Ovarian Cancer

Epidemiology

Ovarian cancer represents 4% of all cancers diagnosed and causes 5% of all cancer deaths. There was no improvement in survival over the last 30 years because 65% -70% of all cases are diagnosed in stage III and IV disease.

Ovarian cancer is the sixth leading cause of cancer in women in Europe (5% of all cancers) In Europe it is estimated that 61,000 cases are diagnosed annually 39,000 pine ovarian cancer deaths. The risk of ovarian epithelial tumors increases with age, most occur in women in peri or postmenopause.  Germinal or embryonic origin tumors are more common in young women. Overall mortality increased for several years but then stopped in the late 1980s.

EU Gross incidence of 18 / 100,000 women per year and 1212 deaths / 100,000 women per year. The average age at diagnosis is 63 years. Incidence increases with age and reaches a peak in the 8th decade.

For ovarian cancer survival is generally low. In Europe, the relative survival was 66%, 45% and 37% at 1, 3 and 5 years of diagnosis. 5 years survival from germ tumors has been reported in girls (92%) and teenage girls and young women (95%).

In Romania the estimated incidence for 2000 was 14.18 per 100,000 and mortality from 7.33 per 100,000 inhabitants.

Risk Factors

1. Age: Epithelial ovarian cancer is a disease of older women. The incidence rate increases with each decade of life and reaches peak at the end of the 7th decade. Except for hereditary forms of the disease is unknown epithelial ovarian cancer four years before.

2. Genetic characteristics: about 5% -10% of ovarian epithelial cancers result from an inherited predisposition and identified three distinct patterns:

a). Headquarters specific ovarian cancer syndrome (10% -15%) of all cases. The most important risk factor for ovarian cancer is a family history of ovarian cancer in first-degree relatives (mother, daughter or sister). These women have 4% -7% lifetime chance of developing epithelial ovarian cancer until the age of 70 years with a relative risk of 3.1. The greatest risk occurs in women with 2 or 3 degree relatives with epithelial ovarian cancer (Stratton 1998). At most affected families ther were found mutations in the BRCA1 gene.

b). Breast-ovarian cancer syndrome ovarian cancer in those families is characterized by multiple cases of breast and ovarian cancer in successive generations, a relatively early onset (premenopausal) and evidence of both paternal and maternal transmissions. Hereditary syndrome is due to chromosome 17q mutation of the BRCA1 gene 12-21 (81% of cases) and 13q chromosome less mutation on BRCA2 gene. The mode of transmission is autosomal dominant with variable penetrance, which implies that a single mutant allele is sufficient to promote breast or ovarian cancer and each child has a 50% chance of inheriting a mutant allele. In these families the risk of breast cancer is 35% -85% and 15% of ovarian cancer 60%.

c). Lynch II syndrome or syndrome nonpolipoid hereditary colorectal cancer. (HNPCC) In HNPCC the increased risk for ovarian cancer is associated with an excess of colorectal and endometrial cancer (Lynch 1998). This syndrome could be due to an inherited defect in one of four genes inadequate DNA repair (hMSH2, hPMS1, hMLH1, hPMS2). The risk for ovarian cancer was 12% and 80% for colorectal cancer.

Prophylactic oophorectomy: Patients with a family history suggestive of inherited ovarian cancer should be offered genetic testing checkup.

The potential benefit of genetic testing for BRCA mutations include the identification of women at increased risk of developing ovarian cancer and cancer of the breast, maximize surveillance measures for early detection of the disease, the possibility of offering surgical prophylaxis introduction pharmacological interventions and lifestyle. Currently prophylactic oophorectomy benefits have not been established. Women with mutations in the BRCA1 / BRCA2 should be counseled that this surgery is a possible treatment option.

Numerous reports have described the primitive peritoneal cancer, ovarian cancer similar to 1.8% -10.7% of patients who underwent prophylactic oophorectomy. Prophylactic bilateral oophorectomy may provide benefit for women at high risk for ovarian cancer. However, this process is not completely protective against peritoneal cancer. Patients with HNPCC syndrome have genetic counseling and should be offered prophylactic surgery (hysterectomy and salpingo oophorectomy prevention) to reduce the risk of gynecological malignancies.

