal fistulas, fissures, and abscesses. Chronic inflammation and irritation may allow infection with HPV, which then leads to precancerous changes and to anal cancer.
There are many types of HPV. Types 6 and 11 do not cause cancer, but rather cause warts. Genital warts themselves are not dangerous, but they might indicate exposure to other HPV types, such as 16 and 18, which can cause cancer in some people. In June 2006, the FDA approved a vaccine that protects nearly 100 percent of women against cervical infection and dysplasia due to types 6, 11, 16, and 18. The ability of this vaccine to protect against anal infection and prevent anal cancer is being investigated, but is not known at this time.
Anal and cervical cancers are preceded by dysplasia, the result of persistent infection by the same high-risk types of HPV. Dysplasia simply means the growth or presence of abnormal cells that have the potential to progress to cancer in some persons. Cervical dysplasia can be detected by a cervical Pap smear, in which cells are gently scraped off the surface of the cervix as part of the routine annual pelvic exam. The cells are examined by the pathologist and classified as normal, atypical, low-grade or high-grade squamous intraepithelial lesions, or cancer. Low-grade lesions or mild dysplasia include warts and may often go away without treatment. High-grade dysplasia (HGD) is also known as moderate or severe dysplasia or cervical or anal intraepithelial neoplasia (CIN or AIN) 2 or 3. HGD is considered potentially precancerous. Detecting and removing high-grade CIN has dramatically reduced the incidence of cervical cancer. In parts of the world where women do not have access to cervical Pap smears and treatment, many more women die of cervical cancer than those in countries with good screening programs. Sometimes another term, known as carcinoma in situ, is used to describe CIN 3 or AIN 3; this is not cancer and is the same thing as severe dysplasia. Another term used to describe external or perianal high-grade dysplasia (HGD) is Bowen’s disease.
HGD is a proliferation of abnormal cells infected by HPV that have the potential to progress to cancer in some people. A cancer develops in these vulnerable cells when other genetic changes develop, either serendipitously or as a result of exposure to a noxious agent in the environment, such as tobacco smoke. The lesions consist of abnormal cells, but these cells are not cancer cells and do not invade through the lower membrane that separates the lining cells of the skin or mucous membrane from the muscle and soft tissues underneath. The lesions are often flat and invisible to the naked eye and can be found next to an invasive cancer or within genital warts. When a woman has an abnormal Pap smear, she is referred for colposcopy. Applying vinegar or acetic acid to the cervix makes the lesions appear white so they stand out from the normal tissue and can be detected by using a microscope known as a colposcope. Commonly, a small piece of tissue is removed, which is known as a biopsy. The Pap smear may underestimate the severity of dysplasia present, so the biopsy is the best way to establish a diagnosis. In the same way, the anus can be examined in a procedure known as high-resolution anoscopy (HRA). Far fewer providers are experienced in performing HRA. This procedure was pioneered at the University of California, San Francisco, in the UCSF Anal Neoplasia and Natural History Study.
Anal Pap smears, more appropriately known as anal cytology, have recently been promoted by some as a possible way to screen people at risk for anal cancer. This has yet to become standard practice even for high-risk individuals such as gay men infected with HIV, primarily due to a lack of experienced clinicians and because studies have yet to be performed demonstrating that treatment of anal HGD can prevent anal cancer. There is no treatment for HPV infection, although vaccination at a young age prior to onset of sexual activity may drastically reduce HPV infection and its sequelae.
MSM have a risk for developing anal cancer that is thirty-five-fold higher then expected. Those who are infected with HIV (human immunodeficiency virus), especially those with low immune systems, are at more than twice the risk. Anyone who has anal intercourse may be at slightly higher risk than average for anal cancer, although, by far, most people who develop anal cancer do not report high-risk sexual behavior. HPV is transmitted pretty easily from one person to another and there is likely some degree of self-inoculation. It is thought that HPV probably first infects another part of the genital tract such as the cervix and then migrates to the anus. Thus anal intercourse or other high-risk sexual behavior is not required. In a study from Scandinavia, men whose wives had cervical cancer or cervical HGD had a small but statistically significant increased risk of anal cancer.
Risk Factors
At Significantly Higher Risk
• Anyone infected with the human papillomavirus (HPV), especially the high-risk types such as 16 and 18, or, less commonly, 31, 33, 45, and others, may be at higher risk.
