Ovarian Cancer

.. of segments of chromosomes (particularly 3p and 6q) in some tumors is consistent with a role for loss of tumor suppressor genes. Recently, a genetic linkage study of familial breast/ovary cancer suggested linkage of disease susceptibility with the RH blood group locus on chromosome 1p. Allele loss involving chromosomes 3p and 6q as well as chromosomes 11p, 13q, and 17 have been frequently observed in ovarian cancers. Besides allele loss, point mutations have been identified in the tumor suppressor gene p53 located on chromosome17p13. Deletions of chromosome 17q have been reported in sporadic ovarian tumors suggesting a general involvement of this region in ovarian tumor biology.

Allelic loss of MYB and ESR genes map on chromosome 6q near the provisional locus for FUCA2, the locus for a-L-fucosidase in serum. Low activity of a-L-fucosidase in serum is more prevalent in ovarian cancer patients. This suggests that deficiency of a-L-fucosidase activity in serum may be a hereditary condition associated with increased risk for developing ovarian cancer. This together with cytogenetic data of losses of 6q and the allelic losses at 6q point to the potential importance of chromosome 6q in hereditary ovarian cancer (Altchek, 208-212). Activation of normal proto-oncogenes by either mutation, translocation, or gene amplification to produce altered or overexpressed products is believed to play an important role in the development of ovarian tumors. Activation of several proto- oncogenes (particularly K-RAS, H-RAS, c-MYC, and HER-2/neu) occurs in ovarian tumors.

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However, the significance remains to be determined. It is controversial as to whether overexpression of the HER-2/neu gene in ovarian cancer is associated with poor prognosis. In addition to studying proto-oncogenes in tumors, it may be beneficial to investigate proto-oncogenes in germ-line DNA from members of families with histories of ovarian cancer (Barber, 323-324). It is questionable whether inheritance or rare alleles of the H-RAS proto-oncogene may be linked to susceptibility to ovarian cancers. Diagnosis and Treatment The early diagnosis of ovarian cancer is a matter of chance and not a triumph of scientific approach.

In most cases, the finding of a pelvic mass is the only available method of diagnosis, with the exception of functioning tumors which may manifest endocrine even with minimal ovarian enlargement. Symptomatology includes vague abdominal discomfort, dyspepsia, increased flatulence, sense of bloating, particularly after ingesting food, mild digestive disturbances, and pelvic unrest which may be present for several months before diagnosis (Sharp, 161-163). There are a great number of imaging techniques that are available. Ultrasounds, particularly vaginal ultrasound, has increased the rate of pick-up of early lesions, particularly when the color Doppler method is used. Unfortunately, vaginal sonography and CA 125 have had an increasing number of false positive examinations. Pelvic findings are often minimal and not helpful in making a diagnosis.

However, combined with a high index of suspicion, this may alert the physician to the diagnosis. These pelvic signs include: Mass in the ovarian area Relative immobility due to fixation of adhesions Irregularity of the tumor Shotty consistency with increased firmness Tumors in the cul-de-sac described as a handful of knuckles Relative insensitivity of the mass Increasing size under observation Bilaterality (70% for ovarian carcinoma versus 5% for benign cases) (Barber, 136) Tumor markers have been particularly useful in monitoring treatment, however, the markers have and will probably always have a disadvantage in identifying an early tumor. To date, only two, human gonadotropin (HCG) and alpha fetoprotein, are known to be sensitive and specific. The problem with tumor markers as a means of making a diagnosis is that a tumor marker is developed from a certain volume of tumor. By that time it is no longer an early but rather a biologically late tumor (Altchek, 292).

Many reports have described murine monoclonal antibodies (MAbs) as potential tools for diagnosing malignant ovarian tumors. Yamada et al attempted to develop a MAb that can differentiate cells with early malignant change from adjacent benign tumor cells in cases of borderline malignancy. They developed MAb 12C3 by immunizing mice with a cell line derived from a human ovarian tumor. The antibody reacted with human ovarian carcinomas rather than with germ cell tumors. MAb 12C3 stained 67.7% of ovarian epithelial malignancies, but exhibited an extremely low reactivity with other malignancies. MAb 12C3 detected a novel antigen whose distribution in normal tissue is restricted. According to Yamada et al, MAb 12C3 will serve as a powerful new tool for the histologic detection of early malignant changes in borderline epithelial neoplasms. MAb 12C3 may also be useful as a targeting agent for cancer chemotherapy (Yamada, 293-294).

Currently there are several serum markers that are available to help make a diagnosis. These include CA 125, CEA, DNB/70K, LASA-P, and serum inhibin. Recently the urinary gonadotropin peptide (UCP) and the collagen-stimulating factor have been added. Although the tumor markers have a low specificity and sensitivity, they are often used in screening for ovarian cancer. A new tumor marker CA125-2 has greater specificity than CA125. In general, tumor markers have a very limited role in screening for ovarian cancer.

The common epithelial cancer of the ovary is unique in killing the patient while being, in the vast majority of the cases, enclosed in the anatomical area where it initially developed: the peritoneal cavity. Even with early localized cancer, lymph node metastases are not rare in the pelvic or aortic areas. In most of the cases, death is due to intraperitoneal proliferation, ascites, protein loss and cachexia. The concept of debulking or cytoreductive surgery is currently the dominant concept in treatment. The first goal in debulking surgery is inhibition of debulking surgery is inhibition of the vicious cycle of malnutrition, nausea, vomiting, and dyspepsia commonly found in patients with mid to advanced stage disease. Cytoreductive surgery enhances the efficiency of chemotherapy as the survival curve of the patients whose largest residual mass size was, after surgery, below the 1.5 cm limit is the same as the curve of the patients whose largest metastatic lesions were below the 1.5 cm limit at the outset (Altchek, 422-424). The aggressiveness of the debulking surgery is a key question surgeons must face when treating ovarian cancers.