3. Hormonal Features

The use of exogenous hormones for menopause symptoms may be associated with an increased risk of ovarian cancer. It was shown that prolonged periods of hormone therapy replacement (> 5-10 years) confers an increased risk of 1.5- 2 times. A decreased risk of ovarian cancer following the use of oral contraceptives for 5-10 years. Lactation is associated with a decreased risk of ovarian cancer. Excess weight confers a moderate increase in risk for ovarian cancer.

4. Environmental characteristics diet rich in meat and low in vegetables is associated with an increased risk of ovarian cancer. Women who consume large amounts of low fat milk, or lactose calcium had a lower risk of ovarian cancer. Exposure to talc or asbestos may initiate ovarian carcinogenesis. Smoking offers an increased risk of ovarian cancer in general and mucinous tumors.

Screening

Screening for ovarian cancer has not been shown to reduce mortality in the general population is not currently recommended. Statistical low prevalence of ovarian cancer in the general population (0.04%) makes effective screening almost impossible. It would be recommended screening women at high risk for ovarian cancer (hereditary ovarian cancer syndrome). It consists of: pelvic exam, transvaginal ultrasound and CA 125 annually.

Histologic Types

I. Epithelial tumors 85-90% (all can be benign, borderline, malignant)

1. Serous cystadenocarcinoma 75% -80%

1. Mucinous cystadenocarcinoma10%

2. endometrioid carcinoma 10%

3. Clear cell carcinoma (mezonefromul (<1%))

4. Brenner tumors <1% (transitional cell)

5. Undifferentiated carcinoma <1%

6. Mixed epithelial tumors

II. 10% Germ Cell Tumors

1. Disgerminoma (secret LDH)

2. Teratomas (not AFP and – ¢ HCG secreting)

• immature teratoma

• mature teratomas

• monodermal and highly specialized

a struma ovaries

a carcinoid

a ovaries and carcinoid struma

3. endodermal sinus tumors (secrete AFP)

4. embryonic carcinoma (AFP secret and – ¢ HCG)

5. Poliembrioma

6. Choriocarcinoma (secret – ¢ HCG)

7. Joint Forms

III. Stromal tumors of the sexual cords 8%

1. stromal cell tumors

These are tumors: Borderline, rarely malignant, produce estrogen

2. Sertoli-Leydig cell tumor

These are tumors with low malignancy (borderline), rarely malignant, secrete androgens.

3. steroid cell tumors

4. Gynandroblastomas

5. mixed mesodermal sarcoma

IV. 5-6% metastatic tumor metastasis to other organs.

1. metastasis of tumor genital

• tubal carcinoma

• carcinoma of the cervix

• carcinoma of the uterine body

2. Metastasis of the breast tumor-

3. Krukenberg tumors arise in ovarian stroma and have characteristic signet ring cells, mucin-rich; they are bilateral. Tumor home is rare stomach and colon, breast, biliary tract

4. ovary metastasis of colon adenocarcinoma

5. intestinal carcinoid can metastasize to the ovary

6. leukemia and lymphoma affect bilateral ovaries

Ovarian Epithelial tumors can be benign, with low malignancy (borderline) and malignant (invasive).

Epithelial tumors with low malignancy (borderline) have a very good prognosis compared with malignant (invasive), occurring predominantly in premenopausal women tend to remain confined to the ovary. Histologically they have stromal invasion.

Malignant epithelial tumors are characterized histologically by an infiltrative growth pattern, disorganized, with stromal invasion.

Histological grade (grading) is an independent prognostic factor in epithelial tumors.

