SOME GENETIC INHERITANCE IS SEEN WITH THE DISEASE
SIXTH MOST COMMON CANCER IN WOMEN. RISK IS INCREASED IN WOMEN WHO HAVE NOT HAD CHILDREN & POSSIBLY THOSE WITH EARLY MENARCHE OR LATE MENOPAUSE. WOMEN WITH H/O BREAST CANCER HAVE AN INCREASED RISK OF EOC.
Lactose consumption and the use of talcum powder on the vulva and perineum may be associated with increased risk. A steady decreased risk is observed with increasing parity and with use of the combined oral contraceptive pill.
Disorders of the genes associated with breast cancer, BRCA1 and BRCA2, and more rarely, genes within the Lynch II syndrome complex, are associated with ovarian cancer. Mutations in these genes are inherited in an autosomal dominant pattern, with the mutated gene coming from either parent.
PREVENTION & SCREENING :
CA125 is not useful when used alone as a single one-time test for ovarian cancer screening, but it may have increased value when serial measurements are performed over time and if it is incorporated into a risk of ovarian cancer algorithm. Other markers have been investigated, including lysophosphatidic acid, tumor-associated glycoprotein 72 (TAG 72), OVX1, and macrophage colony-stimulating factor (M-CSF). Still, other markers are undergoing active investigation
The risk of developing EOC is significantly reduced by bearing children, using the combined oral contraceptive pill, undergoing tubal ligation, and undergoing bilateral oophorectomy.
Evidence suggests that taking the oral contraceptive pill for at least 5 years reduces the relative risk of developing EOC to 50% of the risk for a woman who has never taken it.
For patients who are known carriers of BRCA1 or BRCA2 mutations, bilateral oophorectomy may be performed as soon as childbearing is complete, and probably before the patient is aged 35 years. This reduces the chance of developing EOC, but it does not prevent carcinoma of the peritoneum.
STAGING :
EOC is staged according to Federation International de Gynecologie et Obstetrique (FIGO) (ie, International Federation of Gynecology and Obstetrics) rules as follows:
Stage I - Growth limited to the ovaries
IA - Growth limited to 1 ovary, no ascites present containing malignant cells, no tumor on the external surface, capsule intact
IB - Growth limited to both ovaries, no ascites present containing malignant cells, no tumor on the external surfaces, capsules intact
IC* - Tumor either stage IA or IB, but with tumor on surface of 1 or both ovaries with capsule ruptured, with ascites present containing malignant cells, or with positive peritoneal washings
Stage II - Growth involving 1 or both ovaries with pelvic extension
IIA - Extension and/or metastases to the uterus and/or tubes
IIB - Extension to other pelvic tissues
IIC* - Tumor either stage IIA or IIB, but with tumor on surface of 1 or both ovaries, with capsule(s) ruptured, with ascites present containing malignant ovaries, or with positive peritoneal washings
Stage III - Tumor involving 1 or both ovaries with histologically confirmed peritoneal implants outside pelvis and/or positive retroperitoneal or inguinal nodes; superficial liver metastasis equals stage III; tumor limited to true pelvis, but with histologically proven malignant extension to small bowel and omentum
IIIA - Tumor grossly limited to the true pelvis, with negative nodes, but with histologically confirmed microscopic seeding of abdominal peritoneal surfaces, or histologically proven extension to small bowel mesentery
IIIB - Tumor of 1 or both ovaries with histologically confirmed implants, peritoneal metastasis of abdominal peritoneal surfaces, none exceeding 2 cm in diameter; nodes are negative
IIIC - Peritoneal metastasis beyond the pelvis larger than 2 cm in diameter and/or positive retroperitoneal or inguinal nodes
Stage IV - Growth involving 1 or both ovaries with distant metastases; if pleural effusion is present, positive cytology must be apparent to allot a case to stage IV; parenchymal liver metastasis qualifies as stage IV disease
*In order to evaluate the prognostic impact of the different criteria for allotting cases to stage IC or IIC, knowing if rupture of the capsule was spontaneous or caused by the surgeon is of value. Also of value is knowing if the source of malignant cells detected was peritoneal washings or ascites.
TREATMENT :
Treatment of ovarian cancer is undertaken after consideration of many factors, including the extent of disease spread, symptoms, and patients' wishes and fitness to undergo treatment.
