12

Anal Cancer
DAVID P. RYAN, MD CHRISTOPHER G. WILLETT, MD

Kanker anal merupakan 1,5% dari keseluruhan kanker digestive. Di amerika ada 3300 kasus baru yang diawasi pada tahun 1999. Patofisiologi dan pengobatan kanker anal selalu berkembang. Tiga puluh tahun yang lalu, kanker anal dipercaya sebagai akibat dari inflamasi kronik local di area perianal dan diobati dengan abdominoperineal resection. Dari hasil penelitian yang ditemukan dengan mempelajari epidemiologi dan klinis, kita sekarang mengetahui pertumbuhan kanker anal berhubungan dengan infeksi human papillomavirus(HPV) dan pasien dengan kanker anal dapat diobati dengan mengistirahatkan sphincter ani pada kebanyakan pasien. ANATOMY AND HISTOLOGY The anus can be divided into the mucosa-lined anal canal and the epidermis-lined anal margin. The proximal end of the anal canal begins anatomically at the junction of the puborectalis portion of the levator ani muscle with the external anal sphincter and extends to the anal verge over approximately 4 cm (Figure 121). The anal canal is divided by the dentate line, a macroscopic landmark overlying the transition from glandular to squamous mucosa that is often referred to as the transitional zone. The anal margin begins approximately at the anal verge and represents the transition from the squamous mucosa to the epidermis-lined perianal skin. In part due to the lack of an easily identifiable landmark between the rectum and the anus and in part due to the widely variable histologic appearance of the transitional zone, there is much confusion regarding the pathologic classification of tumors arising in this area. In some people, abrupt transition from rectal glandular mucosa to anal squamous mucosa is present. In others, an intervening segment of junctional, basaloid, or so-called cloacogenic mucosa is present. Cloacogenic mucosa referred to areas consisting of pseudostratified epithelium with cuboidal or polygonal surface cells that closely resembles urothelium (Figure 122). Basaloid features are identified in approximately 25 percent of squamous cell cancers5 and should be distinguished from basal cell carcinomas of the anal margin, which behave biologically as skin cancers. The terms junctional, basaloid, and cloacogenic have

been abandoned and are referred to now as non-keratinizing squamous cell carcinomas. Tumors arising within the anal canal distal to the dentate line usually lack these features and are known as keratinizing squamous cell carcinomas (Figures 123 and 124; Table 121). Since the transitional zone can vary widely among individual patients, the critical distinction between a rectal cancer and an anal cancer depends upon the pathologic classification and not the judgment of the surgeon. Adenocarcinomas arising in the transitional zone have the same natural history as other rectal adenocarcinomas and should be treated accordingly. Squamous cell carcinomas arising in the transitional zone (Figure 125) may vary morphologically but there are no discernible differences in biology, natural history, and treatment outcome among subtypes.6,7 The anal margin extends from the anal verge to the perianal skin. Distinguishing between tumors of the anal canal and anal margin can be very difficult