• All HIV-positive persons are felt to be at higher risk. The immunosuppression of HIV may allow the HPV virus to be more active.
• Men who have sex with men are at higher risk through acquisition of HPV through receptive anal intercourse and have a prevalence of anal HPV infection of 60 percent.
• Anal cancer is more common in women over forty and in African-American women.
• Anal margin cancer (cancer involving the tissue encircling the anus) is more common in men.
• There is a possible increased incidence of anal cancer in cigarette smokers.
• The association with a history of chronic anal irritation that was felt for decades to be the primary cause of anal cancer may still be true for some who develop anal cancer. For instance, chronic inflammation and irritation related to fistulas, fissures, and abscesses might allow entry of HPV into the deeper layers of the epithelium. Anal cancer is associated with benign anal disease. Thus, a history of genital warts, also known as condyloma; chlamydia; trichomoniasis; genital herpes; gonorrhea; or anal abscess, fistula, or fissure are all risk factors, but rather than directly causing anal cancer, they suggest that one may have been exposed to HPV.
• Women who have already had an HPV-related problem, such as cervical, vaginal, or vulvar dysplasia or cancer are at higher risk for anal cancer.
• Immunosuppressed individuals such as those with an organ transplant (kidney, liver) and patients who receive chronic immunosuppression or corticosteroids for autoimmune disorders are probably at higher risk in a manner similar to HIV-positive patients.
Screening
Although anal cancer is close to the surface, it is not as easy to detect as one might imagine. A careful anal exam is an important part of a yearly physical. A digital rectal examination and anoscopy should be performed whenever there are rectal symptoms such as pain, bleeding, and itching and hemorrhoidal complaints. A physician with a special interest in anal or rectal disease should examine all patients with hemorrhoids, inflammation, and local anal symptoms. A biopsy should be obtained of any suspicious or persistent lesions in this area.
Given the similarities in this cancer to cervical cancer, anal Pap smears (or anal cytology screening) are proposed as a possible way to screen those without symptoms who may have precancerous lesions. Standards have been established for specimen adequacy. More pathologists, particularly in large urban centers, are becoming experienced at interpreting anal cytology. For the anal Pap test, a moistened Dacron or polyester swab is placed just inside the anus and rotated as it is withdrawn to obtain samples of cells for analysis. Any level of abnormality is considered an indication for referral for high-resolution anoscopy (HRA). In fact, screening is not recommended unless someone experienced in HRA is available to follow up on the results.
A colposcope is a microscope that is used to examine the anal canal and surrounding tissue after applying acetic acid. While there are many doctors in gynecology who are expert in the recognition of cervical dysplasia (found during colposcopy as opposed to high resolution anoscopy), there are few doctors expert in the recognition of anal dysplasia, but more are being trained. Without the use of vinegar or acetic acid to highlight abnormal cells, an inexperienced health care provider may notice nothing unusual in the exam even when severe dysplasia is present. If anal dysplasia is recognized, a biopsy will be taken and examined by a pathologist to confirm the presence of dysplasia, to exclude the presence of an early invasive cancer, and to grade any dysplasia as mild, moderate, or severe.
If moderate or severe dysplasia is confirmed, the area can be ablated in a simple office procedure using infrared coagulation. The IRC2100 infrared coagulator (Redfield Corporation, Rochelle Park, N.J.) has been used extensively since 2002 to treat anal HGD and condyloma. Historically, patients were treated with radical excisions requiring skin grafts and often developed recurrences. Using HRA, destruction of the abnormal lesions can be targeted and the areas most worrisome for cancer can be biopsied. Although anal surgery is often difficult and painful, patients recover within a few weeks. And although recurrences may occur, they can often be managed in the office. In fact, the recovery after office-based infrared coagulation is much easier and there is increasing evidence regarding the effectiveness of infrared coagulation in treating anal HGD. Current techniques have begun to make the prevention of anal cancer a reality, but formal large randomized studies demonstrating the effectiveness of this approach in preventing anal cancer have yet to be performed. Patients who have been diagnosed with anal HGD should be monitored with careful exams every three to four months by clinicians experienced in managing anal dysplasia.
One might wonder if there is a way to test for the presence of the human papillomavirus, particularly the higher-risk HPV types. HPV testing is currently available, but its usefulness in managing anal dysplasia is not clear. In risk groups with a high prevalence of HPV infection such as HIV-positive MSM, it probably is not helpful. However, in patient groups who do not have a high prevalence, but who may be at increased risk, a negative HPV test combined with a negative anal cytology may indicate an individual who does not need to be seen as frequently. The vaccine that has recently been approved for prevention of cervical cancer may help to prevent anal cancer as well, but the studies demonstrating effectiveness will not be completed until 2008 or 2009.
