Stage 0 cancer

Carcinoma in situ (stage 0) is treated with local ablative or excisional measures such as cryosurgery, laser ablation, and loop excision. Surgical removal is preferred in that it allows further pathologic evaluation to rule out microinvasive disease. After treatment, these patients require lifelong surveillance. Stadium 0 kanker

Karsinoma in situ (stadium 0) diperlakukan dengan langkah-langkah ablatif atau Excisional lokal seperti cryosurgery, ablasi laser, dan eksisi loop. Operasi pengangkatan lebih disukai dalam yang memungkinkan evaluasi lebih lanjut patologis untuk menyingkirkan penyakit microinvasive. Setelah pengobatan, pasien tersebut memerlukan pengawasan seumur hidup. Stage IA1 Cancer

The treatment of choice for stage IA1 disease is surgery. Total hysterectomy, radical hysterectomy, and conization are accepted procedures. Lymph node dissection is not required if the depth of invasion is less than 3 mm and no lymphovascular invasion is noted.

Selected patients with stage IA1 disease but no lymphovascular space invasion who desire to maintain fertility may undergo therapeutic conization with close follow-up, including cytology, colposcopy, and endocervical curettage. Patients with comorbid medical conditions who are not surgical candidates can be successfully treated with radiation.

According to National Comprehensive Cancer Network (NCCN) guidelines, pelvic radiation therapy is currently a category 1 recommendation for women with stage IA disease and negative lymph nodes after surgery who have high-risk factors (eg, a large primary tumor, deep stromal invasion, or lymphovascular space invasion).[47] Tahap IA1 Kanker

Pengobatan pilihan untuk penyakit stadium IA1 adalah operasi. Histerektomi total, histerektomi radikal, dan conization diterima prosedur. Diseksi kelenjar getah bening tidak diperlukan jika kedalaman invasi kurang dari 3 mm dan tidak ada invasi lymphovascular dicatat.

Pasien tertentu dengan stadium IA1 penyakit tetapi tidak ada invasi ruang lymphovascular yang ingin mempertahankan kesuburan dapat mengalami conization terapeutik dengan dekat tindak lanjut, termasuk sitologi, kolposkopi, dan kuretase endoserviks. Pasien dengan kondisi medis komorbid yang tidak kandidat bedah dapat berhasil diobati dengan radiasi.

Menurut National Cancer Komprehensif Jaringan (NCCN) pedoman, terapi radiasi panggul saat ini menjadi kategori 1 rekomendasi untuk wanita dengan kelenjar getah bening stadium IA penyakit dan negatif setelah operasi yang memiliki faktor risiko tinggi (misalnya, tumor primer besar, invasi stroma dalam, atau invasi ruang lymphovascular). [47] Stage IA2, IB, or IIA cancer

For patients with stage IB or IIA disease, there are 2 treatment options:

Combined external beam radiation with brachytherapy

Radical hysterectomy with bilateral pelvic lymphadenectomy

Radical vaginal trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in women with stage IA2 disease and those with stage IB1 disease whose lesions are 2 cm or smaller.[47] The principal problems with pregnancy after trachelectomy are premature labor and the need to undergo cesarean section for delivery.[51]

Most retrospective studies have shown equivalent survival rates for trachelectomy and hysterectomy, though such studies usually are flawed because of patient selection bias and other compounding factors. However, a 2008 study showed identical overall and disease-free survival rates for the 2 procedures.[52]

Current surgical guidelines for stage IA2 to IIA cervical cancers allow for minimally invasive techniques, such as traditional laparoscopic and robotically assisted laparoscopic techniques, in the surgical management of these tumors. Indeed, it has been shown that these less morbid procedures are equally

effective in achieving adequate surgical margins and lymph node dissection while possessing the added advantage of shorter postoperative recovery times.[53, 54, 55]

An analysis of women from the Surveillance, Epidemiology, and End Results (SEER) database who underwent radical hysterectomy with lymphadenectomy revealed that patients with node-negative early-stage cervical cancer who underwent a more extensive lymphadenectomy had improved survival.[56] Compared with patients who had fewer than 10 nodes removed, patients who had 21-30 nodes removed were 24% less likely to die of their tumors, and those who had more than 30 nodes removed were 37% less likely to die.