Well-differentiated malignant epithelial tumors G1-

G2 moderately differentiated malignant epithelial tumors

Poorly differentiated malignant epithelial tumors G3-

Tumor markers

CA -125 is normal <35U / ml. It is secreted by the epithelial tumors standard tumor marker in the evaluation of pelvic tumor mass. In postmenopausal women with pelvic tumors and elevated CA-125 is recommended laparotomy. CA values ​​in premenopausal women -125 exceed 65-200U / ml to differentiate a benign cyst from a malignant cyst. The functional ovarian cysts CA-125 level is stable or decreasing while CA-125 values ​​malignant cysts grows during this time. The level of CA-125 is elevated in 80% of women with advanced ovarian cancer. It is useful when preoperative and postoperative assessment was increased confirm or deny effective therapy.

CA125 is expressed by epithelial ovarian tumors. Increased levels of CA125 were observed more frequently in women with ovarian carcinoma (82%) than women in the general population (1%), women with benign disease (6%) or women with cancers nonginecologice (28.5%). CA125 levels are elevated in 23% to 50% of cases with stage I and 90% of patients with stage II. A high level of CA125 can confirm a suspicion of ovarian cancer in a postmenopausal woman especially in the presence of pelvic masses. A normal level of CA125 cannot be taken as a guarantee against malignancy, because up to 25% of ovarian cancers have tumor markers negative (Mann 1988). In addition to many gynecological premenopausal women are known to be associated with elevated levels of CA125. Examples include uterine leiomyomas, endometriosis and pregnancy and all may be associated with additional abnormal pelvic mass. Liver disease and lung and other malignancies can also lead to increases in CA125 plus limited use as a primary diagnostic tools.

Recently determining blood lisophosfatidic acid (LPA), which possess similar activities and mitogenic growth factor has been studied in patients with ovarian cancer.

AFP is secreted by endodermal sinus tumor and embryonic carcinoma

HCG is secreted by embryonic carcinoma and choriocarcinoma. They are useful in preoperative recognition of germ cell tumors that secrete. Tracking the level of AFP and HCG is effective in assessing treatment efficacy even when there were increased preoperatively.

Placental alkaline phosphatase, LDH and are produced by disgerminomas and can be useful for monitoring the disease.

Signs and symptoms:

Ovarian cancer does not produce many symptoms in the early stages. This is why 75-80% of cases are detected at advanced stages. Most patients show symptoms 6-12 months before ovarian cancer detection. Symptoms are due to appear in late stages of tumor that increases abdominal pressure. It is not known what percentage of ovarian cancer produce symptoms in the early stages. We know that 90% of patients with stage I ovarian cancer is present with symptoms before being diagnosed. Almost half of the cases symptoms at least three months before being detected and 11% have symptoms less than 1 year. Common symptoms are nonspecific and may be caused by a number of other non-cancer diseases.

Only 20% of patients with ovarian cancer are diagnosed at an early stage when the disease is curable.

89% of women with early ovarian cancer and 97% of patients with advanced ovarian cancer have symptoms 6-12 months before diagnosis

However, if a woman experiences one of these sudden symptoms, and if they persist for more than 2-3 weeks, then it requires a gynecological clinical examination and laboratory explorations in order to detect a possible ovarian cancer.

The most common symptoms are:

– Abdominal bloating, clothes become narrow

– Abdominal pain or pelvic, abdominal pressure, feeling “bloated”.

– Gastrointestinal symptoms (belching, indigestion, nausea, changes in bowel habits, constipation or diarrhea).

– Drain or vaginal bleeding

– Urinary Disorders: impending urination, burning on urination

– Fatigue and fever

– Pain or bleeding during sex

– Lumbar Pain

– Dyspnea (difficulty breathing)

For these cases we recommend pelvic and rectal clinical examination, transvaginal ultrasonography and tumor marker CA -125. CA 125 test may omit half of patients with ovarian cancer, and half of the tests are false positives.

Ovarian cancer does not cause symptoms. In the early stage frequent urination or constipation accuse patient and occasionally lower abdominal distension, pressure and pain. Ovarian cancer may present as a surgical emergency secondary to torsion or rupture of ovarian tumor. In advanced disease patients present with symptoms related ascites, invasion of bowel and omentum including abdominal distension, abdominal pressure, constipation, nausea or early satiety. The most important sign is the presence of mass rectovaginal pelvic examination.