Common Signs and Symptoms
There are often no symptoms of anal cancer in its early stages. But there may be bleeding, discomfort or pressure, pain, itching, or a palpable anal mass. There may also be local pain or pressure that is not relieved by a bowel movement. Small amounts of anal bleeding not associated with anemia are often attributed to hemorrhoids, and thus the recognition of the cancer is often delayed. If the tumor enlarges enough, eventually a change in bowel habits such as constipation or alternating diarrhea and constipation may be noted. In rare cases, a complete obstruction of the bowel might develop.
Diagnosis
Physical Examination
• Digital rectal exam is important to document the size and location of the tumor. An exam with local or general anesthesia may be necessary. Virtually all patients diagnosed with anal cancer have an abnormality that can easily be felt, which makes the digital exam the best way to detect anal cancer.
• A small anal mass, often like hemorrhoids, may be found. Sometimes the mass protrudes and reaches a significant size. The mass is generally firm and can even feel rock hard.
• Physical examination will attempt to determine if there has been local invasion into the muscle sphincter. The exam may reveal firmness or immobility of structures.
• Enlarged lymph nodes in the groin may indicate metastases. This is a finding that suggests very advanced anal cancer and is associated with a poor prognosis.
Blood and Other Tests
• Complete blood count.
• Liver function chemistries (alkaline phosphatase, LDH, AST).
• CEA (carcinoembryonic antigen), elevated in colon and rectal cancers, is normal in anal tumors. There is no comparable blood test that is useful as a tumor marker for anal cancer.
• Tests of kidney function (creatinine).
• An HPV test for the human papillomavirus, even if available, does not change the prognosis or management and thus is not routinely performed.
• Test for hidden blood in the stools.
• Anal Pap smears can be performed any time that anal cancer is suspected, but often do not detect the presence of cancer. If cancer has already been diagnosed with a biopsy, anal cytology does not provide any additional information.
Imaging
• CT and MRI scans of the pelvis to assess local invasion and whether the iliac and groin (inguinal) lymph nodes are involved (30 percent of patients have inguinal metastases).
• Endoanal ultrasound may help assess the size of the tumor, the extent of invasion into the sphincter muscle, and whether lymph nodes surrounding the rectum have been involved. This is a specialized procedure that is becoming more widely used. The lymph nodes in the pelvis need to be evaluated nonetheless and thus the CT or MRI of the pelvis is necessary.
• New data suggests that a positron-emission tomography (PET)/CT scan may be useful for evaluating the tumor and lymph nodes. In this study, sugar that is bound to a radioactive tag is injected and concentrates in tissues that are metabolically more active, such as cancer cells.
• Abdominal CT scan or ultrasound, especially if the liver is enlarged or if liver function tests are abnormal. However, less than 10 percent will have liver metastases at the time of diagnosis.
• Chest X-ray in order to screen for pulmonary metastases.
Anoscopy and Biopsy A biopsy of the abnormal area is mandatory to establish the diagnosis and verify the type of cancer before treatment is begun. If this cannot be done in the office, then an examination under anesthesia may be necessary. The tumor size is best determined by a physical examination rather than a scan.
Staging
The stage of anal cancer describes whether the cancer has remained within the anus, has spread to lymph nodes near the anus, or has spread to other sites, usually within the abdomen or other organs. The stage as defined by the TNM (tumor, node, metastases) classification is important in determining the initial treatment options, prognosis, and the probability of cure.
T represents the size of the tumor and whether it has invaded adjacent organs; involvement of the sphincter muscle without invasion of adjacent organs does not classify the tumor as a T4 or more advanced tumor, nor does invasion of the rectal wall, perianal skin, or subcutaneous tissue.
Tumor size is described in the following manner:
Tx: Tumor size cannot be determined.
T0: No evidence of tumor.
Tis: Carcinoma in situ (no evidence of invasion, a potentially precancerous lesion).
T1: Tumor is less than 3/4 inch (2 cm).
T2: Tumor is greater than than 3/4 inch (2 cm) but less than 2 inches (5 cm).
T3: Tumor is greater than 2 inches (5 cm).