EPIDEMIOLOGY Pada awalnya, kanker ani dipercaya terbentuk di area yang mengalami iritasi kronik yang berhubungan dengan penyakit anus yang jinak seperti hemoroid, fisura, dan fistula. Lebih lanjut, laporan kasus dari pertumbuhan kanker anus pada pasien dengan inflammatory bowel disease memberi anggapan bahwa kanker anus memiliki hubungan yang sama seperti hubungan antara inflammatory bowel disease dan colorectal neoplasia. Anal Cancer and Sexual Activity Penelitian kasus terbaru menunjukan pasien dengan anogenital condylomata beresiko tinggi mengalami pertumbuhan kanker anus, sedangkan hemorrhoid, fistula, dan fisura hanya sedikit berpengaruh pada pertumbuhan kanker anus. Terlebih lagi, Frisch dan koleganya mendapatkan daftar dari RS Danish dengan daftar kanker dan hasilnya tidak ada dari 651 pasien dengan crohn disease atau 506 pasien dengan ulcerative colitis dari sekitar 68.549 pasien terdapat pertumbuhan kanker anus. Disusul oleh laporan bahwa terdapat peningkatan insidensi kanker anus pada kaum homoseksual. Daling dan koleganya melaporkan dari hasil rata-rata populasi, penelitian kasus kanker anus yang dilakukan antara tahun 1978 dan 1985 dengan menggunakan pasien dengan kanker colon di area geografik yang sama sebagai control. Wanita dengan kanker anus lebih menyerupai control yang memiliki riwayat penyakit seksual(relative risk atau RR = 32.5), herpes simplex (RR = 4.1) chlamydia trachomaou (RR = 2.3) sedangkan pria dengan kanker anus menyerupai control pada org yang belum pernah menikah(RR = 8.6) kaum homoseksual aktif (RR = 50), pasangan yang melakukan aktifitas anal seksual (RR = 30), dan yang memiliki penyakit genital (RR = 27) atau gonorrhea (RR = 17.2). Mereka menemukan bahwa AIDS sangat berpengaruh pada stage awal Hasil studi mengonfirmasi adanya hubungan antara kanker anus dengan analseksual pada pria. Untuk mendapatkan bukti yang lebih baik dan akurat mengenai hubungan antara aktifitas seksual dengan dengan kanker anus pada heteroseksual pria dan wanita, Frisch dan koleganya mengadakan penelitian kasus dari 417 pasien dengan kanker anus dibandingkan dengan 534 pasien dengan adenocarcinoma rectum dan 554 control yang normal. Pada wanita, analisis multivariatif menunjukan resiko relative yang terbaik dari kanker anus terjadi pada wanita dengan 10 dan atau lebih partner seksual(RR = 4.5); riwayat kelainan anus (RR = 11.7), kelainan genital (RR = 4.6), gonorrhea (RR = 3.3), atau cervical dysplasia(RR = 2.3); dan wanita yang sedang menjalani test HIV (RR = 1.7) atau yang memiliki partner sexual dengan penyakit menular seksual(RR = 2.4). dari 321 wanita dengan kanker anus, 10 % wanita yang melakukan aktifitas anal seksual sebelum umur 30 tahun dan 4 percent wanita dengan paling sedikit dua partner. Wanita tersebut memiliki peningkatan resiko yang signifikan dari kanker anus pada analisis multivariate. Pada pria heteroseksual, analisis multivariate menampakan peningkatan resiko yang signifikan dari kanker anus dengan 10 dan atau lebih seksual partner (RR = 2.5) atau riwayat kutil anus (RR = 4.9) atau sifilis/hepatitis (RR = 4.0). disitu ditemukan bahwa kanker anus telah menjadi penyakit menular seksual. Studi tersebut telah memberi banyak bantuan untuk memastikan hubungan aktifitas seksual dengan pertumbuhan kanker anus dan dalam laporan menunjukan hubungan yang kuat antara kanker serviks dan kanker anus pada wanita. Penelitian dari Danish Cancer Registry menunjukan kemungkinan untuk pertumbuhan kanker anus atau vulva setelah diagnosis kanker serviks lebih banyak dari kanker gaster dan colon. Di masa mendatang, pasien dengan kanker anus sangat mungkin memiliki kanker vulvar, vaginal, dan serviks sebelumnya.

Rabkin dan koleganya mereview data yang didapatkan dari the Surveillance, Epidemiology, and End Results Program (SEER), yang mengambil insidensi dan data kelangsungan hidup dari seluruh masyarakat memperlihatkan sekitar 14percent dari populasi di Amerika Serikat terkena kanker. Mereka menemukan factor resiko dari pertumbuhan kanker anus dan kanker vagina setelah didiagnosa kanker cerviks yang invasive adalah 4.6 dan 5.6 untuk masing-masing. Danish dan SEER menemukan bahwa radioterapi dapat mengatur kanker cerviks. Anal Cancer and HPV Diketahuinya ada hubungan antara kanker cervics dan HPV, munculnya hubungan antara kanker cervics dan kanker anus, dan kaitan dengan aktifitas seksual menimbulkan spekulasi bahwa kanker anus berhubungan dengan HPV. DNA HPV diisolasi dengan polymerase chain reaction (PCR) di 46 sampai 100 persen in situ dan invasive squamous cell carcinoma anus. Kondisi premalignansi dari cervical intra epithelial neoplasia (CIN) berkaitan dengan infeksi HPV pada cerviks. Sama dengan CIN, anal intraepithelial neoplasia (AIN) dapat dibagi sesuai morfologinya menjadi low grade atau high grade. Lesi yang tersering adalah polypoid condiloma akuminata. Faktanya memberi kesan grade tertinggi AIN yang merupakan tanda untuk karsinoma anus. AIN terkadang berkembang dari yang ringan menjadi berat, ada di area yang berdekatan dengan squamous cell carcinoma, dan berhubungan dengan HPV. Sama dengan yang terjadi pada kanker serviks, HPV 16 adalah tipe yang paling banyak diisolasi pada keganasan anus dan ini dapat menjadi tanda adanya AIN yang berat dan kanker yang invasive, dimana AIN yang ringan secara berkala menunjukan tipe HPV yang lain. Penelitian terbaru dari Frisch dan koleganya, DNA HPV terisolasi oleh PCR pada 88% dari 394 pasoen dengan kanker anus kontras dengan 0 sampai 20 pasien dengan adenocarsinoma rectum. Dari pasien dengan kanker anus tersebut, 73% pasien terpapar HPV 1. Tidak berbeda antara HPV-positif dan HPV-negatif tumor dapat ditemukan dengan memandang umur pasien, ada atau tidaknya dysplasia, diferensiasi duktus, atau prognosanya. Anal Cancer and HIV