A fixed pelvic mass, rugged, solid, is highly suggestive of ovarian malignancy. The diagnosis of pelvic mass ultimately requires an exploratory lapararatomy. Preoperative evaluation should include hematological and biochemical chest X-ray, transvaginal ultrasound and CA 125 Patients with ascites and no pelvic mass should undergo an abdominal-pelvic CT or MRI to rule out a tumor liver or pancreas. Colonoscopy and gastric radiography are indicated if the patient has severe anemia and weight loss or if there is clinical evidence of bowel obstruction.

When ovarian cancer is suspected, a pelvic exam is recommended. If palpable adnexal mass is detected in postmenopausal women is recommended exploratory laparotomy. In premenopausal women is recommended only if the observation period is not clinically suspected adnexal mass (furniture, mostly cystic lesion is unilateral and less than 8 cm. In general observation should not last more than two months, in which Hormone suppression period is used. If no regression occurs in tumor mass or if they increase in size exploratory laparotomy should be performed.

In the world, women’s lifetime risk of ovarian cancer is 1 in 70. In the US the risk is 1 in 55.

TNM staging

Category TNM Stg.FIGO

Tx – primary tumor cannot be evaluated

T0 – No primary tumor signs

T1 I

Ta1 IA tumor is confined to one ovary, capsule

intact. No tumor on the surface

ovary. No malignant cells in ascites

or peritoneal lavage fluid

IB T1b Tumor is limited to both ovaries,

capsules intact, no tumor in the ovarian surface. No malignant cells in ascites or peritoneal lavage fluid.

T1c IC Tumor is limited to one or both

ovary with one of the following: capsule ruptured, tumor on ovarian surface, malignant cells in ascites or peritoneal lavage fluid.

T2 II Tumor affects one or both ovaries with

Pelvic extension and / or implants

T2a IIA Extension and / or implantation on the uterus and / or

tubes . No malignant cells in the ascites or peritoneal lavage fluid

T2b IIB Extension to other pelvic tissues, cell

malignant ascites or lavage fluid

peritoneal

T2c II C pelvic extension (2a or 2b) cell

malignant ascites or peritoneal lavage fluid

T3 and / or N1 III Tumor invades one or both ovaries

with microscopically confirmed peritoneal metastasis outside the pelvis and / or lymph node metastases are classified as superficial liver regional .Metastases stage III. The tumor is confined to the pelvis but histologically verified malignant extension exists in the small intestine or omentum.

T3a IIIA peritoneal metastasis outside the pelvis

T3b IIIB Macroscopic peritoneal metastasis outside

The pelvis, 2 cm in greatest diameter

T3C III C peritoneal metastases beyond pelvis> 2

cm in greatest diameter and / or

III N1 regional lymph node metastases C

IV M1 distant metastasis (excluding peritoneal metastasis) .If pleural effusion is present must be positive cytology to be classified as stage IV. Parenchymal liver metastases are classified as stage IV.

For staging is recommended:

• Historically, complete clinical examination, genital examination,

• CBC, biochemical tests,

• CXR, abdominal ultrasound,

• C. T. abdominal,

• CA 125 or other tumor markers indicate if

• abdominal cavity exploration laparotomy

• histopathology of pieces harvested.

Staging is based on data found at surgical exploration

The diagnosis is confirmed by histopathological examination.

Natural Evolution

Extension disease is about:

-intraperitoneal: Ovarian cancer usually disseminated through local seeding into the peritoneal cavity followed by implantation on the peritoneum and via local invasion of bowel and bladder.

– By retroperitoneal lymph. The incidence of positive lymph during primary laparotomy was reported to be 24% in patients with stage I, 50% in patients with stage II, 74% in patients with stage III and 73% in patients with stage IV. In this study pelvic ganglia were involved as often as the para-aortic lymph. Tumor cells may also block diaphragmatic lymphatics. Preventing the lymphatic drainage of the peritoneum is thought to play a role in the occurrence of ascites in ovarian cancer. Also transdiaphragmatic dissemination to the pleura is common.