Postoperative irradiation of the pelvis reduces the risk of local recurrence in patients with high-risk factors (ie, positive pelvic nodes, positive surgical margins, and residual parametrial disease).[57] A randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic irradiation.[58]

Postoperative radiation therapy is also recommended in patients who have at least 2 intermediate risk factors (including tumor size greater than 2 cm, deep stromal invasion, or lymphovascular space invasion). For patients with IB2 or IIA cancer and tumors larger than 4 cm, radiation and chemotherapy is selected in most cases. Risks are associated with combined therapy, but many of these patients will meet either intermediate- or high-risk criteria after radical hysterectomy and therefore are strong candidates for this approach. Tahap IA2, IB, IIA atau kanker

Untuk pasien dengan stadium IB atau penyakit IIA, ada 2 pilihan pengobatan:

Dikombinasikan radiasi sinar eksternal dengan brachytherapy

Radikal histerektomi dengan limfadenektomi panggul bilateral

Trachelectomy vagina radikal dengan diseksi kelenjar getah bening panggul sesuai untuk pelestarian kesuburan pada wanita dengan stadium penyakit IA2 dan mereka dengan penyakit stadium IB1 yang lesi

adalah 2 cm atau lebih kecil [47]. Masalah utama dengan kehamilan setelah trachelectomy prematur tenaga kerja dan kebutuhan untuk menjalani operasi caesar untuk melahirkan. [51]

Kebanyakan penelitian retrospektif menunjukkan tingkat kelangsungan hidup setara untuk trachelectomy dan histerektomi, meskipun studi tersebut biasanya cacat karena bias pemilihan pasien dan faktor peracikan lainnya. Namun, sebuah studi 2008 menunjukkan tingkat yang sama kelangsungan hidup secara keseluruhan dan bebas penyakit selama 2 prosedur. [52]

Pedoman bedah saat ini untuk tahap IA2 untuk kanker serviks IIA memungkinkan untuk teknik minimal invasif, seperti teknik tradisional laparoskopi laparoskopi dan dibantu robot, dalam pengelolaan bedah tumor ini. Memang, telah ditunjukkan bahwa morbid kurang prosedur sama-sama efektif dalam mencapai margin bedah yang memadai dan diseksi kelenjar getah bening sementara yang memiliki keuntungan tambahan yang lebih singkat waktu pemulihan pasca operasi [53, 54, 55].

Analisis wanita dari Surveillance, Epidemiologi, dan Hasil Akhir (SIER) database yang menjalani histerektomi radikal dengan limfadenektomi mengungkapkan bahwa pasien dengan node-negatif stadium awal kanker serviks yang menjalani limfadenektomi lebih luas telah meningkatkan kelangsungan hidup. [56] Dibandingkan dengan pasien yang kurang dari 10 node dihapus, pasien yang telah node dihapus 21-30 adalah 24% lebih mungkin meninggal karena tumor mereka, dan mereka yang memiliki lebih dari 30 node dihapus adalah 37% lebih mungkin meninggal.

Iradiasi pasca operasi panggul mengurangi risiko kekambuhan lokal pada pasien dengan faktor risiko tinggi (yaitu, node panggul positif, margin bedah positif, dan penyakit parametrium residu). [57] Sebuah uji coba secara acak menunjukkan bahwa pasien dengan keterlibatan parametrium, panggul positif node, atau positif bedah margin keuntungan dari kombinasi pasca operasi cisplatin mengandung kemoterapi dan radiasi panggul. [58]

Terapi radiasi pasca operasi juga direkomendasikan pada pasien yang memiliki minimal 2 faktor risiko menengah (termasuk ukuran tumor lebih besar dari 2 cm, invasi stroma dalam, atau invasi ruang lymphovascular). Untuk pasien dengan IB2 atau IIA kanker dan tumor yang lebih besar dari 4 cm, radiasi dan kemoterapi dipilih dalam banyak kasus. Sejumlah resiko dihubungkan dengan terapi kombinasi, tapi banyak dari pasien ini akan memenuhi kriteria baik menengah atau risiko tinggi setelah histerektomi radikal dan oleh karena itu kandidat yang kuat untuk pendekatan ini. Stage IIB, III, or IVA cancer

For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was the treatment of choice for many years. Radiation therapy begins with a course of external beam radiation to reduce tumor mass and thereby enable subsequent intracavitary application. Brachytherapy is delivered by means of afterloading applicators that are placed in the uterine cavity and vagina.

