Cervical Cancer

Cervical cancer is usually a squamous cell carcinoma caused by infection with human papilloma virus and rarely is an adenocarcinoma. Cervical cancer is asymptomatic; the first symptom of early cervical cancer is vaginal bleeding often postcoital. Diagnosis is made by screening with Pap test and biopsy-Babes. Staging is the clinic. Treatment usually involves surgical resection for disease in the initial stages and chemoradiation for locally advanced disease. If metastatic disease is often uses chemotherapy alone.

Epidemiology

In the US for 2013 it was estimated 12,300 new cases and 4,000 deaths. In EU crude incidence of cervical cancer is 13.2 / 100,000 women / year and crude mortality rate is 5.9 / 100,000 women / year. Cervical cancer is the 3rd leading cause of gynecologic cancer and the 8th leading cause of cancer among US women.

Cervical cancer is for women between 20-40 years second cause of death from cancer, after breast cancer.

In Romania the estimated incidence for 2000 was 38.98 to 100,000 women, and mortality from 15.19 to 100,000 women, ranking 2 after breast cancer.

Risk Factors

Sexual 1.Comportamentul

a) -The first sexual intercourse at a young age.

b) -The first pregnancy at a young age.

c) Multiple sexual  partners.

d) -The use of oral contraceptives or contraceptive barriers.

High parity was long recognized as a risk factor for cervical cancer, HPV infection parity but the relationship is not safe. The number of full-term pregnancy was associated with increased risk regardless of age at first pregnancy. These data were real if the analysis was limited to patients with HPV infection for seven or more pregnancies versus no pregnancy (19). Long-term use of oral contraceptives has been associated with cancer of the cervix, but the relationship with HPV infection was not sure.

Compared with women who have never used oral contraceptives, those who had used oral contraceptives for more than five years had no increased risk of cervical cancer. The overall risk for women who had used oral contraceptives for 5-9 years was 2.82. and for those who have used ≥ 10 years overall risk was 4.03 (20). The increased risk associated with use of oral contraceptives is proportional to the duration of use (21). Women who began sexual activity before age 16 and women with multiple sexual partners are at increased risk of infection with HPV (human papillomavirus) and cervical cancer occurrence. We recommend regular gynecological exam at the onset of sexual activity or at age 18. Prevention of sexually transmitted diseases reduces cervical cancer risk.

2. HPV infection

In practice HPV is the most common sexually transmitted infection (STI) with a standardized prevalence by age group 10.5%. In U.S. it affects 6 million individuals aged 15-24. Infection with human papilloma virus (HPV) types 6,11,16,18,31,33 in particular is an important risk factor.

Molecular techniques for finding human papilloma virus DNA are highly sensitive and specific. Epidemiological studies have demonstrated convincingly that the major risk factor for development of preinvasive and invasive cervix carcinoma is ​​HPV infection, which far outweighs other known risk factors such as multiple marriages, increased number of sexual partners, young age at first intercourse, socioeconomic status low positive history of smoking (15,16).

Some patients with HPV infection appears to present a low risk for development of preinvasive and invasive malignancies, while others appear to be at increased risk and are candidates for intensive Screening of programs and / or early intervention. Complications of HPV can be classified according to cell proliferation: benign nevi (condyloma acuminata or papillomas) or precancerous growths and cancerous anogenital tract inferior (LGT) and upper aerodigestive tract (UADT). The first damage caused by the most common are 2 types of low oncogenic risk HPV type 6 and 11 and cancerous lesions of the most aggressive and common types of HPV increased oncogenic risk (HR-HPV) type 16 and type 18.

From a million Papanicolaou tests (Pap) cervical squamous intraepithelial lesions reported as low grade (LSIL) in the US, 15% are caused by HPV type 6 or type 11. About 50% of vaginal lesions, vulvar and existing epithelial (prevalence) HPV types 6 or 11 are home.

