Anal Cancer

Anal cancer

What every physician needs to know:

1. Anal cancer is a rare malignancy with approximately 5,300 new cases diagnosed annually in the United States.

2. As a result of carefully conducted epidemiologic and clinical studies, it is now established that anal cancer is closely associated with human papillomavirus (HPV) infection.

3. The cure of anal cancer is possible in the majority of patients with preservation of the anal sphincter.

4. This malignancy has been historically treated by abdominoperineal resection, with associated high rates of morbidity and local recurrence. Pioneering work by Nigro (a surgeon) led to the discovery that radiation therapy combined with the drugs 5-fluorouracil (5-FU) and mitomycin resulted in high rates of local control, disease-free, colostomy-free and overall survival without surgical intervention.

5. Subsequent randomized trials (Table I) from Europe and the United States have shown the superiority of the combination of radiation therapy, 5-FU and mitomycin over a) radiation therapy alone, b) radiation therapy with 5-FU only and c) a neoadjuvant approach of cisplatin or 5-FU alone followed by concurrent radiation, cisplatin and 5-FU (discussed below).

Table I.

6. Recent advances in anal cancer therapy include the integration of PET scanning into staging, radiation treatment planning and disease monitoring, as well as the use of intensity modulated radiation therapy (IMRT). Ongoing studies are evaluating the use of capecitabine, oxaliplatin and anti-epidermal growth factor receptor agents with radiation therapy in this malignancy.

Are you sure your patient has anal cancer? What should you expect to find?

Rectal bleeding is the most common initial symptom of anal cancer, occurring in about 45% of patients. Anorectal pain or the sensation of a rectal mass is present in approximately 30%, while 20% have no tumor-related symptoms. Bleeding from a mass at, or just above, the anal sphincter may be falsely attributed to hemorrhoids and may delay the diagnosis.

A typical appearing anal cancer is illustrated in Figure 1. These masses are generally exophytic, indurated and situated near/overlapping the anal verge, often involving the anal canal superiorly and/ or perianal skin inferiorly. More advanced lesions may be ulcerated with raised edges. Some tumors are located exclusively within the anal canal and others on the perianal skin outside of the anal canal.

Figure 1.

Beware of other conditions that can mimic anal cancer:

Among patients with anal squamous cell carcinoma (SCC), a history of anorectal condyloma is present in about 50% of homosexual men and less than 30% of women and heterosexual men; these values are much greater than in normal controls (1-2%). Tumors of the perianal skin, especially Bowen’s disease or Paget’s disease, may present with pruritus ani, a bleeding erythematous or eczematous plaque.

Which individuals are most at risk for developing anal cancer:

The female gender, individuals with cervical/vulvar/vaginal dysplasia or cancer, infection with HPV, lifetime number of sexual partners, genital warts, cigarette smoking, receptive anal intercourse, immunodeficiency associated with transplantation and infection with human immunodeficiency virus (HIV) have all been associated with this malignancy.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, Ct/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Clinical staging for anal canal cancers consists of:

• physical examination

• biopsy of the primary tumor

• colonoscopy

• palpation of the groin with biopsy of suspicious lymph nodes

• CT of the chest

• CT or MRI of the abdomen and pelvis

• PET scan

• For women, a gynecologic examination should be performed to assess potential vaginal involvement, including screening for cervical cancer.

The sensitivity of physical examination and CT/MRI is suboptimal to detect nodal metastases, many of which are equal to or less than 5mm – below the limit of detection. Adding a PET-CT scan to the staging workup improves the selection of patients who need higher dose radiation therapy to the groin by identifying nodes that would be included in the radiation field. Additionally, HIV testing is recommended in the setting of risk factors for such, and CD4 levels evaluated in HIV-positive patients.

Staging

TNM and group staging of anal cancer are listed in Table II.

What should the initial definitive therapy for anal cancer be?

Radiation therapy

1. The standard therapy for anal cancer is radiation therapy combined with concurrent 5-FU and mitomycin. There is substantial variability in specific regimens. The original Nigro regimen included chemotherapy combined in week 1 and week 5 with radiation therapy:

• 5-FU 1000mg/m²;/day continuous IV infusion days 1-4 and 29-32.

• Mitomycin 10mg/m²; IV days 1 and 29.

2. Typical toxicities during treatment include skin reactions in treated regions of the pelvis, diarrhea, urinary frequency, neutropenia and thrombocytopenia. These are usually self limiting but can be severe. Unusual toxicities of mitoycin C include hemolytic uremic syndrome, interstitial pulmonary fibrosis, and protracted bone marrow suppression. Potential adverse effects associated with this combined modality therapy include soft tissue necrosis requiring surgical intervention, pelvic bone fractures, sexual dysfunction, and altered bowel function.