T4: Tumor of any size that invades adjacent organs such as the vagina, urethra, and bladder.
N indicates whether the cancer has spread to any of the nearby lymph nodes and is described in a similar fashion:
Nx: Lymph nodes cannot be assessed.
N0: No involvement of any lymph nodes.
N1: Spread to perirectal lymph nodes (located around the rectum in the pelvis).
N2: Spread to unilateral internal iliac or inguinal lymph nodes (located only on one side of the body [unilateral] either next to the main blood vessel deep in the pelvis [iliac] or in the groin or crease of the leg [inguinal]).
N3: Spread to perirectal and inguinal lymph nodes or to bilateral internal iliac or inguinal lymph nodes (involving both left and right sides of the body).
M indicates whether the cancer has spread to other organs such as the liver, lungs, or bone:
Mx: Spread of the cancer cannot be assessed.
M0: No evidence of spread to distant organs.
M1: Spread to distant organs.
The T, N, and M are combined to determine the stage of the cancer:
Treatment Overview
Surgery, radiotherapy, and chemotherapy have all been used to treat anal cancer. More than thirty years ago, it was first noted that chemotherapy and radiation therapy might work so well that radical and extensive surgery could be avoided. This has since become the standard treatment approach for most patients. A major mechanism of chemotherapy is to sensitize the tissues to the effects of radiation therapy and improve the effect of the radiation. The chemotherapy also has an effect on any cancer cells that might have spread but were still too small to be detected by common imaging tests. Therefore, patients treated with the combination of radiation and chemotherapy generally do better than patients treated with surgery or radiation alone.
The prognosis depends on the size and location of the tumor. The outlook is more favorable if the tumors are small (less than 2 inches [5 cm]) and there is no lymph node involvement or invasion into adjacent organs. The prognosis may be better if the primary tumor is in the anal margin (skin around the anal opening) rather than the anal canal. Primary tumors less than 3/4 inch (2 cm) in size have an even better prognosis, as do tumors that are well differentiated (more mature) rather than undifferentiated or poorly differentiated.
Large studies have shown that chemotherapy added to radiation therapy provides a higher chance of cure than radiation therapy alone. Similarly, when one receives combination chemotherapy (administering two or more drugs) as opposed to single agent chemotherapy, again in combination with radiation, the effect is better. However, there is a fair amount of acute toxicity associated with this therapy. As the intensity of therapy increases, the cure rate increases—but so does the toxicity. The most difficult and common problem is the painful radiation burns of the genital skin and anus. While these generally heal well, patients are occasionally left with a chronic anal injury known as radiation proctitis or an ulcer that never heals. In studies, 6 to 12 percent of patients will require a colostomy (the bowel is diverted through the abdominal wall and empties into a bag) in order to manage the chronic toxicity. Even in the absence of severe injury like this, most subjects will have some mild impairment of anal function or overall quality of life in the years following this treatment, yet patients overwhelmingly prefer this to the idea of losing their anus. The tolerability of the therapy is even less in those who are infected with the human papillomavirus, especially in those with low immune systems such as those with a CD4 lymphocyte count of less than 200, but radiation and chemotherapy remain the standard of care for HIV-positive patients with invasive anal cancer.
A new way of delivering radiation that is becoming increasingly used is known as intensity-modulated radiation therapy (IMRT). This technique uses sophisticated modeling techniques guided by CT scan images of the patient to design a unique treatment regimen for each patient. The theoretical advantage is that a higher dose of radiation can be delivered to the tumor, while the normal tissues surrounding the cancer are spared from the effects of the radiation, therefore minimizing some of the side effects and toxicity.
Prior to the discovery that combined modality therapy was an effective treatment for anal cancer and was able to preserve the function of the anus, the standard of care was a radical operation known as an abdominoperineal resection (APR), with removal of the anus and placement of a colostomy. For patients who do not respond to combined modality therapy or who develop local recurrences, an APR provides a chance for cure in 40 to 50 percent of patients. An APR will result in a loss of anal function, a colostomy, and possibly urinary and/or sexual malfunction. An APR may be performed for those who are not likely to tolerate combined modality therapy such as the elderly, the infirm, or those with advanced HIV infection.
Following complete eradication of the tumor by radiation and chemotherapy, careful follow-up is vital. The lymph nodes in the groin have to be watched carefully, since the most common site of local recurrence is in the pelvis and lymph nodes. If the tumor recurs, salvage surgery may be needed.