In total 70% of the 493,000 cases of cervical cancer diagnosed are determined by the type 16 or 18. The median age at diagnosis is 45 years. The vaccine is made from the major capsid protein L1 of HPV naturally. L1 capsid protein when it is inserted in fungi or insects like virus assembles itself in particle (VLP virus-like particle which are similar to the external envelope of natural HPV. The vaccine is manufactured by Merck (USA) and Glaxo-Smith-Kline (Belgium). Since there VLPs are recombinant proteins naked viral DNA, they lack oncogenic properties and in addition are nontoxic and noninfectious. Studies have clearly shown that VLP vaccine generate neutralizing antibodies that prevents the HPV infection and squamous epithelial cells. The vaccine produced by GSK called Cervarix, is produced by fruit moth is a bivalent formulation of HPV L1 VLP type of 16 and 18 and an adjuvant (aluminum salts and monophosphoryl lipid A).

Merck has manufactured a vaccine called Gardasil / Silgard the fungus Saccharomyces cerevisiae (mushroom pins), is a vaccine containing VLPs URL qadrivalent and HPV types 6, 11, 16, 18, and adjuvant is an aluminum salt. Currently Gardasil is licensed in over 55 countries including 25 European countries, for children and teenagers 9-15 years and in adult females aged 16-26 years. The vaccine is administered intramuscularly in three doses 20-40μg per dose in a period of 6 months.

There is now a vaccine that protects against two HPV types that cause most cervical cancers (types 16 and 18). The vaccine is recommended for girls and women between 9-26 years before they make contact with HPV. The vaccine may also benefit women who are sexually active and have not yet been infected with HPV. The vaccine prevents HPV infection but do not get rid of it once infection has occurred.

Women who have never been infected with HPV, the vaccine protects against 7 out of 10 cases of cervical cancer is safe, very efficient and has fewer side effects.

The pace in which an invasive cancer develops from CIN is usually slow, perhaps measured in years and decades (4). This provides opportunity for natural history by screening to detect this process effectively during the preinvasive phase, thus allowing early treatment and cure. Since many of these preinvasive lesions (LSIL especially) would never progress to invasive cancer (5-7) screening risk management seeks treatment for women who need to be treated.

The main etiologic factor in the development of preinvasive and invasive cancer is infection with HPV specific types that is passed through sexual contact. Thus sexually inactive women rarely develop cervical cancer, while women sexually active at an early age with multiple sexual partners, have a greatly increased risk. About 95% of women with invasive cancer of the cervix have evidence of HPV infection (8-11).

Many women with HPV infection never develop invasive cancer however; this infection is needed so darn u enough for developing invasive cancer (12). Although mortality from cervical cancer increases with age (maximum mortality for white is between 45 and 70 years) the prevalence of CIN is highest in women between 20-30 years. Mortality is rare printer women younger than 30 years; HSIL is rare among women older than 65 years who were previously tracked through screening. Approximately 70% of ASCUS and CIN1 lesions regress in six years, while about 6% of CIN1 lesions progress to CIN 3 or  worse .Aprox 10% -20% of women with CIN 3 lesions progressing to invasive cancer (4.7 , 13).

Noninvasive squamous cell cervical abnormalities are graded histologically as cervical intraepithelial neoplasia (CIN) 1, CIN2sau CIN3 in agreement with the severity replaceable epithelial cell changes and the percentage of abnormal cell growth. CIN 3 is a reasonably reproducible diagnostic and has a 30% risk of turning into invasive cancer after several years if untreated (1). CIN 2 has a poor reproducibility and biological behavior is variable. CIN 3 is therefore a more rigorous endpoint for clinical trials.

3. Smoking may be associated with an increased risk of squamous cell cancer of the cervix (1,16,17). The risk increases with the duration and intensity of smoking. Case-control studies of HPV infected women examined the effect of different types and levels of exposure to tobacco and found similar data (17,18). There are studies showing and otherwise.

4. Diet

Multiple studies have shown an association between intake of certain micronutrients and lower risk of cervical cancer, but data are conflicting. Oral Folate proved to have no protective effect.

