CANCERS OF THE FALLOPIAN TUBE AND OVARY

CANCERS OF THE FALLOPIAN TUBE AND OVARY

Ovarian cancer is a generic term for a family of diseases, including epithelial ovarian cancers, germ cell tumours of the ovary, and stromal cancers arising in the ovary. Cancer originating in the epithelium of the fallopian tube and ovarian surface is the fourth most common lethal cancer in American women. Approximately 22,000 new cases of ovarian cancers will be diagnosed each year, and because most are diagnosed at advanced stages, roughly 15,000 of these women will eventually die of their disease despite current therapy. Internationally, the incidence of ovarian cancer is highest in white women, and societies characterized by low parity, high-fat diets, and older populations. Ovarian cancer incidence is highest in North America and Europe, with lower incidence in Asia and Sub-Saharan Africa. In the United States, risk factors for ovarian cancer include family history of breast or ovarian cancer, early menarche, delayed menopause, and nulliparity, whereas oral contraceptives, aspirin, and breast-feeding are consistently shown to reduce risk. The median age of onset for ovarian cancer is approximately 60 years, although familial ovarian cancers occur roughly 10 years earlier than the sporadic form.

The indolent borderline tumours of the ovary (or tumours with low malignant potential) form a distinct group of epithelial ovarian cancers characterized by slow growth, rare metastatic spread, and a very different pattern of genetic alterations. These rare borderline tumours are primarily managed by surgical resection as necessary.

The histologic appearance (and accompanying genetic characteristics) allows epithelial ovarian cancers to be divided into serous, mucinous, clear cell, and endometrioid cancers. Although distinct on histologic and molecular grounds, the clinical management of these ovarian cancers has not yet diverged. High-grade serous ovarian cancer (HGSOC) comprises over 80% of the total number of patients and is the best characterized subset of ovarian tumours.

At least 85% of ovarian cancers are sporadic and not associated with heritable abnormalities. However, approximately 10 to 15% of HGSOCs are linked to families carrying germline mutations that are inherited in an autosomal dominant fashion. The affected genes include BRCA1 and BRCA2, which are critical cell cycle checkpoint regulators involved in the maintenance of DNA integrity, particularly in the homologous recombination pathway that is important for double-strand DNA repair. Certain ethnic populations founded from small ancestral populations such as the Ashkenazi Jews have a high frequency of mutations in these genes. In addition to these genes, other less common germline mutations in DNA repair–linked genes, includingCHEK2, ATM, and PALB2, also can increase ovarian cancer risk. Affected members of these breast/ovarian cancer families have an increased risk for both early-onset breast and ovarian cancer and a high lifetime risk for these cancers. In sporadic ovarian cancers, these same genes may be lost through somatic mutation or gene silencing. It is now estimated that 50% or more of all ovarian cancers have a BRCA-like phenotype. Interestingly, BRCA1/2 mutated ovarian cancer appears to have a superior survival compared to sporadic ovarian cancer. Mutations in BRCA1 or BRCA2 confer a “collateral sensitivity” to cisplatin and other chemotherapy agents that induce double-stranded DNA damage. This collateral weakness has been targeted through the development of poly-ADP-ribose polymerase inhibitors. A smaller group of familial ovarian cancers is linked to families with Lynch syndrome (HNPCC) and impairment of DNA mismatch repair.

It is now accepted that most serous ovarian cancers arise through a well-defined series of mutations in the fallopian tube epithelium. Through sequential losses of the homologous DNA repair competence (via loss of BRCA1, BRCA2, PALB2, or other genes in the DNA repair pathway) and p53 function, a defined sequence of events leads to serous carcinoma in situ and eventually carcinoma involving the ovary, lymph nodes, and peritoneal surfaces of the abdominal organs. The lifetime risk for women carrying an altered, high-risk allele for one of these genes may approach 70% or more, depending on environmental factors and modifying alleles when the second, nonpathogenic allele is lost.

The diagnosis of ovarian cancer is complicated by the nonspecific nature of the initial symptoms. Unfortunately, small adnexal masses are usually silent, but as a mass increases in size, symptoms include pelvic fullness, constipation, urinary frequency, and dyspareunia. In more advanced disease, the most common symptoms include fatigue, malaise, early satiety, bloating, and loss of appetite. Abdominal girth increase is often noted as malignant ascites accumulates.

Ultrasonography or computed tomography of the abdomen and pelvis will usually strongly support the diagnosis and lead to early surgical intervention. Although peritoneal fluid cytology can sometimes be diagnostic, percutaneous biopsy of adnexal masses should not be part of the initial workup, to avoid contamination of the peritoneal cavity by an otherwise confined tumour. CA-125 is a normal mucin antigen from MUC16 that is often found at abnormally high levels in the serum of patients with ovarian cancer (and sometimes in other cancers, including lung, pancreas, and uterus). However, serologic findings can be supportive but is not diagnostic in affirming or excluding the diagnosis of ovarian cancer because a variety of benign conditions also can elevate the CA-125 value.

The treatment of ovarian cancer begins at the time of exploratory laparotomy, and adequate primary surgery remains the most important determinant of ovarian cancer survival. The surgery should be performed by a trained gynaecologic oncologist in a highly experienced centre to achieve the best outcome. Adequate initial surgery should include a total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection. The upper abdomen and diaphragm should be inspected and biopsy samples obtained. Every effort should be made to remove any visible cancer. If complete resection is not achievable, cytoreduction to tumour bulk less than 1 cm is still useful and will permit intraperitoneal chemotherapy. If a successful complete resection is not possible, neoadjuvant chemotherapy and deferred surgery is an acceptable choice, although the projected survival is inferior to complete primary resection.