Peningkatan insidensi kanker dubur selama tiga dekade terakhir di antara laki-laki di AS telah sangat dipengaruhi oleh epidemi HIV, meskipun hubungan serupa tidak diamati untuk perempuan. Kanker dubur terus meningkat di antara orang dengan HIV meskipun dengan ada terapi antiretroviral yang efektif, karena pengobatan telah memungkinkan mereka untuk hidup lebih lama untuk mengembangkan kanker tersebut. Displasia (pertumbuhan sel yang tidak normal) dubur dan kanker biasanya disebabkan oleh human pappilomavirus (HPV) yang dapat menyebabkan kanker (onkogenik). Tidak seperti kanker serviks yang invasif, kanker dubur tidak diklasifikasikan sebagai kondisi terdefinisi AIDS, meskipun keduanya memiliki penyebab yang sama. Meskipun kanker dubur tetap langka di AS dengan perkiraan kasus sebesar 6230 pada tahun 2012 insidensi (kasus baru) ini terus menerus meningkat di populasi umum sejak 1940. Namun, masih belum jelas, bagaimana peningkatan baru-baru ini mungkin disebabkan oleh HIV. Meredith Shiels dan rekan dari Division of Cancer Epidemiology and Genetics di National Cancer Institute memperkirakan dampak dari epidemi HIV pada kecenderungan total dari insidensi kanker dubur di 17 negara bagian AS dan wilayah metropolitan antara tahun 1980 satu tahun sebelum laporan medis AIDS pertama dan pada tahun 2005.

Para peneliti memperoleh data dari kanker dubur di antara orang dengan HIV dan tanpa HIV dari HIV/AIDS Cancer Match Study. Mereka memperkirakan jumlah kasus kanker dubur di antara orang dengan HIV dan menggunakan angka ini untuk menghitung proporsi dari semua kasus kanker dubur yang terjadi di antara orang dengan HIV. Selanjutnya, mereka memperkirakan kecenderungan dari waktu ke waktu dari tingkat insiden kanker dubur di populasi umum dan setelah mengeluarkan orang dengan HIV. Hasil Penelitian

Dari perkiraan 20.553 kasus kanker dubur yang dilaporkan selama 1980-2005, 1665 (atau 8,1%) terjadi di antara orang dengan HIV. Proporsi dari kasus kanker dubur di antara orang dengan HIV adalah tertinggi pada periode 2001-2005 segera sesudah penemuan terapi antiretroviral yang efektif. Angka ini adalah 28,4% di antara laki-laki dan 1,2% di antara perempuan. Infeksi HIV tidak memiliki dampak pada kecenderungan kanker dubur di antara perempuan selama tahun 1980-2005. Secara keseluruhan, tingkat insiden meningkat sebesar 3,3% per tahun dan tetap 3,3% setelah mengeluarkan perempuan dengan HIV dari analisis. Namun, di antara laki-laki, HIV memiliki dampak yang kuat selama periode ini, dengan tingkat insiden meningkat sebesar 3,4% per tahun namun hanya 1,7%atau separuh setelah mengeluarkan kasus di antara laki-laki dengan HIV. Laki-laki kulit hitam dengan kanker dubur memiliki lebih dari dua lipat prevalensi infeksi HIV dibandingkan dengan laki-laki berkulit putih. Hal ini mencerminkan prevalensi HIV yang lebih tinggi di antara laki-laki berkulit hitam. Proporsi kanker dubur di antara laki-laki dengan HIV adalah lebih besar untuk kanker sel skuamosa dibandingkan dengan adenocarcinoma (31,3% vs 2,7%). Hal ini mungkin disebabkan oleh kanker sel skuamosa lebih terkait dengan HPV.

Berdasarkan hasil studi ini, para peneliti menyimpulkan, Selama 1980-2005, peningkatan tingkat insidensi kanker dubur di AS sangat dipengaruhi oleh epidemi HIV di antara laki-laki namun independen dari infeksi HIV di antara perempuan. Sebagian besar proporsi dari laki-laki di AS yang memiliki kanker dubur di beberapa tahun terakhir adalah di antara orang dengan HIV, mereka melanjutkan. Pengukuran ini akan mencegah kanker dubur di antara laki-laki yang terinfeksi HIV dan dapat mengurangi tingkat kanker dubur secara bermakna pada tingkat populasi. Jumlah CD4 yang rendah terkait dengan peningkatan risiko kanker dubur, meskipun kanker dubur juga terjadi di antara orang dengan HIV yang memiliki jumlah CD4 yang lebih tinggi. Penekanan kekebalan tubuh yang terkait dengan HIV dapat secara langsung menyebabkan perkembangan kanker dubur, mereka menyarankan. Meskipun terapi antiretroviral dapat mengembalikan sebagian fungsi kekebalan tubuh, terapi HIV tidak menyebabkan pengurangan lesi prakanker, dan insidensi kanker dubur telah meningkat dalam era terapi antiretroviral. Mereka mencatat bahwa tidak semua kanker dubur pada Odha selalu disebabkan oleh infeksi HIV, karena laki-laki yang berhubungan seks dengan laki-laki (LSL) akan memiliki peningkatan