Signs and symptoms: no symptoms in the early stage; then appear vaginal discharge, postcoital vaginal bleeding, postmenopausal bleeding.

Screening is done by Babes Pap smear is a screening test and not a diagnostic test. The American College of Obstetricians and Gynecologists (ACOG) and the American Cancer Society recommends: women who are sexually active or have reached the age of 18 must be performed annually clinical examination and pelvic cytology. If three years in a row exam is normal Papanicolau smear test can be conducted more frequently (in 3 years).

Both incidence and mortality from cervical cancer have declined dramatically in populations in which the screening programs introduced were well conducted. The reductions in incidence and mortality from cervical cancer were proportional to the intensity of screening. The risk of cervical cancer was 3-10 times higher in women who did not screening.

Currently the US Food and Drug Administration (FDA) approved the Hybrid Capture 2 test (HC2) for detecting HPV DNA, designed to detect the 13 HPV types of carcinogens. HC2 is approved for use in two contexts: 1). as a secondary test (yards) after an equivocal cytology result of atypical squamous cells of undetermined significance (ASCUS) and 2). for primary screening in conjunction with cervical cytology for women of 30 years and older. Women who are negative by cytology and HPV test were extremely low risk for CIN 2 or CIN 3 and therefore screening should be done less often. Screening more often once in three years do not improve significantly the sensitivity but increase costs and overtreatment.

Pathological Anatomy

I. Cervical intraepithelial neoplasia(CIN). It is characterized by cellular immaturity, cellular disorganization, nuclear abnormalities, increased mitotic activity.

Neoplasia grade is determined based on mitotic activity, nuclear atipical immature cell proliferation.

It is subclassified in CIN grade I or mild dysplasia, CIN Grade II or moderate dysplasia and severe dysplasia CIN grade III or carcinoma in situ. CIN may progress to invasive cancer may be stationed indefinitely or may regress. Spontaneous regression occurs in CIN I and CIN is rare in CIN II and III.

The conference proposed NCI 1988 Bethesda classification system comprising:

a). ASCUS Atypical squamous cells of undetermined-significance

b). Squamous intraepithelial lesion (SIL) low grade including CIN I and atypical cytological associated with human papillomavirus infection.

c). Squamous intraepithelial lesion (SIL) high grade CIN II and CIN includes carcinoma in situ III and

d). Invasive squamous cell carcinoma.

II. adenocarcinoma in situ (AIS). Normal endocervical glands are replaced by high columnar cells, irregular, increased mitotic activity, but there is no stromal invasion. AIS is frequently multifocal and conization not a safe therapeutic intervention. 20% -50% of women with AIS have CIN.

III. Microinvasive carcinoma. Depth be measured with a micrometer invasion of the epithelium to the deepest point of invasion. Lesions that have invaded <3mm are assigned std.I-A1 and rarely metastasize. Lesions that have invaded the stroma of 3-5 mm are assigned stg.I-A2 and pelvic lymph metastasize 5% – 10%. The term does not apply to microinvasive adenocarcinoma here there are only AIS term or invasive adenocarcinoma.

IV invasive squamous cell carcinoma accounts for 80% – 85% of all cervical cancers. It has three varieties:

a) carcinoma, large cell non-keratinous carcinoma, it is the most common

b) large cell carcinoma, squamous keratinized

c) small cell carcinoma has a worse prognosis as one large cell

d) small cell anaplastic carcinoma presents neuroendocrine secretion intracellular and has a poor prognosis

V. carcinoma is 15-20% of cervical cancers.

VI. Adeno carcinoma squamous

VII. Rarely can occur: adenosarcomas, leiomiosarcomas, lymphoma, malignant melanoma

VIII. Metastatic colon tumors, breast, and other offices, are extremely rare.

Diagnosis and staging. Cervical cancer is the only gynecological malignancy in the field is still only clinically staged.