Surgery
Surgery is the initial treatment of choice, provided patients are medically fit. Patients who are not fit for surgery may be given chemotherapy and considered for surgery later. The aim of surgery is to confirm the diagnosis, define the extent of disease, and resect all visible tumor. The role of cytoreduction was demonstrated by Griffiths in 1975 and has been confirmed by many others.
The incision for surgery should be midline abdominal. In young women with early-stage disease, a transverse incision may be considered. Careful inspection and/or palpation of the abdominal contents should be performed, including all peritoneal surfaces, the liver, large and small bowel and mesentery, stomach, appendix, kidneys, spleen, retroperitoneal spaces, and all pelvic structures.
Appropriate surgery, depending on whether or not disease is visible outside the ovaries, is described below. It is essential that where no disease is visible outside the ovaries, the patient be adequately surgically staged because the incidence of microscopic metastases is significant. Surgery for patients with stage IV disease should be individualized, particularly when disease is in the liver and above the diaphragm. Patients who are in stage IV because of small-volume disease in the liver, abdominal wall, or lung should undergo cytoreductive surgery if medically fit.
Surgery for ovarian cancer
No visible disease outside of an ovary
Aspirate ascitic fluid for cytology studies.
Perform peritoneal washings* for cytology if ascites is not present.
Remove the ovary and ovarian tumor intact.
Perform diaphragmatic scraping for cytology studies.
Obtain peritoneal biopsy specimens.
Perform a subcolic omentectomy.
Obtain bilateral para-aortic and pelvic node samples.
Obtain biopsy samples of adhesions or other suspicious areas.
If the patient does not desire future fertility, perform a total abdominal hysterectomy and excise the opposite ovary.
Remove the appendix if mucinous tumor is present.
Macroscopic disease outside of the ovary
All visible tumor should be removed. This may require extensive surgery, including bowel resection, excision of peritoneal implants, liver resection, omentectomy, and splenectomy.
The extent of bowel resection should depend on the role this plays in achieving maximal cytoreduction.
*Fluid must have been in contact with broad surfaces of the peritoneum above the liver, the paracolic gutters, and the pelvis. All specimens may be placed in the same container with heparin at a concentration of 1 U/mL of aspirate and sent for cytology studies.
Role of laparoscopy
Laparoscopy may be used for diagnostic purposes in a patient with low risk for ovarian cancer and to remove cystic masses, according to guidelines developed by the American College of Obstetricians and Gynecologists. The mass must be 10 cm or smaller as viewed by a sonogram, must have a distinct border and no solid parts, and must not be associated with ascites. The serum CA125 level must be normal (<35 U/mL), and the patient must have no family history of ovarian cancer. If chance exists that ovarian cancer is present, such surgery is best arranged in conjunction with a specialist in gynecologic cancer surgery. The patient then can undergo all necessary surgery for her cancer under a single anesthetic, without delay. Laparoscopy also has a role in second-look inspection and in the staging of apparently early-stage disease found by chance during another surgery.
Chemotherapy
Only a small percentage of women with EOC can be treated with surgery alone. These include patients with stage IA grade 1 and stage IB grade 1 serous, mucinous, endometrioid, and Brenner tumors. Clear-cell carcinomas are associated with a significantly worse prognosis in stage I, and patients with subtypes should be considered for chemotherapy at all stages.
Patients not treated with chemotherapy should be monitored closely with clinical examination, serum CA125 estimation, and ultrasonography of the residual ovary at regular intervals. Surgery to remove the uterus and residual ovary should be considered when the patient no longer desires to remain fertile.
Higher-risk early-stage disease includes all histologic subtypes with stage IA and stage IB grade 2 and all stage I grade 3. These patients should be treated with front-line chemotherapy with a taxane/platinum combination for a minimum of 3 courses. They should consider participating in clinical trials.
Patients with stage II cancer and greater should receive front-line chemotherapy and should strongly consider participation in clinical trials. Standard therapy is currently a taxane/platinum combination, usually with carboplatin and either paclitaxel or docetaxel for a minimum of 6 courses. Carboplatin is given at an area under the curve (AUC) of 6-7.5 mg/mL/min (using the Calvert formula). Paclitaxel is dosed at 175 mg/m2 and docetaxel at 60-75 mg/m2. Cisplatin at 50-75 mg/m2 can be substituted for carboplatin. Docetaxel in combination with carboplatin has been shown to provide equivalent survival rates with less neurotoxicity but greater neutropenia.