Additionally, the results from large, well-conducted, prospective randomized clinical trials have demonstrated a dramatic improvement in survival when chemotherapy is combined with radiation therapy.[59, 60, 61] Consequently, the use of cisplatin-based chemotherapy in combination with radiation has become the standard of care for primary management of patients with locally advanced cervical cancer.[47] Tahap IIB, III, atau kanker IVA

Untuk karsinoma serviks stadium lanjut (stadium IIB, III, dan IVA), terapi radiasi adalah pengobatan pilihan selama bertahun-tahun. Terapi radiasi dimulai dengan program radiasi sinar eksternal untuk mengurangi massa tumor dan dengan demikian memungkinkan aplikasi Intracavitary berikutnya. Brachytherapy disampaikan melalui afterloading aplikator yang ditempatkan dalam rongga rahim dan vagina.

Selain itu, hasil dari besar, baik dilakukan, percobaan prospektif klinis acak telah menunjukkan peningkatan yang dramatis dalam bertahan hidup ketika kemoterapi dikombinasikan dengan terapi radiasi. [59, 60, 61] Akibatnya, penggunaan berbasis cisplatin dalam kombinasi kemoterapi dengan radiasi telah menjadi standar perawatan untuk manajemen utama dari pasien dengan kanker serviks stadium lanjut. [47] Stage IVB and recurrent cancer

Individualized therapy is used on a palliative basis. Radiation therapy is used alone for control of bleeding and pain, whereas systemic chemotherapy is used for disseminated disease.[47] For recurrent disease, the choice of therapy is influenced by the treatments previously employed.

Treatment of pelvic recurrences after primary surgical management should include single-agent chemotherapy and radiation, and treatment for recurrences elsewhere should include combination chemotherapy.[62, 63, 64] For central pelvic recurrence after radiation therapy, modified radical

hysterectomy (if the recurrence is smaller than 2 cm) or pelvic exenteration should be undertaken.[65, 66]

For disease recurring after chemotherapy and radiation therapy, a disease-free interval of more than 16 months is considered to designate the tumor as platinum-sensitive.[67] The standard of care in these cases is chemotherapy with a platinum-based doublet of paclitaxel and cisplatin.[63, 64, 68, 69]

The NCCN also recommends bevacizumab, docetaxel, gemcitabine, ifosfamide, 5-fluorouracil, mitomycin, irinotecan, and topotecan as possible candidates for second-line therapy (category 2B recommendation), as well as pemetrexed and vinorelbine (category 3 recommendation). In addition, bevacizumab as single-agent therapy is also acceptable.[47]

Recurrences arising in a previously irradiated field or after a disease-free interval of less than 16 months are less likely to respond to subsequent therapies. Consequently, patients with such recurrences should be strongly encouraged to participate in clinical trials. Special efforts should be made to ensure that they receive comprehensive palliative care, including adequate pain control. Tahap IVB dan kanker berulang

Terapi individual digunakan secara paliatif. Terapi radiasi digunakan sendiri untuk mengontrol perdarahan dan nyeri, sedangkan kemoterapi sistemik digunakan untuk penyakit disebarluaskan. [47] Untuk penyakit berulang, pilihan terapi dipengaruhi oleh perlakuan sebelumnya bekerja.

Pengobatan kambuh panggul setelah manajemen bedah primer harus mencakup satu agen kemoterapi dan radiasi, dan pengobatan untuk kambuh di tempat lain harus mencakup kemoterapi kombinasi. [62, 63, 64] Untuk kekambuhan panggul pusat setelah terapi radiasi, dimodifikasi radikal histerektomi (jika kekambuhan adalah exenteration lebih kecil dari 2 cm) atau panggul harus dilakukan [65, 66].

Untuk penyakit berulang setelah kemoterapi dan terapi radiasi, interval bebas penyakit lebih dari 16 bulan dianggap sebagai menunjuk tumor platinum sensitif. [67] Standar perawatan dalam kasus ini adalah kemoterapi dengan doublet berbasis platinum paclitaxel dan cisplatin. [63, 64, 68, 69]

NCCN juga merekomendasikan bevacizumab, docetaxel, gemcitabine, ifosfamid, 5-fluorouracil, mitomycin, irinotecan dan topotecan sebagai kandidat untuk terapi lini kedua (kategori 2B rekomendasi), serta pemetrexed dan vinorelbine (kategori 3 rekomendasi). Selain itu, bevacizumab sebagai single-agen terapi juga dapat diterima [47].

Kambuh yang timbul dalam bidang sebelumnya iradiasi atau setelah interval bebas penyakit kurang dari 16 bulan cenderung tidak merespon terapi berikutnya. Akibatnya, pasien dengan rekurensi tersebut harus didorong untuk berpartisipasi dalam uji klinis. Upaya-upaya khusus harus dilakukan untuk memastikan bahwa mereka menerima perawatan paliatif komprehensif, termasuk kontrol nyeri yang memadai.