risiko bahkan tanpa HIV. Tapi laki-laki gay dengan HIV memiliki prevalensi yang lebih tinggi dari displasia dubur dan risiko 10 kali lipat dari karsinoma sel skuamosa dubur dibandingkan dengan LSL HIV negatif
THERAPY Until recently, an abdominoperineal resection (APR) represented the treatment of choice for tumors arising in the anal canal. This radical operation requires the removal of the anorectum and the need for a permanent colostomy. The overall probability of 5-year survival following an APR ranges from 40 to 70 percent with an associated mortality of approximately 3 percent.8,1113,6062 Over the past 30 years, the treatment of anal cancer has shifted to a nonsurgical paradigm. Combined Modality Therapy Extending prior observations by others who had demonstrated a radiation potentiating effect by the concomitant administration of fluoropyrimidines in a variety of gastrointestinal malignancies,6368 investigators at Wayne State administered preoperative 5fluorouracil (5-FU) and mitomycin combined with intermediate-dose radiation therapy (30 Gy) to patients with anal canal cancers as a means of decreasing the surgical failure rate.69 The surprising finding of complete pathologic responses in the first three patients on treatment resulted in a strategy directed at sphincter preservation. Patients were initially treated with chemoradiation therapy and subjected to subsequent APR only if residual tumor remained at the time of a postradiation biopsy.70 The Wayne State investigators found that a majority of patients treated with combined modality therapy could be cured without an APR. This finding was subsequently confirmed by multiple investigators70 94 (Table 123). Typically, patients are treated with radiation fields initially encompassing the pelvis from the S1-S2 level, the inguinal lymph nodes, and the anus (Figure 129). After 30 to 36 Gy, the treatment fields are reduced to the low pelvis encompassing the anal tumor. With this technique, the total dose to the primary dose is escalated to 45 to 50 Gy. During the 5to 6-week course of irradiation and chemotherapy, there is frequently marked regression of the tumor as well as a brisk perineal skin reaction. Figures 1210 to 1212 show the response of an anal cancer and surrounding normal tissues to combined modality

therapy. Figure 1213 shows fibrosis and retraction of the perianal and anal region several years following therapy of a similarly advanced tumor. A combined modality approach has been used successfully in HIV-positive patients with similarly good response rates, though toxicity appears to be more common, particularly as radiation doses are increased above 30 Gy.95,96 Radiation Therapy Revisited Many investigators questioned the additive benefit of chemotherapy to radiation in the treatment of anal cancer. The use of radiation therapy alone, either by external beam or brachytherapy (ie, direct intratumoral implantation of radioactive seeds), as primary treatment for anal canal cancer has been associated with local control and overall survival rates in approximately 70 to 90 percent of selected patients14,87,91,97104 (Table 124). However, the local control and survival rates for patients with large tumors or nodal involvement were less than 50 percent in some series.14,91,105 The optimal dose of radiation therapy in the treatment of anal cancer has been the subject of considerable debate. Retrospective studies have shown that the dose of radiation is a significant prognostic indicator with improved disease-free survival in patients receiving at least 54 Gy of external beam radiation.91,106 Late toxicity from radiation therapy such as anal ulcers, stenosis, and necrosis can lead to colostomies in 6 to 12 percent of patients who are free of disease.14,87,107 Allal and colleagues reviewed their experience with 144 patients with anal cancer and demonstrated that late complications were dose dependent. After 5 years, 10 percent of patients required an APR for late complications, and the rate of serious complications was 23 percent for patients who had at least 39 Gy to the pelvis before a boost of radiation to the tumor and 7 percent for patients who had less than 39 Gy of external beam radiation. 108 An attempt to reduce this toxicity by divid-ing a total radiation dose of 59 Gy into a split-dose schedule (2-week delay after 36 Gy) proved unsuccessful, resulting in diminished tumor control but similar toxicity.76 Through a series of randomized studies, investigators in Europe and the United States have successfully addressed some of the questions surrounding the additive benefit of chemotherapy to radiation in the treatment of anal cancer. Phase III Trials in Anal Cancer