3. Overall survival is approximately 60% and is dependent on T and N stage.

4. In sum, combined modality therapy with radiation therapy, 5-FU and mitomycin results in long-term disease-free survival and sphincter preservation in the majority of patients with anal cancer and superior outcomes relative to radiation therapy alone or radiation therapy combined with 5-FU only, albeit at the expense of higher treatment-related morbidity.

What other therapies are helpful for reducing complications?

IMRT

1. Recent clinical series of IMRT-based therapy of anal cancer have reported a significant reduction in acute treatment-related toxicity (primarily bowel and skin related) and similar disease-related outcomes versus historical controls using 2-D and 3-D planning (Figure 2).

Figure 2.

The Radiation Therapy Oncology Group (RTOG) recently completed a prospective phase II study (RTOG 0529) combining 5-FU, mitomycin and IMRT-based radiotherapy. The primary goal of this study was determination of the feasibility of this approach in a cooperative group setting, as well as determination of treatment related toxicity and preliminary disease-related outcomes in these patients.

In a preliminary report, patients were analyzed, comparing toxicity outcomes to patients treated in RTOG 9811 (described above) where conventional radiation planning was used. Rates equal to, and more than, grade 3 dermatologic toxicity were superior in the IMRT study (20% versus 47%, p<0.0001), as were rates of equal to, and more than, grade 3 GI and genitourinary toxicity (22% versus 36%, p=0.014). A recent update of this study showed this approach also yielded similar two-year disease-related outcomes compared to that of RTOG 9811.

2. One of the most challenging aspects of treating anal cancer patients with IMRT is the accurate definition of target volumes. With IMRT, there are very precise and conformal high-dose regions enveloping the tumor with a steep dose gradient. If a target/desired treatment volumes are not accurately defined, there is the real potential for radiation underdosing of disease and resultant clinical failure.

Knowledge of patterns of failure and routes of spread are paramount. Along these lines, real-time quality assurance was performed in RTOG 0529, and a secondary endpoint was whether or not IMRT could be performed in a broader and multi-institutional setting. After the initial QA was performed, initial radiation contours needed to be modified in 79% of cases, thus illustrating the challenge of implementing this new and complex planning technique in a cooperative group setting and importance of knowledge of target design using these advanced technologies.

What should you tell the patient and the family about prognosis?

The main prognostic factors are tumor diameter and nodal status. In a cohort study of 19,195 patients with squamous cell anal cancer who were reported to the National Cancer Database between 1985 and 2000, five-year overall survival rates, stratified according to AJCC stage were as follows:

• Stage I (tumors 2cm or less in greatest diameter without nodal involvement) – 70%

• Stage II (tumors greater than 2cm in diameter without invasion of adjacent structures or nodal involvement) – 59%

• Stage III (tumors with invasion of adjoining structures and/or nodal involvement) – 41%

• Stage IV (tumors with metastases) – 19%

Recent analysis of the RTOG 9811 trial demonstrated tumor size and nodal involvement to correlate highly with survival. Patients with a tumor diameter of 5cm, or less, and no nodal involvement achieved a 3-year survival of 81%, 5cm, and above, and no nodal involvement 73%, 5cm, or less, and involved nodes 65%, and 5cm, and above, and nodal involvement 48%.

Follow-up surveillance and therapy/management of recurrences.

1. Following primary treatment, assessment of response is typically performed at six to eight weeks following the completion of therapy. However, as noted above, there is controversy regarding the need for early biopsy if the physical examination is negative. Squamous cell regress slowly and generally continue to decrease in size for 3 to 12 weeks following therapy. We do not recommend biopsy unless there is suspicion of persistent or progressive disease. If there is no residual disease, patients are re-examined every 6 weeks.

2. There are no prospective trials to guide the post-treatment surveillance strategy for patients treated for anal cancer. For patients who have a complete remission from initial chemoradiotherapy, expert guidelines suggest the following every 3 to months for five years:

• Digital rectal examination

• Anoscopy

• Inguinal node palpation

If initially a T3-4 disease or inguinal node-positive, or for those with persistent disease at the initial post-treatment biopsy who regress on serial examinations, consider imaging of the chest/abdomen and pelvis annually for three years.

3. If there is progression or persisting disease at 12 weeks after completion of combined modality therapy, abdominoperinal resection (APR) is the treatment of choice. APR entails removal of the anus, rectum, a segment of the sigmoid colon and regional lymph nodes through incisions in the abdomen and perineum. The end of the remaining sigmoid colon is brought through a permanent colostomy in the abdominal wall.

In the UKCCCR (ACT I) trial, 29 patients with a less than a 50% clinical response to chemoradiotherapy received a salvage APR. Twenty-four (83%) were rendered disease-free, 10 of whom (42%) eventually developed locoregional recurrence.