For diagnosis and staging is recommended:

– History, clinical examination,

-blood work, complete liver tests, kidney tests,

– genital and rectal examn

– cervical biopsy, pathological review

Relevant experience ≤ imaging options for stages IB1:

            Pulmonary –X-ray

            -CT Or PET-CT

            -MRI If indicated

smoking definitive obstacles

-Testing HIV (Category 3)

-cistoscopy, proctoscopy

 The diagnosis is confirmed by histopathology.

Frequent errors in diagnosis and management of gynecological malignancies

1. Failure to perform a complete history and physical examination

2. Over-examinations and laboratory and clinical data underestimation of clinical suspicion

3. Failure to perform a pelvic exam as part of an initial exam.

4. The absence of endocervical cells on the Pap smear may indicate that the sample was not collected scuamocolumnar junction (where cervical cancers arise) and the smear is not adequate and therefore should be repeated.

5. cervical lesions should be biopsied visible from or sent for colposcopy urgent. Pap test is a good diagnostic test for invasive cancers since the bleeding and inflammation can stop the pathologist to read smears.

6. Abnormal vaginal bleeding leaks and requires that the patient will have a pelvic exam. Many patients sent diagnosed with cervical cancer have not performed pelvic exam since it was supposed that symptoms were be due to infection or abnormal menstrual periods.

Differential Diagnosis

1. Endometrial Cancer

2. primary or metastatic melanoma

3. epithelial or non-epithelial tumors of the ovary.

FIGO staging, TNM

Tx: primary tumor cannot be evaluated

T0: No evidence of primary tumor

Stage * (0 does not exist) (Tis) – carcinoma in situ, intraepithelial carcinoma, squamous preinvasive

Stage I – strictly limited to cervical carcinoma (extension to the uterus not taken into account)

Stage IA ** – Invasive cancer identified only microscopically. All

gross lesions even with superficial invasion are staged IB

Stromal invasion is deeper than 5 mm and 7 mm wide.

Stage IA1 (T1a1NoMo) – stroma invasion is not measured

depth of 3 mm and 7 mm wide.

Stage IA2 (T1a2NoMo) – stroma invasion measured in depth exceeds 3mm but is less than 5 mm and not larger than 7 mm.

Stage IB – clinical lesions limited to the cervix or microscopic lesions greater than IA2

Stage I B1 (T1b1NoMo) – clinical lesion is not more than 4

cm in greatest diameter

Stage I B2 (T1b2NoMo) – Clinical lesion greater than 4 cm in greatest diameter

Stage II carcinoma extends beyond the cervix but does not extend to the pelvic wall or lower 1/3 of the vagina. 2/3 carcinoma invading the upper vagina.

Stage IIA (T2aNoMo) – Invasion of the upper 2/3 of the vagina; there is no apparent invasion of the parameters.

Stage II-A1 (T2a1NoMo) ≤ 4 cm -lesion clinically visible in greatest diameter

Stage IIA2 (T2a2NoMo) visible clinical -lesion> 4 cm in greatest diameter

Stage IIB (T2bNoMo) – obvious parametrial invasion

Stage III carcinoma has spread to the pelvic wall. On rectal examination there is free space between the tumor and pelvic wall ***. The tumor invades the lower third of the vagina. All cases of kidney hydronephrosis are included if there are no other causes.

Stage IIIA (T3aNoMo) – No extension to the pelvic wall. The tumor invades the lower third of the vagina

Stage IIIB (T3bNoMo) – Extension to the pelvic wall and / or hydronephrosis or non-functioning kidney

                       T1-3 N1Mo

 Stage IV carcinoma exceeded invaded the pelvic wall or lining of the bladder or rectum Clinical. Bullous edema does not allow allocation to stage IV.

Stage IVA (T4a any N Mo) – extension to adjacent organs: bladder mucosa, rectal.

Stage IVB (anyT anyN M1) – extension to remote organs.

                   M0- no distant metastases

                   M1 – distant metastasis (including peritoneal dissemination, peritoneal lymph node invasion, mediastinal, para-aortic, lung, liver, bone).