Treatment of the less common adenocarcinoma involving the upper portion of the anus (near the rectum) differs from treatment of squamous carcinoma. Treatment recommendations should follow the recommendations for rectal cancer.
Options by Size of Tumor The success of combined modality therapy (CMT) for anal cancer (meaning radiation combined with chemotherapy) depends on the size of the tumor, the degree of local invasion, and the presence or absence of lymph node involvement. Some recommend less intensive treatment for those with smaller tumors because the cure rate can be fairly good without risking the added toxicity. While cure rates in the range of 70 to 90 percent are achievable with radiation therapy alone for very small tumors, the cure rate is even greater when combined modality therapy is used.
• Carcinoma in situ is not invasive cancer and should not be treated with radiation and chemotherapy. The treatment of choice for carcinoma in situ, also known as a high-grade dysplasia (HGD) or severe dysplasia, is excision and fulguration guided by high-resolution anoscopy or ablation using infrared coagulation for small lesions that are not suspicious for invasive cancer.
• Superficially invasive cancers are tumors in which the depth of invasion is very shallow—less than 3 mm. These early cancers may be treated with excision and fulguration in selected patients. Patients must be followed closely and are at high risk for recurrent HGD or precancerous lesions and for recurrent or second cancers. If recurrent cancer cannot easily be removed without compromising sphincter function, then patients should be referred for CMT.
• Small tumors—those that measure less than 3/4 inch (2 cm) and that are not deeply invasive into the sphincter muscle—can be treated with local excision or radiotherapy alone. A risk of local surgery alone is that microscopic involvement of lymph nodes may be present. Left untreated, they might be hard to detect until they are advanced. Removing the groin lymph nodes as a prophylactic measure does not improve these results and often contributes to lymphedema. If radiation alone (without chemotherapy) were used, and if the cancer were to relapse, a major surgery (APR) would then be required. Therefore many doctors recommend combined modality therapy even for small tumors so as to provide the very best treatment up front. If more conservative treatment is to be used, it may be best reserved for those with well-differentiated tumors or tumors in the anal margin and for patients who are likely to return regularly for close follow-up.
• Tumors measuring 3/4 to 2 inches (2 to 5 cm) are best treated by chemotherapy (5-fluorouracil + mitomycin, or 5-FU + cisplatin) plus radiotherapy, leaving surgery for “salvage” therapy. This is the standard of care for anal cancer.
• Tumors larger than 2 inches (5 cm) are treated similarly, using combined modality therapy. Investigational studies are under way with the goal of improving outcome in these patients with a poorer prognosis. Although treatment with chemotherapy prior to starting radiation had seemed successful by adding two cycles of chemotherapy (using 5-FU + cisplatin) before the start of combined therapy, recent data suggest that this is not helpful. There was no improvement using this approach compared with the standard 5-FU + mitomycin combined with radiation therapy.
Options by Lymph Node Status The lymph nodes in the groin (inguinal), pelvis, and perirectal area may become involved by anal cancer.
• Usually the inguinal lymph nodes are treated prophylactically for a portion of the radiation, even for small tumors less than 3/4 inch (2 cm).
• When lymph nodes can be felt, a higher dose of radiation is delivered to the involved lymph nodes along with chemotherapy. Palpable groin node involvement suggests advanced disease, and involvement by cancer can be verified by performing a fine needle aspiration of the lymph node. Patients with involved lymph nodes are less likely to be cured with CMT, but some patients do quite well.
• Surgical removal of groin nodes (lymph node dissection) can be done for palliation of local symptoms.
Treatment by Stage
Stage 0
TNM Tis, N0, M0
Carcinoma in situ—a very early, microscopic, noninvasive cancer that has not spread below the basement membrane, or the bottom layer of anal epithelium. This is also known as severe dysplasia or anal intraepithelial neoplasia 3.
Standard Treatment Surgical removal of the tumor or lesion and treatment of any other areas of HGD.
Five-Year Survival 100 percent
Stage I
TNM T1, N0, M0
A tumor less than 3/4 inch (2 cm) that may invade the sphincter muscle, but with no evidence of spread to lymph nodes or other organs.
Standard Treatment Small tumors of the skin around the anus and of the anal margin are treated by chemotherapy and radiation, with a 95 percent or higher success rate. Occasionally, if the tumor can be removed without compromising the sphincter and getting a margin of normal tissue around the cancer, surgery may be an acceptable option. Patients must be followed very carefully for evidence of recurrence.