Calvert formula for calculating total dose of carboplatin: Total dose (mg) = target AUC x (GFR + 25), where GFR = glomerular filtration rate, taken to be the creatinine clearance in mL/min and AUC in mg/mL/min. The normal range of AUC for treatment of ovarian carcinoma varies from 5-8. Patients who have received extensive prior chemotherapy or radiation should start with an AUC of less than 5.
Neoadjuvant chemotherapy
This is given to patients with disease that is initially considered inoperable or it is given if the patient is unfit for surgery at the time of diagnosis. If the patient has a good response to 3 or more cycles of chemotherapy, surgery, called interval debulking, may be performed followed by further chemotherapy.
Intraperitoneal chemotherapy
Use of chemotherapy agents instilled into the peritoneal cavity has the theoretical advantage that much higher concentrations can be obtained locally without the risk of adverse systemic effects; however, the agents are unable to penetrate more than a few millimeters. At least 3 randomized studies comparing chemotherapy regimens, including the intraperitoneal route with the intravenous route, have shown a survival advantage for the arms receiving intraperitoneal chemotherapy. Thus, intraperitoneal chemotherapy should be strongly considered for the treatment of front-line disease following surgery where 5 mm of less-residual disease exists. This route of chemotherapy administration requires the placement of a subcutaneous tube into the peritoneal cavity; this is associated with a number of complications including infection, blockage, and discomfort. Nevertheless, randomized studies show a survival benefit and disease-free survival benefit.
Radiation therapy
Radiation has not been widely accepted as a routine treatment modality in the initial treatment of patients with EOC, despite reports of efficacy for higher-risk stage I and II disease and in stage III disease where small-volume residual disease is present after surgery.
Second-look laparotomy
Second-look laparotomy is performed at the end of initial treatment when no disease is evident. The aim is to inspect the abdominal cavity for disease and perform an extensive biopsy when no macroscopic disease is found. This surgery went out of fashion because (1) at this time, no adequate treatment exists for patients found to have the disease; and (2) of those patients who had negative findings at surgery (a complete pathologic response), 50% would have recurrence by 5 years and 60% would have recurrence by 10 years. However, research is producing novel potential therapeutic options and second-look laparotomy should still be considered when performed as part of a research protocol.
Consolidation chemotherapy
Ovarian cancer has a very high response rate, but most patients have recurrent cancer following initial therapy. Much interest abounds in research into treatments to prevent or prolong the interval of recurrence. A Gynecologic Oncology Group protocol was discontinued when a statistical improvement in disease-free survival was demonstrated in patients receiving 12 months versus 3 months of additional monthly paclitaxel after initial therapy. However, questions remain about this study, which was not completed as designed. Since no consensus on management in this situation exists, patients should be encouraged to participate in clinical trials of consolidation therapy.
Estrogen replacement therapy after treatment of epithelial ovarian cancer
The safety of estrogen replacement therapy (ERT) after treatment for EOC has not been tested in a randomized trial, but current evidence suggests that the benefits of ERT outweigh the risks.
Younger women with endometrioid subtypes are of concern because these tumors theoretically are estrogen-sensitive. If estrogen is used in such patients, a progestogen probably should be given with it.
Recurrent disease
In most patients, ovarian cancer recurs, and the prognosis for these patients is poor. The goal of further therapy is to achieve a response to treatment and to prolong meaningful quality survival.
Treatment of recurrent disease may involve surgery, chemotherapy, and radiation. If a localized mass is present, surgery may play a role prior to the initiation of further chemotherapy. Response is more likely in patients who previously had a good response to first-line therapy and who had a long interval between the completion of initial therapy and the time of recurrence.
Patients whose previous response to platinum agents was good and who have gone at least 6 months since completing initial therapy may be re-treated with a taxane together with carboplatin or cisplatin. Patients with platinum-resistant disease who respond poorly to treatment with platinum agents initially and have a short interval to recurrence, do poorly. These patients should be offered participation in clinical trials. Agents with some activity in this situation include topotecan, etoposide, liposomal doxorubicin, and docetaxel and altretamine. Single-agent therapy is usually given for recurrent disease.
