Description of the Normal Ovaries

The ovaries are the two "egg shaped" ("ovoid") structures which are suspended in the female pelvis. They are normally of a pinkish-grey color, and are land 1/2 inches in length, 3/4 of an inch in width, 1/3 of an inch thick, and weigh 1/4 of an ounce apiece. They are smooth in a youngster, but tend to be puckered and pockmarked in older women. The outer coat of the ovary is a tough glisteny membrane called the "tunica albuginea". There is one ovary on either side of the uterus (womb), and they connect to the uterus via the fallopian tubes. Along with the lower cervix, vagina and vulva, these "organs" make up the female reproductive system. A "system" is made up of several organs, an "organ" is made up up various tissues, and a "tissue" is made up of many individual "cells", which are the smallest unit of human life. A network of "ligaments" of connective tissue suspends the ovaries in the pelvis. Specifically, each "broad ligament" helps connect the ovaries to the uterus; the fallopian tubes are embedded in the upper portion of the broad ligament. The "ligament of the ovary" connects the lower portion of the ovaries to the uterus, while the "round ligament" tethers the uterus itself inside the pelvis. Thus the actual position of the ovaries in the female pelvis will vary with the position of the uterus, but normally the ovaries are very close to the inner muscular "pelvic wall". The upper portions of the ovaries are free of attachments. The "ampulla" of the fallopian tubes curves around each ovary to receive its contents, but it also can miss allowing an egg, germ or cancer cell to get onto the "peritoneal" membrane lining that surrounds the inner pelvis and abdomen. This is an important "route of spread" for ovarian disease.

The blood supply to the ovaries and fallopian tubes are from a tributary of the great descending "aorta" which emanates from the heart and supplies the entire body below the heart with fresh blood. Specifically, the paired "gonadal" or "ovarian" arteries from the aorta conduct blood to the ovaries to nourish them. The importance of the ovaries is highlighted by the fact that they have their own blood vessels supplying them, in contrast to other pelvic organs which share sub-branches of the aorta. Used blood drains from the ovaries into a network ("plexus") of veins, called the "pampiniform plexus", ultimately this collected blood drains back to the heart by way of the large "inferior vena cava" which collects used blood from the lower body. This venous drainage system can act as a route of spread for infection or cancer. When blood goes into the smallest vessels, called "capillaries", the fluid portion of the blood ("serum") seeps out to bathe the individual cells with oxygen and nutrients. This fluid is then called "lymph", and it is recollected by "lymph channels". The lymph channels conduct the lymph fluid to local "lymph nodes" which abnormally pea-sized glands stuffed with white blood cells. Lymph nodes "filter" the lymph fluid, and the nodes interconnect to send the purified lymph back toward to heart to rejoin the bloodstream. Regarding the ovaries, the lymph drainage occurs along the ligaments and the fluid is processed in "groups" of "regional lymph nodes". These are named according to the major blood vessels they are near. For the ovary, the regional lymph node groups in the pelvis include the the "iliac', "hypogastric", "sacral", and "obturator" nodes. These are all subgroups of "pelvic" lymph nodes. Drainage of lymph fluid to further regional nodes, including the "inguinal" in the groin and the "Para-aortic" in abdomen can occur. When lymph nodes trap germs or cancer cells, they swell ("lymphadenopathy"). Lymph nodes are considered "enlarged" when they are larger than 1 cm (-1/2 inch) across. The lymph system can act as a conduit for spread of infections or cancer, but conversely it may help limit these processes by trapping and destroying germs or cancer cells.