Note: * FIGO no longer includes stage A

** All macroscopically visible lesions even with superficial invasion are T1b / IB

*** On rectal examination there is free space between the tumor and the pelvic wall

All cases with hydronephrosis or nonfunctional kidney included here provided it is not due to another cause.

TREATMENT

Therapeutic Indication

Preinvasive disease (FIGO classification does not exist in Stage 0)

a) It is recommended cryosurgery, laser therapy or Electro if:

-the whole transformation zone was visualized colposcopic

-biopsies conducted are consistent with Papanicolaou test results.

– negative endocervical curettage

-there is suspected occult invasion to cytology or colposcopy. Relapses occur in 10-15%.

b). Conization is recommended when you do not meet these criteria. The cure rate is higher than 90%. Tracking is done by Pap test endocervical curettage and 3 months for 1 year and then annually.

Stage IA (I A1 and I A2) the standard treatment is surgical.

Stage I A1 (without lymphovascular space invasion).

Conization is recommended for diagnosis:

            a. patient with negative margins and inoperable; observation recommended

b. negative margins and operators; extrafascial hysterectomy is recommended.

c. dysplasia or carcinoma positive margins; Modified radical hysterectomy is recommended or lymph node dissection plus extrafascial

Patients who want children indicated conization. In this case conization edges must be free of invasive disease or preinvasive 3 mm negative margins. Tracking these patients is intensive Papanicolaou test, colposcopy and endocervical curettage 3 months for 1 year.

Stage I A1 (lymphovascular space invasion) and stage IA2.

It is recommended: a). Modified radical hysterectomy plus pelvic lymph node dissection plus / minus para-aortic lymph node biopsy or

                        b). Pelvic radiotherapy plus brachytherapy (total dose in point A 70-80Gy)

Patients who want children indicated conization. In this case conization edges must be free of invasive disease or preinvasive with negative margins plus free 3mm pelvic lymph nodes dissection. Another option is trachelectomy pelvic lymph node dissection radical addition

 Tracking these patients is intensive Papanicolaou test, colposcopy and endocervical curettage 3 months for 1 year.

The risk of pelvic lymph node metastases in stage I A2 is 5-8%. The cure rate exceeds 95%.

Patients who have serious medical problems or contraindications for surgical treatment and stage IA2 can be treated by intracavitary radiation therapy and pelvic external beam radiotherapy (total dose in point A = 70-80Gy) with 100% cure rate for cancer in situ and 96% for stage IA.

Stage I II A B 1 and 1

Pelvic Lymph node metastases occur in 15% -25% of patients with stage IB but more frequently in stage I to stage I B1 B2 that.

                  a) Otimal treatment: radical hysterectomy and pelvic lymphadenectomy is bilateral para-aortic lymph node biopsy plus. The surgery removes the cervix, uterine body, and paravaginal paracervical tissue, upper vagina ½ and common iliac lymph node excision, external and internal. An advantage of the operation is to preserve ovaries in young people.

If the histopathology of play operators as risk factors: tumor in or near the edge surgical pelvic lymph node metastasis, lymphovascular invasion, tumor larger than 5 cm in diameter then you need to associate concurrent external chemoradiotherapy and intracavitary surgery. Another therapeutic option is:

                     b. pelvic radiotherapy plus brachytherapy (total dose in Section A: 80-85 Gy) plus / minus concurrent cisplatin-based chemotherapy can be used with equal chances of healing. Concurrent cisplatin-based chemotherapy in combination with radiation therapy uses either cisplatin plus 5 fluorouracil alone or cisplatin. In older patients with coexisting medical problems that increase the risk of intraoperative or postoperative complications with tumors larger than 5 cm is recommended pelvic radiation therapy plus concurrent cisplatin-based chemotherapy.

The treatment consists of irradiating the entire pelvis intracavitary brachytherapy associated with uterine, vaginal fornix and the endocervical canal. Pelvic radiotherapy ensures uniform irradiation of the whole pelvis with a total dose of 4500-5500 cGy daily dose of 150-200cGy, 5 days / week. At the end of treatment tumor receives 7500-8500 cGy and 5500-6500 cGy pelvis. Brachytherapy treats the central portion of the tumor. The sequence of two treatment modalities is given tumor volume and size of the vagina.

