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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