The ovaries are the female paired reproductive organs ("gonads") which produce store, and release eggs ("ova") in anticipation of child-bearing. Each part of the reproductive system has its "counterpart" in the opposite sex-- that is what it would have been had the sex been different. The counterpart to the ovaries are the male testicles, to the clitoris is the penis, and to the vulva is the scrotal sac. While in the womb, "hormonal influences" (messenger chemicals) under the control of "genes" within each living "cell" guide the early gonad cells to develop ("differentiate") into either female or male gonads and genitals. The presence of the male hormone "testosterone" is coded for by the "Y" sex chromosome, and if it is present, testicles, a penis, and a scrotum will form. Conversely, in incipient females only the "X" sex chromosomes are present, meaning ovaries, fallopian tubes, a uterus, cervix, vagina and vulva will develop in the early fetal period. From birth, the ovary contains all of the "eggs" that a female will ever have, usually about 100,000. This is different than the male, who continues to produce new sperm through adult life. The ovary produces hormones (estrogen and progesterone) which are critical in female maturation and fertility. The ovary is composed of several types of cells, each of which can give rise to specific cancers. These cells include the primordial eggs themselves ("oocytes"), the supporting cells which contain them ("epithilial cells") and hormone-producing cells ("Granulosa" and "Theca" cells). Young women first start their monthly "periods" at "menarche", which normally occurs around 11 years of age. With each monthly "menstrual cycle" one (or occasionally more) egg(s) are released in anticipation of fertilization. The lining of the uterus ("endometrium") is built up prior to the egg's release to form a nourishing surface for combining egg and sperm, and sustaining the resultant "embryo". If successful fertilization occurs, then the embryo will become a "fetus" after 8 weeks of gestation in the womb, by which time its sex becomes apparent. If no fertilization occurs, then the egg dies, and the inner lining of the uterus sloughs off as a bloody emission called I'menses". As the ovary ages, it gives up its egg cells during each month's period or for a pregnancy. By age 50 or so, the ovary runs out of eggs, loses it's ability to produce hormones, and shrinks ("atrophies"). This process is called "menopause". Most ovarian cancers occur after the age of menopause.

What is Ovarian Cancer?

The ovary is composed of individual cells, including the eggs (oocytes), supporting cells of the organ (epithelial cells), and hormone-producing cells (granuloma and theca cells). These cells divide to produce new ones, and grow very rapidly during womb life, early childhood and puberty. In adulthood, new cells are produced only to replace those that die of old age, injury or disease. As mentioned, no more egg cells are ever produced after womb life, however other ovarian cells are. Normally, division of cells is under very tight control. This control is exerted by the "genes" inside each cell, which are housed in long clumps forming "chromosomes", which are visible under a light microscope. The genes themselves are made up of DNA, the master genetic code material. If the genes are damaged, say by chemicals or radiation, the control over cell division may be lost in one particular cell. Ultimately, cancer is considered a disease of the DNA. Ovarian cancer starts in a single cell. That cell starts dividing haphazardly, making millions and billions of copies of itself. It takes up the nourishment needed by other cells, depriving them so the cancer can continue to grow. Quickly growing cells can clump up to form a "tumor". A tumor simply means a swelling, it can be caused by inflammation or infection. A "benign" tumor only grows in it's local area (although it may get quite large)-- it cannot spread and is not cancer. By contrast, a tumor which can spread to other body areas is called "malignant" and this is cancer. The process of cancer spread to other areas is called "metastasis", so only malignant tumors (i.e. cancer) can metastasize. Theoretically, cancer can spread to any area of the body, and it often grows better in it's area of spread than in It's area of origin ("primary site"). It is this capacity for spread that makes cancer so dangerous. Cancer commonly kills by causing anemia (low red blood cell counts), infection (from poor immune function and low white blood cells counts) and debility (from general malnutrition, dehydration and weakness). With ovarian cancer, a common reason for death is by the tumor pressing on the nearby kidney drainage system leading to kidney failure, called "uremia". In younger women, most ovarian tumors are benign cysts and are not dangerous. Unfortunately, most ovarian tumors in post-menopausal women are cancerous, and lethal if their growth is not arrested.

How Common Is Ovarian Cancer?

Each year in the U.S.A. there are 23,000 new cases of ovarian cancer causing 13,000 deaths. It is the 4th most common lethal cancer in women. The annual number of cases has increased 10% over the past 25 years. Some of this increase is due to better detection and recognition of ovarian cancer. About 1 woman in 70 will develop ovarian cancer, and the average patient is 60 years old. It is more common in industrialized countries, and very rare in children.