– By marrow: liver metastases, lung, bone

Complications

1. Acute Abdomen ruptured ovarian tumor

2. Ascites neoplastic

3. Neoplastic pleurisy

Differential Diagnosis

1. Benign uterine: uterine fibroids

2. Annex chronic

3. Ectopic pregnancy in a woman of childbearing age

4. Sigmoid carcinoma

TREATMENT

TREATMENT

Therapeutic Indication

Only a small percentage of women with epithelial ovarian cancer can be treated only surgery. These include patients with stage IA grade 1 and stage IB grade 1 serous, mucinous, endometrial and Brenner tumors. Clear cell carcinomas are associated with a significantly worse prognosis in stage I, and patients with this subtype histology chemotherapy should be considered for all stages.

Patients untreated with chemotherapy should be closely monitored at regular intervals with clinical examination, serum CA125 and ultrasound estimation if one ovary is still present. Surgery to remove the uterus and ovary waste should be considered when the patient does not want to remain fertile.

I. limited disease includes stages I and II ovarian carcinoma and 25% of all patients with epithelial ovarian tumors

Depending on the characteristics of the primary tumor in patients with limited disease were separated into two groups.

1. Patients with low risk of recurrence (stg.IA, IB, G1)

v histological grade G1

v capsule intact

v no tumor on the external surface of the ovaries

v peritoneal cytology negative

v without ascites

v invasion restricted to the ovaries

2. Patients with high risk of relapse (stg.IA, IB, G2, G3, I c)

v histological grade 2 SI3

v ovarian capsule rupture

v tumor on the external surface

positive peritoneal cytology v

v ascites

v out of the ovary tumor invasion

For patients with stg.I regardless of risk group initially recommended abdominal hysterectomy with bilateral salpingo-oophorectomy total

a. For patients with low risk of recurrence (stg.IA, IB, G1)

Postoperative adjuvant therapy is not recommended.

                     b. For patients at high risk of relapse (stg.IA, IB, G32 G3)

It is recommended postoperative adjuvant chemotherapy cycles 6-8.

The regimes used:

1Cisplatin / paclitaxel (category 1)

2.Carboplatin / Paclitaxel-3 weeks (category 1)

3 Carboplatin / Paclitaxel, weekly (category 1)

4.Carboplatin / Docetaxel

            1. Cisplatin 75 mg -100 mg / m2 i.v. intraperitoneally on day 2 after the paclitaxel

               Paclitaxel 135 mg / m2 over 24 hours on day 1

               Paclitaxel 60 mg / m2, i.p., day 8

X is repeated every 3 weeks for 6 cycles

2. Paclitaxel 175 mg / m2 over 3 hours on day 1, followed by

      Carboplatin AUC 5-7.5 day 2, the infusion of 1 hour, 1 day

X is repeated every 3 weeks for 6 cycles

3. Docetaxel 60-75 mg / m2 over 1 hour on Day 1,

                Carboplatin in 1 hr IV AUC5-6, it

                Repeat 3 weeks X6 cycles

4. Paclitaxel 60 mg / m2 over 1 hour, weekly

     Carboplatin AUC 2 infusion for 30 minutes per week

                Repeat weekly for 18 weeks.

Cisplatin 50-75 mg / m2 can replace carboplatin. Increasing the dose intensity of cisplatin did not improve progression-free survival or overall survival compared to chemotherapy alone.

5.Carboplatin / Paclitaxel / Bevacizumab (category 3)

            Paclitaxel 175 mg / m2 over 3 hours, day 1, followed by

            Carboplatin AUC 5-7.5 day 2, the infusion of 1 hour, 1 day

            Bevacizumab 7.5 mg / kg IV on day 1 30-90 minutes prior to paclitaxel / carboplatin.

     X is repeated every 3 weeks for 6 cycles. Continue with Bevacizumab additional 12 cycles.

or

       Paclitaxel 175 mg / m2 over 3 hours, day 1, followed by

       Carboplatin AUC 5-7.5 day 2, the infusion of 1 hour, 1 day

       Bevacizumab 15 mg / kg IV in 30-90 minutes on day 1 starting with Cycle 2, before the paclitaxel / carboplatin.