Complications of Therapy Radiation-related complications

During the acute phase of pelvic radiation therapy, the surrounding normal tissues (eg, intestines, bladder, and perineal skin) often are affected. Acute adverse gastrointestinal (GI) effects include diarrhea, abdominal cramping, rectal discomfort, and bleeding. Diarrhea can usually be controlled by giving either loperamide or atropine sulfate. Small steroid-containing enemas are prescribed to alleviate symptoms from proctitis.

Cystourethritis also can occur, leading to dysuria, frequency, and nocturia. Antispasmodics often are helpful for symptom relief. Urine should be examined for possible infection. If urinary tract infection (UTI) is diagnosed, therapy should be instituted without delay.

Proper skin hygiene should be maintained for the perineum. Topical lotion should be used if erythema or desquamation occurs.

Late sequelae of radiation therapy usually appear 1-4 years after treatment. The major sequelae include rectal or vaginal stenosis, small bowel obstruction, malabsorption, radiation enteritis,and chronic cystitis. Surgical complications

The most frequent complication of radical hysterectomy is urinary dysfunction resulting from partial denervation of the detrusor muscle. Other complications include foreshortened vagina, ureterovaginal fistula, hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid colon, and bladder and rectovaginal fistulas. Invasive procedures (eg, nephrostomy or diverting colostomy) sometimes are performed in this group of patients to improve their quality of life. Nutrition

Proper nutrition is important for patients with cervical cancer. Every attempt should be made to encourage and provide adequate oral food intake.

Nutritional supplements (eg, Ensure [Abbott Nutrition, Columbus, OH] or Boost [Nestl HealthCare Nutrition, Fremont, MI]) are used when patients have had significant weight loss or cannot tolerate regular food because of nausea caused by radiation or chemotherapy. In patients with severe anorexia, appetite stimulants such as megestrol can be prescribed.

For patients who are unable to tolerate any oral intake, percutaneous endoscopic gastrostomy tubes are placed for nutritional supplementation. In patients with extensive bowel obstruction as a result of metastatic cancer, hyperalimentation sometimes is used. Komplikasi Terapi Radiasi komplikasi terkait

Selama fase akut dari terapi radiasi panggul, jaringan normal di sekitarnya (misalnya, usus, kandung kemih, dan kulit perineum) sering terpengaruh. Akut samping gastrointestinal (GI) efek meliputi diare, kram perut, ketidaknyamanan dubur, dan pendarahan. Diare biasanya dapat dikontrol dengan memberikan baik loperamide atau atropin sulfat. Kecil steroid yang mengandung enema diresepkan untuk mengurangi gejala dari proctitis.

Cystourethritis juga dapat terjadi, menyebabkan disuria, frekuensi, dan nokturia. Antispasmodik sering sangat membantu untuk menghilangkan gejala. Urine harus diperiksa untuk infeksi mungkin. Jika infeksi saluran kemih (ISK) didiagnosis, terapi harus dilembagakan tanpa penundaan.

Kebersihan kulit yang tepat harus dipertahankan untuk perineum. Losion topikal harus digunakan jika eritema atau deskuamasi terjadi.

Gejala sisa akhir dari terapi radiasi biasanya muncul 1-4 tahun setelah pengobatan. Gejala sisa utama termasuk stenosis rektum atau vagina, obstruksi usus kecil, malabsorpsi, enteritis radiasi, dan sistitis kronis. Bedah komplikasi

Komplikasi yang paling sering histerektomi radikal adalah disfungsi kemih akibat denervasi parsial dari otot detrusor. Komplikasi lainnya termasuk vaginanya menyempit, fistula ureterovaginal, perdarahan, infeksi, obstruksi usus, striktur dan fibrosis dari usus atau usus besar rectosigmoid, dan kandung kemih dan fistula rektovaginal. Prosedur invasif (misalnya, nefrostomi atau mengalihkan kolostomi) kadangkadang dilakukan pada kelompok pasien untuk meningkatkan kualitas hidup mereka. Nutrisi

Nutrisi yang tepat adalah penting bagi pasien dengan kanker serviks. Setiap upaya harus dilakukan untuk mendorong dan memberikan asupan makanan yang cukup oral.