Radiation therapy may be an option for patients with medical contraindications or who refuse surgery ones.

Stage I and IIA2 B2.

a) Pelvic Radiotherapy plus cisplatin based chemotherapy plus brachytherapy is the preferred treatment because the surgery cannot get adequate resection margins. Patients should be treated with the maximum dose radiotherapy (8500 cGy) delivered both externally and by brachytherapy (total dose in point A ≥ 85 Gy).

Another option (category 2B):

b). Total hysterectomy plus pelvic lymph nodes dissection plus / minus para-aortic lymph node biopsy.

Another option is (Category 3):

c). Pelvic Radiotherapy plus concomitant cisplatin-based chemotherapy plus brachytherapy (total dose in point A 75-80 GY) plus adjuvant hysterectomy

After surgery for stages I and IIA can find the following situations:

I. negative node. In this situation we recommend:

or follow a.-

b. pelvic radiotherapy if there is a combination of risk factors (large primary tumor, deep stromal invasion and / or lymphovascular space invasion).

            II positive pelvic lymph nodes and / or positive surgical margins and / or positive parameter

                        Recommended: Pelvic Radiotherapy plus concomitant chemotherapy based on cisplatin plus / minus vaginal brachytherapy

            III. Positive para-aortic lymph through surgical staging. It indicates CT chest CT or PET: a. Metastasis negative distance. Radiation therapy is recommended plus para-aortic lymph nodes chemotherapy plus concurrent cisplatin-based Pelvic Radiotherapy ple / minus brachytherapy.

                        b. Positive distant metastases. Consider biopsy of suspicious areas. If the biopsy is negative, recommended for distant negative metastasis. If the biopsy is positive then it is recommended systemic therapy plus / minus Radiotherapy

Stage I B 2 stage II A2

 I .It indicates radiological imaging:

            a. lymphadenopathy negative. Pelvic radiotherapy plus chemotherapy is recommended concurrent cisplatin-based brachytherapy plus

            b. lymphadenopathy positive needle biopsy is considered and pelvic lymphadenopathy If lymphadenopathy is positive para-aortic recommended brachytherapy plus radiotherapy plus chemotherapy extended field-based concurrent cisplatin

            II. Another option is surgical staging (category 2B) or laparoscopic extraperitoneal lymph node dissection.

            a. lymphadenopathy negative. Pelvic radiotherapy is recommended plus cisplatin based chemotherapy plus brachytherapy

              b. positive lymphadenopathy. It is recommended further radiological imaging to detect distant metastases:

1. distant metastases absent: pelvic radiation therapy plus radiotherapy is recommended para-aortic lymph nodes plus cisplatin based chemotherapy plus brachytherapy

                                    2. Positive distant metastases. We recommend systemic radiotherapy plus / minus 2 systemic therapy. Stg IB, II stage A2, stage IIB, IIIA, IIIB, IVA

Nodal status

1. adenopathy positive pelvic and para-aortic lymph node negative by surgical staging. Pelvic Radiotherapy plus chemotherapy is recommended concurrent (category 1) plus brachytherapy.

2. adenopathy paraortic positive by surgical staging. It is recommended further radiological imaging to detect distant metastases:

1. distant metastases absent: pelvic radiation therapy plus radiotherapy is recommended para-aortic lymph nodes plus cisplatin based chemotherapy plus brachytherapy

                                    2. Positive distant metastases. We recommend systemic therapy plus / minus systemic radiotherapy

Stage IB2, IIA2,

Stage IIB, IIIA, IIIB, IVA

Results imaging

Positive adenopathy by CT, MRI and / or PET

1). Pelvic lymph node positive para-aortic lymph node negative:

            a). Pelvic Radiotherapy plus cisplatin based chemotherapy plus brachytherapy (category 1) para-aortic lymph node positive or ± RT

            b). Laparoscopic or extraperitoneal lymph node dissection

                        paraaortic -ganglion negative. We recommend pelvic RT plus cisplatin based chemotherapy plus brachytherapy

                        paraaortic -ganglion positive. It is recommended extended field RT plus cisplatin based chemotherapy plus brachytherapy.