     X is repeated every 3 weeks for 6 cycles. Continue with Bevacizumab 16 additional cycles.

6. Pazopanib

Adding pazopanib, a kinase inhibitor, the standard chemotherapy regimen postoperative prolonged progression-free survival in advanced ovarian cancer.

Most of the women in a study had stage III / IV disease (91%) at baseline, no residual disease after surgery (58%).

At a median follow up of 24 months, patients treated with 800 mg pazopanib once daily had prolonged progression-free survival compared with those who received placebo. However, pazopanib group had a higher incidence of adverse events and serious adverse events, of which the most common were hypertension, diarrhea, nausea, headache, fatigue, and neutropenia. There were four fatalities, three in the pazopanib group and one in the placebo group.

The following surgical procedures should be part of surgical treatment in patients with ovarian cancer, and carcinoma of the fallopian tube primary peritoneal, in an effort to staged disease and obtain a maximal cytoreductive with residual disease less than 1 cm. Ascites or peritoneal aspiration cytology should be performed in all patients. It makes total hysterectomy with bilateral and omentectomy salpingo-ovaryectomy if omentum is invaded. All suspects or enlarged lymph nodes should be excised if possible. In all patients with tumor nodules smaller than 2 cm or lymph node dissection is performed periaortitis and bilateral pelvic. All patients with residual disease after surgery cytoreductive small volume are potential candidates for intraperitoneal chemotherapy. These patients have a catheter placed intraperitoneally at the time of initial surgery.

Second-look surgery is not recommended after chemotherapy treatment. There is no evidence that there is a survival benefit for second look surgery after completing chemotherapy in patients whose disease appears to be in complete remission. It should effectuate only as part of a clinical trial.

            Other therapeutic modalities:

Pelvic external beam radiation and the entire abdomen

Intraperitoneal radiotherapy.

Stg II, III and IV.advanced disease.

            All patients are recommended exploratory laparotomy.

Cytoreductive surgery or aggressive debulking surgery is a macroscopic designed to remove the tumor completely. Total abdominal hysterectomy and surgery include salpingo-oophorectomy, and complete resection of metastatic lesions omentectomy the peritoneal surface of the intestine.

            The aim of optimal cytoreductive surgery is the complete removal of all visible or palpable tumors and residual disease to be less than 1 to 0.5 cm in the largest diameter.

Suboptimal cytoreductive surgery is when residual disease greater than 1-2 cm in greatest diameter. Survival of patients with optimal residual disease was 25-40 months, compared to 10 to 18 months in those with suboptimal disease. The benefit of cytoreductive surgery is to remove large tumor masses with poor vascular supply, which have a slower growth phase, instead leaving smaller tumors which are more sensitive to chemotherapy.

            In stg.II, III and IV followed by cytoreductive surgery are recommended for 6-8 cycles of adjuvant chemotherapy.

            For optimal cytoreductive surgery stg.IV is not recommended in patients with:

v parenchymal liver disease

v inguinal lymph enlargement

v supraclavicular lymph

v parenchymal lung metastases

v tumor disease involving hepatic hilum and splenic viewed at CT

v mediastinal metastases

The role of cytoreductive surgery in stage IV remains controversial. A consensus has been reached in the sense that only patients with stage IV pleural effusion or supraclavicular lymph single or with a single cutaneous metastasis can be treated as stage III disease. However cytoreductive surgery in patients with extensive liver metastases or no benefit lung.

For patients with stage IV with or without cytoreductive surgery is recommended 6-8 cycles of multi-agent chemotherapy

Patients staged incomplete:

For patients staged incomplete recommend the following:

1. For patients with IA and IB stg, G1, as if the stage is confirmed not require any therapy.

2. For patients with stg IA, IB, G2-3, the minimal residual disease is suspected recommend completing surgical staging.

3. For patients with stg II, III and IV disease who are considered unresectable disease, it is recommended surgery after 3-6 cycles of chemotherapy completion. Surgery should be followed by postoperative chemotherapy postoperatively depending on the outcome. Cytoreductive surgical treatment should be recommended in all patients with stg II-IV with potentially resectable residual disease.