Suplemen gizi (misalnya, Pastikan [Abbott Nutrition, Columbus, OH] atau Boost [Nestl HealthCare Gizi, Fremont, MI]) digunakan ketika pasien memiliki berat badan yang signifikan atau tidak dapat mentoleransi makanan biasa karena mual yang disebabkan oleh radiasi atau kemoterapi. Pada pasien dengan anoreksia berat, nafsu makan stimulan seperti megestrol dapat diresepkan.

Untuk pasien yang tidak dapat mentolerir setiap asupan oral, tabung gastrostomy endoskopi perkutan ditempatkan untuk suplemen gizi. Pada pasien dengan obstruksi usus yang luas sebagai akibat dari kanker metastatik, hiperalimentasi kadang-kadang digunakan.

Treatment Protocols

Treatment protocols for cervical cancer are provided below, including treatment by stage, chemoradiation therapy, and chemotherapy. Treatment recommendations for early stage disease

Stage IA1 disease:

Primary treatment of early stage cervical cancer is surgery or radiation therapy[1, 2, 3, 4, 5, 6, 7, 8]

Treatment recommendations include extrafascial hysterectomy, modified radical trachelectomy or hysterectomy with pelvic node dissection[9] Treatment recommendations for stage IA2

Stage IA2 disease:

Patients with stage IA2 tumors are treated with radical hysterectomy or radical trachelectomy with pelvic lymph node dissection

Alternative options include brachytherapy with or without pelvic radiation therapy (total point A dose: 75-80 Gy)[10] Treatment recommendations for stage IB and IIA

Stage IB and IIA:

Patients with stage IB or IIA disease can be treated with surgery (radical trachelectomy, pelvic lymphadenectomy, radical hysterectomy plus bilateral pelvic lymph nodes dissection), pelvic radiotherapy or chemoradiation[11, 12, 13, 14, 15, 16, 17, 18, 19, 20]

If lymph nodes are positive, then a hysterectomy is not recommended; instead patient should receive chemoradiation

Patients with stage IB or IIA may also be given pelvic radiotherapy and brachytherapy with or without concurrent cisplatin-based chemotherapy[1, 21, 22, 7, 23, 24, 25, 26, 27, 28, 29, 10]

Chemoradiation therapy: Cisplatin 40 mg/m2 (maximum 70 mg) IV once weekly plus radiation therapy 1.8-2 Gy per fraction (minimum 4 cycles; maximum 6 cycles); some institutions add 5-fluorouracil (5-FU) 500 mg/m2 IV on days 2-5 and last 5d of therapy to cisplatin Treatment recommendations for advanced stage disease

Stage IIB, IIIA, IIIB, and IVA:

Traditionally, advanced disease includes stages IIB-IVA; however, many oncologists now also include patients with IB2 and IIA2 in the advanced disease category[10]

Treatment recommendations for advanced disease include concomitant chemoradiation and brachytherapy[21, 22, 23, 24, 25, 26, 27, 28, 29]

Chemoradiation therapy: Cisplatin 40 mg/m2 (maximum 70 mg) IV once weekly plus radiation therapy 1.8-2 Gy per fraction (minimum 4 cycles; maximum 6 cycles); some institutions add 5-fluorouracil (5-FU) 500 mg/m2 IV on days 2-5 and last 5d of therapy to cisplatin Treatment recommendations for metastatic disease

Stage IVB:

Patients with metastatic disease are primarily treated with cisplatin-based chemotherapy

Also individualized radiation therapy should be considered for control of pelvic disease and other symptoms[1, 7, 10]

Systemic therapy for stage IV recurrent or metastatic disease[30, 31, 32, 33, 34] :

Paclitaxel 135 mg/m2 IV over 24h (dosing at 175 mg/m2 IV over 3h is also acceptable) plus cisplatin 50 mg/m2 IV; every 3wk or

Topotecan 0.75 mg/m2 IV (or 0.6 mg/m2 IV if prior radiation therapy) on days 1-3 plus cisplatin 50 mg/m2 IV; every 3wk or

Paclitaxel 175 mg/m2 IV over 3h on day 1; every 21d

Second-line therapy for stage IV recurrent or metastatic disease:

National Comprehensive Cancer Network (NCCN) recommends agents such as bevacizumab, docetaxel, gemcitabine, ifosfamide, 5-FU, mitomycin, irinotecan, and topotecan, which are listed as category 2B (recommendations based on lower level of evidence)[10]

Category 3 (recommendations based on any level of evidence) recommended drugs include pemetrexed and vinorelbine[10]