There are currently a number of phase III trials ongoing for the treatment of anal cancer (Table 125). The Anal Cancer Trial Working Party of the United Kingdom Coordination Committee on Cancer Research (UKCCCR)109 randomized 585 patients to receive either radiotherapy administered as 45 Gy of external beam with either a 15 Gy external beam boost or a 25 Gy brachytherapy boost, or radiotherapy with concurrent 5-fluorouracil (5-FU) and mitomycin. Similar response rates were noted in both groups, with a trend toward a more favorable response in the combined modality therapy (CMT) arm. However, there was a significant improvement in local control for patients treated with CMT (61% vs 39%, p = .0001). Deaths from anal cancer were also reduced in the CMT arm (28% vs 39%, p = .02), but overall survival was not statistically significant. Of note, the CMT group experienced significantly more acute morbidity, including six deaths, but late morbidity was the same. The European Organization for the Research and Treatment of Cancer (EORTC)7 randomized 110 patients with T3-4, N0-3 or T1-2, N1-3 anal cancer to receive either radiotherapy (45 Gy with a 15 or 30 Gy boost) with concurrent chemotherapy (5-FU and mitomycin) or radiotherapy alone. The CMT group experienced a higher pathologic complete remission rate (80% vs 54%), an 18 percent higher 5-year locoregional control rate (p = .02), a 32 percent higher colostomy-free rate (p = .002), a higher event-free survival rate, and a higher progressionfree survival rate. Overall survival, however, was not significantly different. As opposed to the UKCCCR trial, acute and late side effects were not significantly different between the groups, and one death occurred in the CMT group. Multivariate analysis established that the presence of either skin ulceration or nodal involvement was a poor prognostic factor and that women had better local control and survival than men. These two trials have established that the addition of chemotherapy to radiation therapy improves local control and disease-free survival but not overall survival. Role of Mitomycin Assessing the contribution of mitomycin in a curative combined modality regimen was thought important since the drug is not a radiation sensitizer, has only modest antitumor activity against squamous cell cancers like those from the anus, and has been associated with chronic toxicity to the kidneys,110112

lungs,113,114 and probably bone marrow.115,116 The RTOG/ECOG6 randomized 310 patients with anal cancer of any tumor or nodal stage to CMT with or without mitomycin. The addition of mitomycin resulted in a statistically significant improvement in colostomy-free survival at 4 years (71% vs 59%, p = .014), and disease-free survival at 4 years (73% vs 51%, p = .003). Overall survival and negative biopsy rate post-therapy did not differ significantly in the two arms. Grade IV toxicity (23% vs 7%) and fatal neutropenic sepsis (4 patients vs 1 patient, p .001) were significantly more common in the mitomycin arm. Of note, colostomy-free survival was 42 and 37 percent for node-positive patients in the 5-FU and 5-FU with mitomycin arms, respectively. Furthermore, the addition of mitomycin on the treatment plan for T3/4 tumors did not impact significantly on subset analysis. Role of Local Excision Whether local excision can ever be applied to the management of patients with squamous cell cancer of the anus remains an unresolved question. Early series reported that the probability of 5-year survival in patients with anal margin cancers less than 2 cm is greater than 80 percent.11,12,61 It is difficult to draw conclusions from these early reports as some patients may have had cancers of the perianal skin and some patients received APRs for local tumor control. There is a lack of data demonstrating the natural history of high-grade AIN, incidentally noted squamous cell cancers after excision of highgrade AIN, and T1 tumors following local excision. Two recent series have begun to shed light on these questions. Brown and colleagues have reported their experience with 46 patients who underwent local excision for high-grade AIN.117 More than 40 percent of patients had positive surgical margins and over 50 percent of these patients had recurrent lesions after 1 year. For patients who had complete microscopic excision, 13 percent developed recurrent AIN. In addition, the morbidity of local excision was not trivial as 11 percent developed complications of anal stenosis and/or fecal incontinence. Hu and colleagues at Memorial Sloan Kettering Cancer Center reported their experience with local excision and CMT in a selected group of 25 patients.118 For the entire group, 5-year, diseasefree survival was 78 percent and overall survival was