2). Positive pelvic lymph nodes, positive para-aortic lymph node: lymph node dissection is considered laparoscopic or extraperitoneal. It is recommended extended field RT plus cisplatin based chemotherapy plus brachytherapy.

3). Distant metastasis with biopsy confirmation when indicated. RT ± systemic therapy is recommended identified.

Cisplatin based chemotherapy and 5 FUR reduced the risk of death by 20-40% and is associated compulsory radiotherapy treatment.

Schemes used in combination with radiotherapy for stage IB-IVA are:

1. cisplatin 40 mg / m2 IV once a week (not exceeding 70 mg / week) plus radiotherapy 1.8-2 Gy per fraction (minimum 4 cycles; a maximum of 6 cycles) or

2. Cisplatin 50-75 mg / m2 IV on day 1 plus

    5 Fluorouracil (5-FU) 1000 mg / m2 IV continuous drip, days 2-5 and days 30-33 (total dose 4,000 mg / m2 per cycle) or

3. Cisplatin 50-75 mg / m2 IV on day 1 plus

     5-FU 1000 mg / m 2 IV continuous drip 24 hours 1-4 days (total dose 4000 mg / m2 per cycle) at 3 weeks a total of 3-4 cycles.

Stage IV and recurrent disease. For the rectum or bladder tumors extensive radiotherapy is recommended aggressive sometimes followed by surgery. Pelvic exenteration should be considered if 3 months after the end of radiotherapy central disease persists and if the tumor is fixed to the pelvic wall.

In patients with recurrent disease or tumor fixed to the pelvic wall not suitable for surgical treatment of interstitial radiotherapy is recommended implantation of I125.

Palliative radiotherapy is indicated in lymph node metastases, lung and bone. The radiation dose is 30 Gy in 10 fractions.

Carcinoma of the cervix after hysterectomy found at histopathology simple.

In patients treated by simple hysterectomy and invasive carcinoma which is recommended:

a) If it is found at histopathology microinvasive carcinoma (I A1) without lymphovascular invasion is not recommended additional treatment. It follows the patient.

b) If there are notes of microinvasive carcinoma (I A1) with lymphovascular invasion or invasive carcinoma (≥ IA2) is recommended:

– Clinical examination and history

– Full blood count with differential white blood

– The study of kidney function

– Case studies in tumor imaging ≥ I B1:

Pulmonary  X-ray

-CT Or- PET-CT

– MRI if indicated

– Tumor free margins at the imaging study.

We recommend

– Pelvic irradiation with a total dose of 5000 Gy c 6 weeks after surgery plus brachytherapy ± chemotherapy. Or:

Full -parametrectomy plus vaginectomy plus pelvic lymph node dissection plus / minus para-aortic lymph node dissection.

If lymph nodes are negative follow-up is recommended.

If lymph nodes are positive or positive resection margins or positive parameters recommended pelvic RT plus cisplatin based chemotherapy ± vaginal brachytherapy if margins are positive.

     – Whether microscopic or macroscopic disease is extended to the resection margins, or macroscopic residual disease whole pelvis irradiation plus recommended vaginal brachytherapy.

Recurrent carcinoma

1. Relapse after surgery. May be central recurrence (of the vagina) or pelvic wall recurrence. The prognosis is better for patients with relapsed center. The recommended treatment is aggressive external radiotherapy. 5-year survival rate is 20-40%.

2. Relapse after irradiation final. Depending on the extent of disease is recommended prior hysterectomy, pelvic exenteration previous or total exenteration. Pelvic wall invasion is a contraindication to exenteration. Unilateral leg swelling, pain and sciatic type ureteral obstruction indicates tumor invasion of unresectable disease pelvic wall.