The debulking of very large metastatic masses makes no sense from the oncologic perspective. As for extrapelvic masses the debulking, even if more acceptable, remains full of danger and exposes the patient to a heavy handicap. For these reasons the extra-genital resections have to be limited to lymphadenectomy, omentectomy, pelvic abdominal peritoneal resections and rectosigmoid junction resection. That means that stages IIB and IIC and stages IIIA and IIB are the only true indications for extrapelvic cytoreductive surgery. Colectomy, ileectomy, splenectomy, segmental hepatectomy are only exceptionally indicated if they allow one to perform a real optimal resection. The standard cytoreductive surgery is the total hysterectomy with bilateral salpingoophorectomy.

This surgery may be done with aortic and pelvic lymph node sampling, omentectomy, and, if necessary, resection of the rectosigmoidal junction (Barber. 182-183). The concept of administering drugs directly into the peritoneal cavity as therapy of ovarian cancer was attempted more than three decades ago. However, it has only been within the last ten years that a firm basis for this method of drug delivery has become established. The essential goal is to expose the tumor to higher concentrations of drug for longer periods of time than is possible with systemic drug delivery. Several agents have been examined for their efficacy, safety and pharmacokinetic advantage when administered via the peritoneal route. Cisplatin has undergone the most extensive evaluation for regional delivery. Cisplatin reaches the systemic compartment in significant concentrations when it is administered intraperitoneally.

The dose limiting toxicity of intraperitoneally administered cisplatin is nephrotoxicity, neurotoxicity and emesis. The depth of penetration of cisplatin into the peritoneal lining and tumor following regional delivery is only 1 to 2 mm from the surface which limits its efficacy. Thus, the only patients with ovarian cancer who would likely benefit would be those with very small residual tumor volumes. Overall, approximately 30 to 40% of patients with small volume residual ovarian cancer have been shown to demonstrate an objective clinical response to cisplatin-based locally administered therapy with 20 to 30% of patients achieving a surgically documented complete response. As a general rule, patients whose tumors have demonstrated an inherent resistance to cisplatin following systemic therapy are not considered for treatment with platinum-based intraperitoneal therapy (Altchek, 444-446). In patients with small volume residual disease at the time of second look laparotomy, who have demonstrated inherent resistance to platinum-based regimens, alternative intraperitoneal treatment programs can be considered.

Other agents include mitoxantrone, and recombinant alpha-interpheron. Intraperitoneal mitoxanthone has been shown to have definite activity in small volume residual platinum-refractory ovarian cancer. Unfortunately, the dose limiting toxicity of the agent is abdominal pain and adhesion formation, possibly leading to bowel obstruction. Recent data suggests the local toxicity of mitoxanthone can be decreased considerably by delivering the agent in microdoses. Ovarian tumors may have either intrinsic or acquired drug resistance.

Many mechanisms of drug resistance have been described. Expression of the MDR1 gene that encodes the drug efflux protein known as p-glycoprotein, has been shown to confer the characteristic multi-drug resistance to clones of some cancers. The most widely considered definition of platinum response is response to first-line platinum treatment and disease free interval. Primary platinum resistance may be defined as any progression on treatment. Secondary platinum resistance is the absence of progression on primary platinum-based therapy but progression at the time of platinum retreatment for relapse (Sharp, 205-207). Second-line chemotherapy for recurrent ovarian cancer is dependent on preferences of both the patient and physician. Retreatment with platinum therapy appears to offer significant opportunity for clinical response and palliation but relatively little hope for long-term cure.

Paclitaxel (trade name: Taxol), a prototype of the taxanes, is cytotoxic to ovarian cancer. Approximately 20% of platinum failures respond to standard doses of paclitaxel. Studies are in progress of dose intensification and intraperitoneal administration (Barber, 227-228). This class of drugs is now thought to represent an active addition to the platinum analogs, either as primary therapy, in combination with platinum, or as salvage therapy after failure of platinum. In advanced stages, there is suggestive evidence of partial responsiveness of OCCA to radiation as well as cchemotherapy, adriamycin, cytoxan, and cisPlatinum-containing combinations (Yoonessi, 295).

Radiation techniques include intraperitoneal radioactive gold or chromium phosphate and external beam therapy to the abdomen and pelvis. The role of radiation therapy in treatment of ovarian canver has diminished in prominence as the spread pattern of ovarian cancer and the normal tissue bed involved in the treatment of this neoplasm make effective radiation therapy difficult. When the residual disease after laparotomy is bulky, radiation therapy is particularly ineffective. If postoperative radiation is prescribed for a patient, it is important that theentire abdomen and pelvis are optimally treated to elicit a response from the tumor (Sharp, 278-280). In the last few decades, the aggressive attempt to optimize the treatment of ovarian clear cell adenocarcinoma and ovarian cancer in general has seen remarkable improvements in the response rates of patients with advanced stage cancer without dramatically improving long-term survival. The promises of new drugs with activity when platinum agents fail is encouraging and fosters hope that, in the decades to come, the endeavors of surgical and pharmacoogical research will make ovarian cancer an easily treatable disease.

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