86 percent. Of note, 30 Gy of radiation appeared to be an adequate dose. These series demonstrate that AIN is a multifocal process due to HPV infection and complete local excision is often inadequate or not possible. By extension, the same concerns apply to small or incidentally found squamous cell carcinomas of the anus. Even when local excision is combined with chemoradiation, there appears to be a 20 percent risk of therapeutic failure. Therefore, local excision as sole therapy for anal cancer should not be considered adequate. More studies are needed to help define the best therapeutic options for patients with small (or incidentally found) tumors. Platinum-Based Regimens Presently, interest has arisen at replacing mitomycin with cisplatin. The platinum compounds, not available at the time the combined modality strategy evolved for anal canal cancers, are generally considered to be more effective than mitomycin in the treatment of squamous cell carcinomas. The combination of cisplatin and 5-FU given concurrently with radiation therapy in patients with anal cancer showed that only 14 percent of patients required a colostomy after 37 months and that 94 percent were alive.72 This encouraging outcome has been confirmed in another series involving 30 patients.119 An ongoing study in the United States is comparing cisplatin and 5-FU to mitomycin and 5-FU and also is examining the optimal dose of radiation. Locally Recurrent Disease Although some patients may be salvaged with surgery, locally recurrent anal cancer can be a difficult clinical problem associated with profound morbidity and suffering. Figures 1214 and 1215 show a photograph and CT scan of a patient with an anal cancer with massive recurrence filling the perineum and posterior pelvis. For patients with persistent disease after primary CMT, surgical removal either by local excision or APR remains the treatment of choice. A recent retrospective review of 21 patients who underwent APR after locoregional recurrence revealed a 58 percent 3-year survival rate.120 In the UKCCCR trial, 29 patients with a less than 50 percent response were treated with an APR, 24 patients (83%) were rendered disease free, and 10 of the 24 patients (42%) eventually developed locoregional recurrence.

The RTOG/ECOG treated patients with persistent disease after primary chemoradiotherapy with salvage 5-FU, cisplatin, and radiation therapy (9 Gy boost). Of 22 patients, 12 (55%) were rendered disease free after salvage therapy. Of the 12 successfully salvaged patients, 4 had 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 salvage therapy, 9 underwent APR. After 4 years, 3 remain alive without disease and 7 have died, including 6 with recurrent disease. Metastatic Disease In the EORTC and UKCCCR trial, 17 and 10 percent, respectively, of patients in the combined modality arms developed distant metastases. When reported, the liver is the most frequent site of distant metastases. 10,104,121 Reports of treatment for metastatic disease are rare and include partial responses with cisplatin, 5-FU, and methyl-CCNU.122124 There is little published experience with newer agents such as taxanes and irinotecan in this disease. Since cervical cancer and anal cancer are both HPV-related malignancies, it may be possible to extrapolate from the experience of chemotherapy in advanced cervical cancer. In cervical cancer, the two most active agents in the advanced setting are cisplatin and paclitaxel. 125127 Two recent phase II studies of cisplatin and paclitaxel demonstrated an objective response rate of 47 and 46 percent, respectively, and have led to a phase III effort by the Gynecologic Oncology Group comparing cisplatin versus the combination of cisplatin and paclitaxel.128,129

Procedures used to diagnose anal cancer

Terkadang dokter dapan mendeteksi kanker anus dengan fisik diagnostic yang sederhana, terutama untuk membedakan dengan diagnose hemorrhoid. Menemukan kanker anus dengan cara ini sangatlah efektif karena tumor akan dapat ditemukan secara dini. Namun tidak semua pertumbuhan tumor dapat ditemukan dengan rectal toucher. Tetapi apabila dokter tidak menemukan tumor dengan rectal toucher, cara lain mungkin dibutuhkan jika memang kita telah mencurigai pasien dengan kanker anus. Endoscopy Sebagian tipe endoskopi dapat digunakan untuk melihat penyebab dari gejala kanker anus. Yang biasa digunakan untuk melihat adanya kanker anus adalah: Anoscopy : alat anoscopy merupakan pipa yang pendek biasa disebut juga hollow tube, panjangnya sekitar 3-4 inci dan diameter sekitar 1inci, dan memiliki lampu di ujungnya. Dengan ini kita dapat melihat anus dan rectum bagian bawah. Alat biasanya tidak akan membuat pasien merasa kesakitan. Rigid procto sigmoidoscopy: sama dengan anoscope, hanya saja alat ini lebih panjang, panjangnya sekitar 10 inci, jadi alat ini bias digunakan untuk melihat rectum secara keseluruhan dan juga colon sigmoid bagian bawah. Pada penggunaan alat ini kita harus mengosongkan usus dari pasien agar gambaran yang kita inginkan dapat terlihat dengan jelas.

Biopsy
Jika ada kecurigaan pertumbuhan kanker, dokter akan mengambil contoh jaringan untuk dilihat jika itu suatu kanker. Hal ini disebut dengan biopsy. Ini dapat dilakukan jika jaringannya mudah dijangkau. Pasien mendapatkan anestesi local sebelum biopsy dilakukan. Lalu ,memotong sedikit jaringan dan dikirim ke laboratorium. Dokter patologi anatomi akan melihat contoh jaringan di bawah mikroskop. Jika terdapat kanker, doker patologi anatomi akan mengirim kembali laporan yang berisi penjelasan tipe sel dan tingat kanker. Jika tumor sangat kecil dan tidak tumbuh dibawah permukaan anus kedalam jaringan yang lain, kita akan mencoba membuang semua tumor pada saat biopsy. Tipe lain biopsy dengan mengecek penyebaran kanker ke limfe nodul, seperti : Fine-needle aspiration biopsy: Kanker anus terkadang dapat menyebar ke system limfatik sampai limfe nodul. Limfe nodul adalah kumpulan dari system sel imunitas yang berukuran sebesar kacang. Pembengkakan limfe nodul dapat memberikan tanda penyebaran kanker anus. Limfe nodul dapat juga membengkak karena infeksi. Untuk melihat jika itu kanker dikarenakan pembengkakan life nodul, kita boleh mengambil sedikit contoh dari cairan dan jaringan limfe