Treatment after primary therapy:

Stg II, III, IV. If complete remission occurs observation is recommended or treatment with paclitaxel.

If partial remission or progression, we recommend observation, sought therapy, supportive therapy or inclusion in a clinical trial.

            For patients with ovarian cancer stg.III and IV second-look laparotomy is not recommended for routine only if the patient participating in a clinical trial.

             Schemes of chemotherapy in epithelial ovarian tumors

I Line

1). Cisplatin 75mg / m2 iv I Paclitaxel day after

Paclitaxel 135 mg / m2 over 24 hours or 175 mg / m2 over 3 hours on I

            Repeat 3 weeksiX 6 cycles

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2). Carboplatin AUC 5-6 iv on day 1 after Paclitaxel

Paclitaxel 135 mg / m2 over 24 hours or 175mg / m2 over 3 hours.

            Repeat 3 weeks x 6-8 cycles

For combination with Paclitaxel 73% clinical response rate, complete remission in 51% to 26% pathologic complete response. Disease-free survival of 18 months, overall survival 38 months.

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Line II

            1). Topotecan (Hycamtin) 1.5 mg / m2 iv days 1-5

                        Repeat 3 weeks

2). Liposomal doxorubicin (Caelyx) 50 mg / m2 iv Day 1.

            It is repeated every 4 weeks.

Second-look surgery is a surgical treatment systematically planned to evaluate patients after chemotherapy and clinical examination and imaging shows no signs of illness. The purpose of second-look surgery is to fully explore the abdominal cavity, a biopsy of any abnormal biopsy found and peritoneal surface where they are likely to find tumor. If the disease is present additional therapy is recommended.

Cytoreductive surgery is a surgery interval in patients after a short course of induction chemotherapy, usually 2-3 cycles of chemotherapy to remove as much of the primary tumor and metastatic order to facilitate the response to subsequent chemotherapy and to improve survival.

Cytoreductive surgery: suboptimal cytoreduction interval after surgery followed by 3 cycles of chemotherapy. It was concluded that cytoreductive surgery improves survival interval in some patients (bad medical condition, inexperienced surgeon).

Cytoreductive surgery after neoadjuvant chemotherapy interval. 3-4 cycles of chemotherapy is administered neoadjuvant cytoreductive surgery and then performs the interval. Arguments for this time interval is chosen the surgery chemotherapy-induced fibrosis is less extensive after 3 cycles only after 6 cycles, more patients can be chemoresistant after 6 cycles until after 3 cycles of chemotherapy and survival of patients with second-look after 6 cycles of chemotherapy was not improved. The therapeutic benefit of neoadjuvant chemotherapy followed by interval remains controversial. It should be considered for patients who are not candidates for surgery.

            Treatment of recurrent or persistent disease

            In patients with persistent or recurrent disease secondary cytoreductive surgery is recommended. Secondary goal of cytoreduction is to remove macroscopic residual disease. Indicate in patients with good performance status, no signs of ascites, have had responded to previous chemotherapy, have a long disease-free interval of at least 9-12 months after diagnosis of the primary tumor.

In patients with free interval greater than 6 months after surgery chemotherapy regimens are given the same probability there to answer.

            In patients resistant or not responding administered cytostatic agents II line.

1) Topotecan (Hycamtin) 1.5 mg / m2 / day x 5 days iv.

Repeat every 3 weeks the 20% response rate, duration of remission median survival 25 weeks and 63 weeks.

            ————————————————– ———————–

              2) liposomal doxorubicin (Doxil) – 50 mg / m2 iv Day 1

             Repeat 3 weeks

————————————————– ———————–

3) Gemzar 1g / m2 / week x 3 weeks

Repeat 3 weeks

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4) Vinorelbine 15-25 mg / m2 i.v. Weekly 4-6 weeks

            Repeat 2-3 weeks

————————————————– ———————–

5) Etoposide 50 mg / m2 / day p.o. – 21 days.