4. Although local recurrences are successfully salvaged with surgery in many cases, locally recurrent anal SCC can be a difficult clinical problem that is associated with profound morbidity and long-term disease control in about 30-40% of cases. In one series of 185 consecutive patients with anal cancer treated with either RT alone or chemoradiotherapy, 42 developed local failure requiring salvage therapy. Twenty-six patients (62%) underwent potentially curative surgery, including 23 APRs and 3 local excisions. The five-year rates of overall survival, secondary local control, and locoregional control rates were 45, 53, and 43%, respectively.

5. For patients who undergo APR for biopsy-proven persistent or recurrent disease, recommendations include inguinal node palpation every 3 to 6 months for 5 years, and annual radiographic imaging of the chest/abdomen/pelvis for 3 years.

6. The relative efficacy of nonsurgical salvage in patients with persistent disease is not known. At least some of these patients may be successfully salvaged with further sphincter-sparing therapy. As an example, in the initial RTOG study, 22 patients had persistent disease following primary chemoradiotherapy with salvage 5-FU, cisplatin, and RT (9-Gy boost). 12 (55%) were rendered disease-free after salvage therapy; among these patients, 4 required subsequent APR and are free of disease, 4 died (3 with recurrent disease), and 4 remain disease free.

Of the 10 patients who had unsuccessful non-operative salvage therapy, 9 underwent APR. After four years, 3 were alive without disease and 7 had died, 6 with recurrent disease. However, the role of ‘salvage’ chemoradiotherapy in this situation remains unclear given that some patients may have been rendered disease-free simply by allowing further disease regression.

7. The liver is the most frequent site of distant metastases, followed by lung and extrapelvic lymph nodes. However, the development of distant metastases is infrequent, overall, in patients with SCC of the anal canal. In the UKCCCR and EORTC trials described above, for example, distant metastases developed following combined modality therapy in 10% and 17%, respectively.

8. The only widely published active regimen for treatment for metastatic disease is cisplatin plus 5-FU.

• Cisplatin 100 mg/m²; day 1, plus 5-FU 1000 mg/m²;/day days 1-5 every 4 weeks.

The role of other combination regimens such as mitomycin/doxorubicin/cisplatin followed by bleomycin and CCNU is uncertain, particularly for salvage of patients who have received prior chemotherapy.

9. Single case reports and small series describe activity for single agent carboplatin, doxorubicin, irinotecan alone, and cetuximab with or without irinotecan (in patients whose tumors do not have mutated K-ras).

Pathophysiology

1. HPV infection is the most commonly diagnosed sexually transmitted disease in the United States and provides at least part of the link between sexual activity and anal cancer. A close association exists between infection by oncogenic HPV and many premalignant and malignant lesions of the genital tract, anus, and rectum. While a number of HPV types can be found in the anogenital tract, only a few have been associated with cancer.

2. HPV DNA has been isolated from 46 to 100% of in situ and invasive SCCs of the anus, and epidemiologic studies have shown that up to 93% of anal SCCs are associated with HPV infection. Women are more likely to have HPV-associated anal cancer than men.

3. The spectrum of HPV types in the anal canal is similar to that described in the cervix and is associated with the same “risk” phenotypes. As in cervical cancer, HPV 16 is the most frequently isolated type in anal malignancies and its presence predicts for preinvasive as well as invasive cancer. In contrast, low grade in situ lesions frequently are associated with other HPV subtypes, including HPV 18, 31, 33 and 35.

4. The premalignant condition of cervical intraepithelial neoplasia associated with HPV infection (CIN or squamous intraepithelial lesions) also occurs with HPV infections involving the anus (termed anal intraepithelial neoplasia, AIN, also known as anal squamous intraepithelial lesions, ASIL). As i/n CIN, AIN can be morphologically low grade or high grade.

5. HPV infection in the anal canal and perianal region may be subclinical or clinically apparent as condylomata. AIN, particularly high grade AIN, is considered to be the precursor of anal cancer. Progression of AIN to invasive anal SCC is related to many factors, including HIV seropositivity, a lower CD4 count, the type of HPV infection, and higher levels of DNA of high-risk HPV types in the anal canal. It is presumed that HIV seropositivity places patients at higher risk of developing anal cancer, but not all studies have demonstrated this to date.

6. The incidence of HPV infection in men who have sex with men (MSM), a group at high risk for both AIN and invasive anal cancer, is independent of the presence of HIV infection. As an example, in one study of MSM, 29 individual HPV types and 10 HPV groups were identified within the anal canal, both in men with and without accompanying HIV infection.

7. A substantial minority of anal cancers are not associated with HPV infection. No difference has been noted between HPV-positive and HPV-negative tumors in regards to patient age, the presence of adjacent dysplasia, ductal differentiation, or prognosis.

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