Occasionally, radiation therapy is used alone for small lesions, particularly if there is a contraindication to chemotherapy.
Combination chemotherapy with 5-fluorouracil + mitomycin with primary radiation therapy (CMT) is considered the standard of care. CMT is more effective for larger lesions than radiation therapy alone, and patients are less likely to need surgery and a colostomy and more likely to be cured. 5-FU + cisplatin is an alternative chemotherapy combination with radiotherapy, though the role of cisplatin is less established than that of mitomycin. Both combinations seem to be equally effective. There may be less hematologic toxicity using cisplatin. A recent study evaluated the role of giving chemotherapy before the radiation as a form of induction therapy to shrink the tumor, thinking that this might improve the effectiveness of the radiation. This study used 5-FU + cisplatin for two cycles before the radiation and then repeated it with the radiation. This regimen was compared to the standard of 5-FU + mitomycin given with radiation. The induction therapy with 5-FU + cisplatin was not better than just giving 5-FU + mitomycin with the radiation. Patients treated with the induction chemotherapy required more colostomies than those treated with the standard therapy, although the proportion of patients who were alive five years after therapy was similar in both groups.
The standard approach prior to thirty years ago—an abdominoperineal resection (APR), which involves removal of the anus and rectum and requires a colostomy—is now rarely used except for recurrent disease. If there is still tumor in the anal canal after chemotherapy and radiation, then surgical removal may be necessary, ranging from simple excision with sphincter preservation for very small recurrences to a complete APR with colostomy.
Five-Year Survival Over 95 percent
Stage II
TNM T2–3, N0, M0
T2 tumors are larger than 3/4 inch (2 cm) but less than 2 inches (5 cm). T3 tumors are ones that measure more than 2 inches (5 cm), but do not involve adjacent organs.
Standard Treatment Current treatment is combination chemotherapy with 5-FU + mitomycin or 5-FU + cisplatin plus radiation therapy. Depending on how much the tumor shrinks once the minimum radiation dose has been given, which is usually 45 Gy, a boost dose directly to the cancer or involved nodes of 10 to 14.4 Gy may be given. Usually higher doses are used for T3 tumors.
Five-Year Survival 79 percent for T2 and 53 percent for T3
Stage IIIA
TNM T1–3, N1, M0 or T4, N0, M0
The cancer has spread to nearby lymph nodes or has invaded nearby organs such as the vagina, urethra, or bladder (it is often hard to determine Stage IIIA, since many patients clinically appear to be Stage II).
Stage IIIB
TNM T4, N1, M0 or any T, N2–N3, M0
The cancer has spread to the internal iliac and/or groin lymph nodes on one or both sides or has spread to adjacent organs such as the vagina, urethra, and bladder. Metastatic disease to the groin (inguinal) nodes is a poor prognostic sign and markedly reduces the chance for cure, although cure is still possible.
Standard Treatment Current treatment is combination chemotherapy with 5-FU + mitomycin or 5-FU + cisplatin plus radiation therapy. Usually higher doses of radiation are used to treat these tumors. The involved lymph nodes also receive a higher dose of radiation. Once treatment is completed, patients are followed carefully every few months. In some cases, the tumor will continue to shrink after the radiation and chemotherapy have finished. Previously, biopsies were done to document response at the end of treatment, but in some cases there was poor healing after these biopsies. Today, most people only biopsy if the tumor begins to grow or if there is some reason to think that it did not completely respond to the treatment.
Five-Year Survival 20 to 60 percent (Stage IIIA)
Five-Year Survival 20 percent (Stage IIIB)
Investigational for Stages I–III Currently there is a trial enrolling patients with anal cancer in Europe that seeks to compare four different treatment strategies: radiation combined with 5-FU + mitomycin versus 5-FU + cisplatin versus the same two strategies followed by two cycles of maintenance chemotherapy with 5-FU + cisplatin. This study may help to answer the question of which is better: mitomycin or cisplatin. Another multisite study in the United States is evaluating the addition of cetuximab (Erbitux) to cisplatin, 5-FU, and radiation. Cetuximab is a monoclonal antibody directed against a protein known as epidermal growth factor receptor (EGFR) that is found on the surface of some cells. Inhibiting EGFR may help cancer cells to stop growing. This monoclonal antibody has been approved for treatment of colorectal cancer, and some studies have demonstrated improvement in patients with squamous cell cancers of the head and neck. Another trial is recruiting HIV-positive patients with anal cancer and is evaluating cetuximab combined with cisplatin, 5-FU, and radiation.