             Was repeated 4 weeks

The response rate to these agents is 10-30%, median duration of response of 8.4 months median survival 10-12 months.

………………………………………….. ………..

6. Docetaxel 40 mg / m2 weekly

7. Taxol 60 mg / m2 IV weekly

8. Bevacizumab 7.5 -15 mg / kg in 100 mL NS IV in 30-90 minutes

                    Repeat 3 weeks for 6 cycles or until progression or unacceptable toxicity occurs

               9. Olaparib 400 mg PO X2 / day continuously as monotherapy in advanced ovarian cancer patients who were treated with three or more prior lines of chemotherapy, with deleterious germline mutations in the BRCA harmful or suspect.

Patients who do not respond to two consecutive therapies without clear evidence of clinical benefit have a diminished probability of receiving additional therapy.

In patients who do not respond to chemotherapy palliative radiotherapy is recommended.

            Pelvic palliative radiation therapy can relieve pain, bleeding. It is given a total dose of 20 Gy. It can also be used in the treatment of metastatic disease, brain, lung, bowel.

Prognostic

The most important positive factors are:

– Young age

– Good performance status

– Cell type other than mucinous and clear cell

– Earlier stage

– Well-differentiated tumors

– Volume tumor cytoreductive surgery less than before

– The absence of ascites

– Residual tumor after surgery smaller primary cytoreduction

For patients with stage I disease, the most important prognostic factor is grading followed by dense adhesions and ascites in large quantities.

1. Stage of disease is the most important prognostic factor. The more advanced the stage the survival is lower: stage I – 80% std. II – 60% std. IIIA – 60% std. III B – 30%, std. III C – 5-10% and std. IV – 5%.

2. The histological poorly differentiated tumors (G3) have a poor prognosis.

3. Clear cell carcinoma histologic type is associated with a worse prognosis than other histologies.

4. The residual disease stage III patients with or without minimal residual disease after initial surgical treatment have a better 5-year survival (30-50%) compared to those with progressive disease after surgical treatment (5-year survival – 10% ).

5. Biomarkers unfavorable prognostic factors are:

• aneuploidy

• oncogene overexpression of HER-2 / neu.

• large number of cells in S phase

Survival at 5 years Frequency stages

stg.IA 90% 26% (IA and IB)

stg.I B 65%

stg. II 45% 15%

stg. III 25% 42%

stg. IV 5% 17%

Tracking patients is made by clinical examination, genital examination, rectal examination, 3 months in the first 2 years, 6 months next 3 years and annually after 5 years. The antigen CA-125 is recommended every control was increased if initial blood counts and biochemistry if indicated. CT / MRI / PET abdominal-pelvic recommended only if there are clinical signs (or CA 125 is elevated) of disease progression.

Therapeutic indication germ cell tumors

It is recommended exploratory laparotomy to determine the extent of disease and to allow surgical resection if possible. Further treatment depends on histology and data found at laparotomy that places patients into two groups:

       I. Stage I, II, III with completely resected endodermal sinus tumor histology, tumor cells mixed embryonal carcinoma, coriocarcinomas, immature teratomas Level II and III.

3 cycles of BEP are recommended:

Etoposide 100 mg / m2 / day i.v. days 1-5

Cisplatin 20 mg / m2 / day i.v. on days 1-5

Bleomycin 30 i.u. i.v day 2,9,16

Repeat in 3 weeks.

Second-look laparotomy is not needed at the end of therapy if signs of disease disappeared and AFP and HCG are normal.

        II. Incompletely resected stage III and stage IV regardless of histology. It is recommended postoperatively 4 cycles or BEP type VAC

VAC: Vincristine 1.5 mg / m2 / day IV for 2 weeks x 12

Actinomycin D 350 mg / m2 / day IV 5 days x 4 weeks x 6

Cyclophosphamide 150 mg / m2 / day IV 5 days x 4 weeks x 6

The response rate is better BEP scheme. Since most tumors are AFP or HCG production, or both, the therapy is monitored by means of these markers.