nodul dengan jarum yang tipis. Laboratorium akan mempelajari cairan itu untuk melihat adanya sel kanker. Prosedur ini disebut fine-needle aspiration biopsy. Jika kanker ditemukan pada limfe nodul, operasi untuk menghilangkan limfe nodul di area tersebut mungkin dapat dilakukan. Sentinel node biopsy: Tes ini kadang digunakan untuk membantu menentukan jika kanker tersebut sudah terdiagnosa menyebar ke limfe nodus. Pada test ini jejak material radioaktif berlevel rendah disuntikan di sekitar tumor.Often a blue dye is injected into the tumor at the same time. The groin lymph nodes are scanned to see where the radioactive material has traveled. The doctor removes any radioactive or blue-stained lymph nodes. Dokter patologi anatomi melihat nodul untuk mengetahui adanya sel kanker. Ini akan membantu memberitau sejauh apa kanker dapat menyebar, karena melalui nodul tersebut sel kanker dapat bermetastase. Tes ini terlihat sangat berguna untuk beberapa kanker, namun belum ada data pasti seberapa membantu tes ini untuk kanker anal.

Imaging studies
Jika terdapat kanker, kita dapat memiih tes ntuk melihat seberapa jauh terjadi penyebaran. Beberapa tes ini digunakan lebih sering dari yang lain.

Ultrasound
Ultrasound mengunakan gelombang suara dan gama untuh memproduksi gambar organ dalam atau massa. Microphone kecil seperti instrument yang disebut transducer, mengeluarkan gelombang berfrekuensi tinggi. Gelombang suara ini dipantulkan kedalam organ tubuh kemudian diterima sebagai gelombang gamma. Gelombang gamma diterima kembali oleh transducer dan dikonversikan computer menjadi gambar kedalam layar. Ultrasounds sangat aman dan tidak menggunakan radiasi. Ultrasound yang paling banyak digunakan adalah yang tranducer-nya diletakan pada kulituntuk mengambil gambar organ yang berada dibawahnya. Untuk kanker anus, tranduser harus dimasukn langsung ke dalam rectum. Atau biasa dikenal dengan nama transrektal atau ultrasound endorektal. Test ini memang membuat pasien agak kurang nyaman, namun tidak sampai membuat pasien merasa nyeri. Dan tes ini berguna untuk melihat seberapa dalam pertumbuhan kanker di jaringan sekitar anus.

Computed tomography (CT) scan

CT scan adalah x-ray tes yang memproduksi gambaran detail secara melintang dari tubuh. Bukan saja dapat mengambil satu gambar, seperti x-ray standar, CT scanner dapat mengambil berbagai gambar ketika alat ini bekerja. Computer mengkombinasikan itu kedalam gambar menjadi beberapa potongan gambar. CT scan dapat digunakan untuk mengetahui jikan kanker anal telah bermetastase ke dalam liver atau organ lain. CT-guided needle biopsy: CT scans dapat juga digunakan sebagai pemandu untuk jarum biopsy kedalam suspect tumor dengan tepat. Untuk cara ini, pasien dibaringkan di meja CT scanner, ketika dokter memasukan jarum biopsy dari kulit sampai ke tumor. CT scan terus menerus

dilakukan samapai jarum tersebut dapat mengambil massa yang akan dibiopsi. Kemudian contoh biopsy yang terbaik atau yang terbesar diambil dan dilihat dibawah mikroskop.