 Stage IV B

            Patients with metastatic disease are mainly treated with cisplatin-based chemotherapy. In addition individualized RT should be considered for pelvic disease control and other symptoms.

First-line therapy for stage IV recurrent or metastatic disease

      1. Bevacizumab 15 mg / kg IV 30-90 min

           Cisplatin 50 mg / m2 IV on Day 1 or 30-90 min 2

           Paclitaxel 135 or 175 mg / m2 IV on day 3 or 24 h in 1-3 wk.

 or

      2. Bevacizumab 15 mg / kg IV 30-90 min

          Paclitaxel 175 mg / m2 IV over 3 hours on day 1

         Topotecan 0.75 mg / m2 IV on days 1-3 min 30 3 wk

 or

      3. Paclitaxel 135 mg / m2 IV in 24 hours (175 mg / m2 IV 3 hours is also acceptable

          Cisplatin 50 mg / m2 IV day 1 to 3 weeks

 or

       4. topotecan 0.75 mg / m2 IV (or 0.6 mg / m2 IV if made prior RT) 1-3 days

           Cisplatin 50 mg / m2 IV day 1 to 3 weeks

or

   5. Paclitaxel 175 mg / m2 IV on days 1-3 weeks 3h

Second line therapy for stage IV recurrent or metastatic disease

It is recommended (category 2B): -Docetaxel

                                                   -Gemcitabine

                                                   -Ifosfamide

                                                   -5 FUR

                                                   -Mitomicine

                                                   -Irinotecan

                                                  -Topotecan

Charts

Tumor dissemination is done by:

1. Extension direct local tissues: vagina tissue and paravaginal, bladder and rectum.

2. Extension iliac lymph nodes about external hypogastric, common iliac and para-aortic lymph.

3. Dissemination through blood: bone metastases, lung, liver, brain.

Complications

1. Bleeding

2. liver and lung metastases

3. renal insufficiency bilateral ureteral obstruction

4. Intestinal obstruction by peritoneal carcinomatosis

5. edema and thrombophlebitis of the lower limbs due to compression of pelvic tumor.

6. Bone and pelvic pain due to tumor invasion.

Prognostic

Prognostic factors:

1. Clinical stage most important prognostic indicator. The more advanced the stage of survival is lower: 100% 0- stage, stage I – 80%, stage II – 60%, stage III – 30% stage IV 5%

2.Invasion lymph nodes has a poor prognosis. The bigger positive nodes are survival is lower.

Nr. GGL. pelvic invaded Survival at 5 years

1 GGL. 62%

2 GGL. 36%

GGL 3-4. 20%

≥ 5 GGL. 0%

3.Size of tumor. In the same stage as the tumor is bigger local recurrence risk is higher.

For stage IB and IIA

Tumor size (cm). The risk of relapse at 10 years

≤ 2 cm 5%

2,1 5 cm 15%

> 5 cm 35%

4. Histological markers. Squamous cell carcinoma small cell has a poor prognosis. Poorly differentiated tumors have a poor prognosis. Positive vaginal margins, positive parameters and extent of the endometrium are unfavorable prognostic factors.

ECOG performance 5.Statusul 3.4 and anemia are unfavorable prognostic factors.

The survival to 5 years

Stage 5-year Survival

Stage I 80-90%

Stage II 60 -75%

Stage III 30-40%

Stage IV 0-15%

Tracking is done through history, clinical examination, gynecological. Babes Papanicolaou cytology for the detection is done annually lower genital tract neoplasia pulmonary thoracic radiography, CT, PET, PET-CT, MRI is recommended based on patient symptoms, in case of suspected local recurrence. Biochemical analyzes and blood count is recommended based on patient symptoms in cases of suspected local recurrence. It recommends the use of vaginal dilator after RT. Educating the patient about symptoms of recurrence potential.

In case of persistent or recurrent disease recommend additional imaging or surgical exploration in selected cases.