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Malignancy – Anal Cancer

Anal cancer

Introduction

Anal cancer is rare in the general U.S. population, but it is the fourth most common cancer in people living with HIV/AIDS (PLWHA) (incidence 0.45/1000 person-years), following non-Hodgkin’s lymphoma, Kaposi’s sarcoma and lung cancer1. Most anal carcinomas are caused by human papillomavirus (HPV), with the vast majority linked to oncogenic HPV types 16 and 18. An analysis of 13 cohort studies from the USA and Canada showed that anal cancer rates were substantially higher for HIV-infected men who have sex with men (MSM), other men and women than for HIV-uninfected individuals, suggesting a need for universal prevention efforts2. Anal cancer rates increased early in the antiretroviral therapy era and then plateaued. HIV-infected MSM experienced the greatest risk for anal cancer with incidence rates higher than 80 times as high as HIV-uninfected individuals3.

HIV-infected patients with anal cancer have lower median nadir CD4 cell count at NADC diagnosis, and a higher percentage have previously had an ADC (AIDS-defining cancer). The majority of anal cancers are localized (60.8%). Risk factors for poorer survival after anal cancer are a previous NADC, HCV co-infection and disseminated cancer at time of diagnosis. They have cumulative mortality estimates of 15% and 30% at 1 and 3 years, respectively4.

 

Signs and Symptoms

Approximately 45% of patients with anal carcinoma present with rectal bleeding, while approximately 30% present with either pain or the sensation of a rectal mass5. It can appear incontinence if the anal sphincters are affected. Some patients are asymptomatic. Many comparative series have shown that people living with HIV who develop anal cancer are younger than HIV negative individuals with anal cancer. However most comparisons suggest that there is no difference in tumour stage at presentation6.

 

Diagnostic Tools

It is recommended a thorough evaluation, including a careful digital rectal examination (DRE), an anoscopic examination, and palpation of the inguinal lymph nodes, with FNA and/or excisional biopsy of nodes found to be enlarged by even clinical or radiologic examination. Evaluation of pelvic lymph nodes by CT or MRI is also recommended. PET/CT scanning has been reported to be useful in the evaluation of pelvic nodes but it cannot be a replacement for diagnostic CT. The routine use of PET/CT scan for staging has not been validated. A CT scan of the abdomen is also recommended to assess possible disease dissemination. Chest CT scan is performed to evaluate for pulmonary metastasis. Gynecologic exam, including cervical cancer screening, is suggested for female patients due to the association of anal cancer and HPV7. The American Joint Committee on Cancer (AJCC) TNM (tumour, node and metastasis) staging is used for anal cancer. The TNM descriptions can be grouped together into a set of anatomic stages/prognostic groups, from Stage 0 to Stage IV as shown in NCCN Guidelines for anal cancer, page 10, version1.20147.

 

Treatment Overview

The management of anal cancer in HIV patients requires a multidisciplinary team (MDT) approach involving oncologists, HIV physicians, surgeons, radiologists, histopathologists and palliative care specialists.

The first-line of treatment for localized anal cancer is8:

  • 5-fluorouracil (5-FU continuous infusion days 1 and 4 and 29-32) and mitomycin C (IV bolus days 1 and 29) chemotherapy.
  • Concurrent radiotherapy to the pelvis.

The first line of treatment for metastatic cancer is9:

  • 5-fluorouracil (5-FU continuous infusion days 1-5) and Cisplatin (day 2).
  • Repeat every 4 weeks.

Management of locally progressive or recurrent anal carcinoma7:

  • Rates of locoregional failure of 10 to 30% have been reported.
  • Patients with biopsy-proven locally progressive disease are candidates for radical salvage surgery with an abdominoperineal resection (APR) and colostomy.

There is consensus now that this chemoradiotherapy (CRT) regime can be safely used for HIV patients and that outcomes are similar. All people living with HIV who are to be treated with CRT should start HAART and opportunistic infection prophylaxis6. The 5-year overall survival has risen from 38% in the pre-HAART era to 68% in modern times10.

 

Screening and Prevention

MSM, women with a history of receptive anal intercourse or abnormal cervical Pap test results, and all HIV-infected persons with genital warts should have anal Pap tests (weak recommendation, moderate quality evidence). HPV vaccination (with a quadrivalent HPV vaccine) is recommended for all females aged 9–26 years and all males aged 9–21 years. Males aged 22–26 years should also be vaccinated if not vaccinated at younger ages (strong recommendation, high quality evidence)11.

If anal cytologic screening (ie, anal Pap smears) is performed and indicates
abnormal findings, then high-resolution anoscopy (HRA) should be performed with biopsy of abnormal areas and appropriate therapy based on biopsy results 12-15.