Human papilloma virus infection

Most squamous cell anal cancers seem to be linked to infection by the human papilloma virus (HPV), the same virus that causes cervical cancer. In fact, women with a history of cervical cancer (or pre-cancer) have an increased risk of anal cancer. HPV is a group of more than 100 related viruses. They are called papilloma viruses because some of them cause papillomas, which are more commonly known as warts. There are several subtypes of the virus, but the one most likely to cause anal cancer is called HPV-16. HPV-16, as well as HPV 18, HPV 31, HPV 33, and HPV 45 are considered high-risk types of HPV because they are strongly linked to cancer. They can also cause cancers of the cervix, vagina, and vulva in women, as well as cancer of the penis in men, and throat cancer in both women and men. Other subtypes of HPV can cause warts in the genital and anal areas. The medical term for these warts is condyloma acuminatum. The 2 types of HPV that cause most cases of anal and genital warts are HPV 6 and HPV 11. They are called low-risk types of HPV because they tend to cause warts but not cancer. HPV infection can cause anal and genital warts, but most people infected with HPV do not have genital warts or any other signs of infection. HPV is passed from one person to another during skin-to-skin contact with an infected area of the body. HPV can be spread during sex -- including vaginal intercourse, anal intercourse, and oral sex - but sex doesn't have to occur for the infection to spread. All that is needed is for there to be skin-to-skin contact with an area of the body infected with HPV. The virus can be spread through genital-to-genital contact. It is even possible for a genital infection to spread through hand-to-genital contact. An HPV infection also seems to be able to be spread from one part of the body to another. This means than an HPV infection may start in the genitals and then spread to the anus. It can be very hard to avoid being exposed to HPV. It might be possible to prevent genital HPV infection by not allowing others to have contact with your anal or genital area, but even then there could be other ways to become infected that arent yet clear. Infection with HPV is common, and in most cases the body is able to clear the infection on its own. But in some cases the infection does not go away and becomes chronic. Chronic infection, especially when it is with high-risk HPV types, can eventually cause certain cancers, including anal cancer. For men, the 2 main factors influencing the risk of genital HPV infection are circumcision and the number of sexual partners. Men who are circumcised (have had the foreskin of the penis removed) have a lower chance of becoming and staying infected with HPV. The risk of being infected with HPV is also strongly linked to having many sexual partners (over a man's lifetime).

In women, HPV infections occur mainly at younger ages and are less common in women over 30. The reason for this is not clear. Certain types of sexual behavior increase a woman's risk of getting a genital HPV infection, such as having sex at an early age and having many sexual partners. Although women who have had many sexual partners are more likely to get infected with HPV, a woman who has had only one sexual partner can still get infected. This is more likely if she has a partner who has had many sex partners or if her partner is an uncircumcised male. In a study that looked at risk factors for anal HPV infection in women, risk was increased in younger women and in those who had more than 5 sexual partners in their lifetime. Ever having anal sex also increased risk. Circumcision and HPV: Men who have not been circumcised are more likely to be infected with HPV and pass it on to their partners. The reasons for this are unclear. It may be that the skin on the glans of the penis goes through changes that make it more resistant to HPV infection. Another theory is that the surface of the foreskin (which is removed by circumcision) is more easily infected by HPV. Still, circumcision does not completely protect against HPV infection -men who are circumcised can still get HPV and pass it on to their partners. Condoms and HPV: Condoms can provide some protection against HPV, but they do not completely prevent infection. One study found that when condoms are used correctly they can lower the genital HPV infection rate in women by about 70% - but they need to be used every time sex occurs. This study did not look at the effect of condom use on anal HPV infection. In another study, men who used condoms less than half of the time had a higher risk of HPV infection. Condoms cannot protect completely because they don't cover every possible HPVinfected area of the body, such as skin of the genital or anal area. Still, condoms provide some protection against HPV, and they also protect against HIV and some other sexually transmitted diseases. Condoms (when used by the male partner) also seem to help genital HPV infections clear (go away) faster in both women and men. For more information about HPV and HPV vaccines, see Human Papilloma Virus and HPV Vaccines FAQ.

Other cancers
Ever having cancer of the cervix, vagina, or vulva is linked to an increased risk of anal cancer. This is likely because these cancers are also caused by infection with HPV. Although it is likely that having penile cancer, which is also linked to HPV infection, would increase the risk of anal cancer, this link has not been shown in studies.

HIV infection
Orang yang terinfeksi dengan human immunodeficiency virus (HIV), virus pada kasus AIDS,lebih banyak mendapatkan kanker anus daripada yang itdak terinfeksi virus tersebut.

Sexual activity
Memiliki banyak pasangan seks menambah resiko terkena infeksi dengan HIV dan HPV. Itu juga menambah resiko kanker anus. Anal seks juga menambah resiko kanker anus pada laki-laki dan perempuan, khusus umur sampai dengan 30 tahun. Olehkarena itu laki-laki yang memiliki pasangan seks laki-laki mempunyai resiko tinggi terkena kanker anus.

Smoking
Merokok juga menambah resiko terjadiya kanker anus. Pecandu rokok memliki kemungkinan terserang kanker anus lebih banyak dibandingkan individu yang tidak merokok. Berhenti merokok dapat mengurangi resiko. Orang orang yang pernah merokok namun telah lama berhenti hanya sedikit saja lebih tinggi pertumbuhan sel kanker nya disbanding yang tidak pernah merokok.

Lowered immunity
Higher rates of anal cancer occur among people with reduced immunity, such as people who have had an organ transplant and must take medicines that suppress their immune system.

Race and gender

Anal cancer is more common in African-Americans than in whites. Overall, it is more common in women than men, but in African Americans it is more common in men than in women