For locally advanced cancers (large T2, T3, or T4), investigators are comparing radiation combined with traditional 5-FU + mitomycin to the combination of mitomycin + cisplatin given with radiation. Another study is evaluating an oral drug known as capecitabine (Xeloda) that is converted by the body to 5-FU along with a drug related to cisplatin known as oxaliplatin (Eloxatin) combined with radiation in patients with locally advanced anal cancer.
For current information on available clinical trials, please check www.clinicaltrials.gov.
Stage IV
TNM Any T, any N, M1
The cancer has spread to the tailbone (sacrum), to distant lymph nodes within the abdomen far from the original cancer site, or to other organs in the body such as the lungs, liver, and/or bone.
Standard Treatment There is no standard treatment for patients with metastatic anal carcinoma. Relieving the symptoms produced by the primary cancer is the major consideration because this is generally not a curable condition.
Palliation Treatment options include palliative surgery, palliative radiation, and palliative combined chemotherapy and radiation.
• Abdominoperineal resection is sometimes needed to control pain, bleeding, or infection caused by tumor breakdown.
• Radiation has helped control pain and bleeding. The use of radiosensitizing chemotherapy such as 5-FU may improve local control.
• Endoscopic laser treatment has been used to reduce local tumor obstruction and also, sometimes, to control bleeding.
• Combination chemoradiotherapy with 5-FU + mitomycin or 5-FU + cisplatin as well as investigational combinations can be considered.
Five-Year Survival Unusual
Investigational This is an uncommon disease and one for which the initial therapy is fairly successful, thus there are few trials looking at new agents specifically for this disease. Investigational agents that are being tested for advanced cancer are probably one’s best choice for experimental therapy.
Treatment Follow-Up
Careful follow-up is essential. This includes a history and physical examination every two to three months for three years after treatment, then every three to six months for the next three to five years.
• A digital rectal exam to feel for evidence of the tumor returning is the most important part of the exam. A recurrence of the cancer in the same location is known as a local relapse. The majority of recurrences occur within the first two years. An abdominoperineal resection (APR) or removal of the anus may cure about half of patients.
• Careful observation for signs of enlarged inguinal lymph nodes.
• Chest X-rays and liver blood tests (alkaline phosphatase, SGOT) at intermittent follow-up visits. This is less important, as there is little benefit to early recognition of metastatic disease.
• CT scans of the abdomen and pelvis are often performed every six months for the first five years, particularly in patients with T3 or T4 tumors.
Recurrent Cancer
There are two reasons for aggressive treatment of a tumor that recurs after nonsurgical therapy: cure and palliation. Repeat staging studies to determine the extent of the cancer are required to help define the expectations of treatment. Cure is the goal whenever possible, but this is in general limited to situations when the recurrent tumor is amenable to surgical removal. In part, this is because resistance to chemotherapy and radiation therapy may now be present. Occasionally, but not very often, radiation therapy can be delivered to a previously treated area. If one has previously received 5-FU or 5-FU + mitomycin, then 5-FU + cisplatin can be tried along with a small boost of radiation therapy whenever possible. This may be successful enough to spare surgery in some cases. However, more often an APR is required. Even if distant metastatic disease is present, the same approach may be used to palliate symptoms related to recurrent tumor within the pelvis. If the tumor is not removable, then a variety of approaches may be considered, but none offer long-term control. Options may include endoscopic laser treatments, hyperthermia, radiation implants, the addition of various chemotherapy drugs, and intraoperative radiation therapy combined with an attempt at surgical resection.
The Most Important Questions You Can Ask
• Are we certain that I have anal cancer? Is it a squamous cell cancer?
• How should the anal cancer be further evaluated?
• What is the stage of my cancer and how does it affect my prognosis?
• For women, are there any signs of other HPV-related lesions in the cervix, vagina, or vulva?
• What are the side effects of radiotherapy and of chemotherapy?
• Is intensity-modulated radiation therapy (IMRT) appropriate for my cancer?
• Is there a clinical trial that I should consider?
• What new advances in therapy are being used to reduce the need for a colostomy?
• How will this treatment affect my long-term quality of life and sexuality?
Aucun commentaire:
Enregistrer un commentaire