The anal cancer screening interval is not well established but it is recommended to be performed each 1-3 years16.


Drug-Drug Interactions17

5FU and NRTI: nucleoside/nucleotide analogues may inhibit 5FU metabolism, leading to increased fluorouracil toxicity. The clinical relevance of this interaction is unknown.

5-FU and brivudin: brivudin enhances 5-FU toxicity. Wait for 4 weeks for use 5-FU after brivudin treatment.

Cisplatin and dolutegravir: in vitro data indicate that dolutegravir is a moderate inhibitor of cisplatin renal elimination so it is recommended to monitoring for cisplatin related side effects.

Cisplatin and cobicistat: in vitro data indicate that cobicistat is a moderate inhibitor of cisplatin renal elimination so it is recommended to monitoring for cisplatin related side effects.

Cisplatin and tenofovir: coadministration may increase the risk of nephrotoxicity (closely monitor renal function).

Cisplatin and fenitoin: cisplatin decreases fenitoin plasma concentrations.

 

When to Refer18

In patients aged 40 years and older, reporting rectal bleeding with a change of bowel habit towards looser stools and/or increased stool frequency persisting for 6 weeks or more, an urgent referral should be made.

In patients aged 60 years and older, with rectal bleeding persisting for 6 weeks or more without a change in bowel habit and without anal symptoms, an urgent referral should be made.

In patients aged 60 years and older, with a change in bowel habit to looser stools and/or more frequent stools persisting for 6 weeks or more without rectal bleeding, an urgent referral should be made.

In patients presenting with a palpable rectal mass (intraluminal and not pelvic), an urgent referral should be made, irrespective of age.

 

References

  1. Palella FJ Jr, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr 2006; 43:27–34.
  2. Mania D. and Aboulafia DM. Screening guidelines for non-AIDS defining cancers in HIV-infected individuals. Curr Opin Oncol. 2013 Sep;25(5):518-525.
  3. Silverberg MJ, Lau B, Justice AC, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America. Clin Infect Dis 2012; 54:1026–1034.
  4. Signe W Worm, Mark Bower, Peter Reiss, Fabrice Bonnet, Matthew Law, Gerd Fätkenheuer, Antonella d’Arminio Monforte, Donald I Abrams, Andrew Grulich, Eric Fontas, Ole Kirk, Hansjakob Furrer,Stephane De Wit, Andrew Phillips, Jens D Lundgren, Caroline A Sabin and for the D:A:D Study Group. Non-AIDS defining cancers in the D:A:D Study - time trends and predictors of survival: a cohort study. BMC Infectious Diseases 2013, 13:471.
  5. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000 Mar 16;342(11):792-800.
  6. British HIV Association guidelines for HIV-associated malignancies 2013. Version 1. 25 July 2013.
  7. NCCN Clinical Practice Guidelines in Oncology. Anal Carcinoma. Version 1.2014.
  8. Ajani JA, Winter KA, Gunderson LL, Pedersen J, Benson AB 3rd, Thomas CR Jr, Mayer RJ, Haddock MG, Rich TA, Willett C. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008 Apr 23;299(16):1914-1921.
  9. Faivre C, Rougier P, Ducreux M, Mitry E, Lusinchi A, Lasser P, Elias D, Eschwege F. 5-fluorouracile and cisplatinum combination chemotherapy for metastatic squamous-cell anal cancer. Bull Cancer. 1999 Oct;86(10):861-865.
  10. Alfa-Wali M, Allen-Mersh T, Antoniou A et al. Chemoradiotherapy for anal cancer in HIV patients causes prolonged CD4 cell count suppression. Ann Oncol 2012; 23: 141-147.
  11. Primary Care Guidelines for the Management of Persons Infected With HIV: 2013 Update by the HIV Medicine Association of the Infectious Diseases Society of America. November 2013.
  12. US Department of Veteran Affairs. Anal dysplasia, 2011. Accessed 15 September 2013.
  13. New York State Department of Health AIDS Institute. Anal dysplasia and cancer, 2007.
  14. AIDSinfo. Guidelines for Prevention and Treatment of Opportunistic iInfections in HIV-infected Adults and Adolescents, 2013
  15. New York State Department of Health AIDS Institute. Mental health care for people with HIV infection: clinical guidelines for the primary care practitioner
  16. European AIDS Clinical Society (EACS) Guidelines. Version 7.0. October 2013.
  17. Drug Interactions. University of Liverpool. Updated October 2013. 
  18. NHS National Institute for Health and Clinical Excellence. Referral Guidelines for suspected cancer. Clinical Guideline 27.