Samples of recurrent tumor or ascitic fluid can be sent to one of several laboratories for chemotherapeutic assay. This assay involves culturing tumor cells in media containing a range of chemotherapy agents. This allows chemotherapy agents to be offered to patients with the greatest potential for activity, and, conversely, this allows for drugs with extreme resistance to be avoided. These assays have a controversial role in the initial treatment of ovarian cancer.
Patients who are sensitive to chemotherapy have overall response rates of 30-60%, with an overall survival of 12-24 months, whereas patients resistant to chemotherapy have expected response rates of 12-32%, with an overall survival of 7-12 months.
The finding of elevated CA125 in the serum in the absence of clinical or radiographic disease is a relatively common situation in patients with EOC following initial treatment. Treatment of these patients is controversial. No current evidence indicates that treating the patient at this time affects survival.
Radiation
Radiation has a palliative role in recurrent disease for symptomatic and persistent masses. Emerging evidence suggests that radiation may improve the prognosis for women with recurrent disease that can be surgically debulked to microscopic disease only. However, morbidity may be high, and each case should be considered individually.
Hyperthermic intraperitoneal chemotherapy
The instillation into the peritoneal cavity of chemotherapeutic agents in a solution heated to between 40Β°C and 43Β°C was first introduced in an attempt to induce longer survival in patients with gastric carcinomas that had spread to the peritoneal cavity. Considerable experimental evidence shows that not only is heat alone tumoricidal, but it also increases the activity of many different chemotherapeutic agents, several of which have activity in ovarian cancer. Over the last 25 years, many reports have surfaced on the use of such therapy in combination with debulking surgery in diseases such as malignant mesothelioma, appendiceal cancer, and colorectal cancer.
In 2003, findings from a randomized controlled trial on patients with peritoneal carcinomatosis from colorectal cancer was published. The trial demonstrated a significant prolongation of life in patients undergoing surgical debulking with hyperthermic chemotherapy in comparison with patients treated with standard palliative surgery and chemotherapy.
Ovarian cancer is a good theoretical target for surgical debulking combined with hyperthermic chemotherapy because it combines 3 separately useful modalities: surgical debulking, intraperitoneal chemotherapy, and heat. Several reports on ovarian cancer have documented promising results. However, no randomized, phase III studies have been performed in ovarian cancer cases and more research is warranted.
LOW MALIGNANT POTENTIAL CARCINOMA OF OVARIES :
Tumors of low malignant potential (LMP) are a distinct variety of EOC that behave in a much less aggressive fashion. These tumors cause great anxiety to patients, and the concept of LMP sometimes is difficult to explain. They comprise approximately 20% of malignant ovarian tumors. The mean age of diagnosis is younger than for invasive EOC, at approximately 48 years, and no large peak of incidence is observed.
These tumors are staged identically to EOC, using the FIGO system (see Staging), but unlike with EOC, the majority of tumors are stage I at presentation (IA, 51%; IB, 6%; IC, 18%; II, 8%; III, 15%; IV, 2%).
Surgery
Surgery begins with a full assessment of the pelvis and abdominal contents as for EOC and is carried out as described in Surgery for ovarian cancer.
Patients who are premenopausal and desire preservation of fertility can be treated with unilateral oophorectomy alone. In selected cases, ovarian cystectomy may be enough for stage IA serous tumors of LMP. Hysterectomy and removal of the other ovary can be performed if the patient no longer desires to remain fertile.
When complete surgical staging is performed in patients with LMP tumors, some patients with disease originally thought to be confined to the ovaries are found to have disease that has spread. However, the value of this has not been defined in early-stage disease.
In advanced disease, patients should undergo cytoreductive surgery, as for invasive EOC, to remove all visible tumor.
Adjuvant therapy
Chemotherapy and radiation therapy are not indicated for LMP tumors following complete resection for stage I and II disease. In cases where disease has spread from the ovaries at the time of surgery, and particularly where implants are found to be invasive, chemotherapy can be considered, but data establishing its efficacy are absent.
Follow-up after initial treatment
Regular follow-up care includes clinical examination and serum CA125 estimation, especially if the original tumor was serous and/or the CA125 was elevated. If a patient retains 1 or both ovaries, annual ultrasound examination may be indicated.
Treatment of recurrence
LMP tumors do not recur in the majority of patients. When they do, initial debulking surgery usually is indicated. Chemotherapy has no proven role.