At the completion of primary surgery, a stage is assigned to the patient’s tumour. Using a combination of residual tumour bulk, tumour histology, grade and stage, one of four treatment plans is chosen. For stage IA or IB, grade 1 or 2 tumours, observation alone is the most acceptable treatment because these patients have a tumour recurrence rate below 5%. For all stage IC cancers, all grade 3 tumours, and the rare stage IIA tumours, the recommendation should be for three to six cycles of platinum-based chemotherapy. For stage IIB to IIIC tumours, with residual disease less than 1 cm in greatest dimension, six cycles of platinum-based intraperitoneal treatment is preferred, and bulkier disease or stage IV disease should receive intravenous platinum-based therapy.

APPROACH TO OVARIAN CANCER BY STAGE*

FIGO STAGE BRIEF DEFINITION USUAL TREATMENT
IA G1/2 One ovary, no surface involvement Staging laparotomy, observation only
IA G3 One ovary, no surface involvement; poorly differentiated Staging laparotomy, chemotherapy for 3 cycles
IB G1/2 Both ovaries, no surface involvement Staging laparotomy, observation only
IB G3 50% or more invasion of myometrial thickness, poorly differentiated Staging laparotomy, chemotherapy for 3 cycles
IC Surface involvement, positive cytology, or intraoperative spillage Staging laparotomy, chemotherapy for 3 cycles
IIA Extension to tubes or uterus Staging laparotomy, chemotherapy for 3-6 cycles
IIB Other pelvic organ extension Staging laparotomy, chemotherapy for 3-6 cycles
IIC Pelvic extension plus surface involvement, positive cytology, or intraoperative spillage Staging laparotomy, chemotherapy with IP route preferred
IIIA Microscopic tumour outside the true pelvis Staging laparotomy, chemotherapy with IP route preferred
IIIB Tumour < 2 cm in dimension outside the pelvis Staging laparotomy, chemotherapy with IP route preferred
IIIC Tumour > 2 cm outside the true pelvis or positive lymph nodes Staging laparotomy, chemotherapy with IP route preferred
IV Involvement of liver parenchyma, extension beyond the abdomen, cytology positive pleural effusion, inguinal lymph nodes Chemotherapy

* Staging laparotomy includes total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy. A pelvic lymph node dissection and upper abdominal exploration is also required. In well-staged, early-stage disease (IA/IB), the need for chemotherapy is based primarily on histologic grade. In advanced disease, optimal debulking to < 1cm residual disease permits the use of intraperitoneal treatment (IP). All primary therapy should include a platinum drug and a second, non–cross-reactive drug such as paclitaxel or liposomal doxorubicin.

Following primary chemotherapy, reassessment of extent of residual disease by CA-125 and computed tomography is performed. For patients with persistent or resistant disease, other palliative chemotherapy can be offered but the outlook for such patients is quite poor. Patients in complete remission can be observed expectantly. Nearly all relapses will occur within a 3-year period, and regular quarterly follow-up is recommended in the United States. Over 75% of patients with advanced ovarian cancer will relapse in 12 to 30 months after diagnosis; although patients can be successfully treated for years, curative treatment is not yet available. Choice of chemotherapy at the time of recurrence depends on treatment-free interval, comorbidities, and residual toxicities. Active agents for retreatment include with carboplatin, gemcitabine, liposomal doxorubicin, pemetrexed, and bevacizumab.

Although screening procedures have been aggressively sought for 25 years, there are no screening strategies that currently can be recommended, even for high-risk patients and definitely not for the general population of postmenopausal women. Combinations of serum CA-125 screening, transvaginal ultrasound testing, and panels of circulating serologic markers have all failed to achieve the requisite sensitivity and specificity in large-scale testing. Testing for germline and somatic mutations is increasingly important to predict the response to therapy and prognosis. The routine genetic testing of women with newly diagnosed ovarian cancer is recommended, in the appropriate circumstance, to discover families bearing BRCA1/2 mutations who will require further monitoring.

Prevention strategies for ovarian cancer remain limited. Oral contraceptive use for 5 years or more can reduce ovarian cancer incidence by approximately 50%. For high-risk women with mutations in BRCA1 or BRCA2, a prophylactic salpingo-oophorectomy by age 40 can reduce ovarian cancer risk by more than 90% and will also reduce breast cancer incidence. Low-dose aspirin use has also been associated with reduced ovarian cancer risk.

Women who remain disease-free for 3 years are likely to be cured of their ovarian cancer. Among patients with recurrence, median survival seems highly dependent on their initial stage and success of their primary debulking surgery. Patients with optimally debulked stage IIIC disease have a median survival in excess of 5 years, whereas patients with stage IV and patients with suboptimal debulking surgery have median survivals of 30 to 48 months. The terminal phase of ovarian cancer is generally characterized by progressive inanition and eventual intestinal obstruction. Ovarian cancer survivors may have intestinal adhesions from surgery and chronic neuropathy or electrolyte wasting from primary chemotherapy. Those ovarian cancer survivors living with chronic ovarian cancer are often able to continue to have productive work and family lives for several years after the diagnosis of ovarian cancer.

 

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