What Causes or Increases the Risk for Ovarian Cancer?

Like any cancer, the exact reason why one woman gets ovarian cancer and another does not remains unknown. However, several "risk factors" have been noted:

Risk Factors for Ovarian Cancer

1) Heredity: Women who's mothers or maternal aunts have had ovarian cancer are at higher risk for developing it. There appears to be a gene which increases risk for ovarian, uterus, breast and colon cancer, called a "Family Cancer Syndrome" gene.

2) Diet: High fat diet, with low intake of fruits and vegetables, increases risk. In fact, eating lots of fruits and vegetables appears protective against it.

3) No Pregnancies: "nulliparous" women make up 1/4 of the population but make up 1/2 of the patients getting ovarian and uterine cancers. Also, women who have fewer babies or who first get pregnant after age 30 are at higher risk. Early first pregnancy and many children appears protective.

4) Hormones: Many menstrual periods in a woman's life (early onset of periods and late menopause) increase risk for ovary, breast and uterus cancer. This is called the "incessant ovulation" theory and relates the estrogen produced by the ovary to development of cancer. Pregnancy and oral contraceptives lower risk because they need progesterone, another female hormone which counters the effects of estrogen. In fact, progesterones may even be used to treat breast and uterus cancers as it can slow their growth. Obesity also increases risk for these cancers, thought due to the fat cells converting other hormones to estrogens ("peripheral aromatization")!

5) Genetic Disease: like "gonadal dysgenesis" (failure to form normal ovaries due to an incomplete set of female chromosomes) or the "Peutz-Jeghers" syndrome (lots of polyps in the digestive tract) may have up to a 15% risk of getting ovarian cancer. Tobacco and caffeine are NOT linked, but alcohol shows a slight increased risk.

What are the Types of Ovarian Cancer?

The are many types of ovarian cancer, with different degrees of aggressiveness and tendencies to spread. Each type of cell in the ovary gives rise to particular tumors. The most common type of ovarian cancer (over 80%) comes from the "epithelial" cells which make up the surface, linings and support structures of the ovary:

Serous Carcinoma makes up 50% ovarian cancer, and 1/3 of patients have disease in both ovaries ("bilateral"). It shows up as a large, irregular mass in the pelvis and tends to be very aggressive.

Mucinous Carcinoma is about 15% of ovary cancer, and appears as large cysts in the pelvis filled with both solid and thick mucous. About 1 0% involve both ovaries. They are a bit less aggressive than serous carcinomas but can leak cancerous cells which seed the pelvis and abdomen growing lots of little tumors making mucous, called "pseudomyxoma peritonei".

Endometrold Adenocarcinomas are about 15% and look just like ordinary cancer of the uterus. In fact, 15% of cases do have a simultaneous cancer of the uterus, which must be looked for. It is associated with endometriosis.

Clear Cell Cancers represent 6% can develop in young women who's mothers took the hormone DES, they get them around age 20. Even though most clear cell patients show up with early disease (unlike other epithelial types which are usually advanced ), it tends to be an aggressive cancer.

"Brenner" or "Urothelial" tumors account for about 5% and look like cells from the urinary tract (i.e. bladder). They are usually benign.

Germ Cell tumors which arise from the eggs themselves. They account for about 5%, and are bilateral in about 1 0% of cases:

Dysgerminoma make up about 1/2 of germ cell tumors and are commoner black women in their twenties. The majority of these are early tumors at dis covery, and they are very treatable with excellent results.

Embryonal Carcinoma arises from the cells which would make up an embryo and this tumor has started to develop, or "differentiate", into trying to form a baby. This tumor is more common in teenage girls, and it is much harder to cure than dysgerminoma, but can be mixed with it.

Choriocarcinoma arises from cells which would make up a placenta in a normal pregnancy. It is a rare tumor which is aggressive and may also be mixed with dysgerminoma.

Endodermal Sinus Tumors and Teratoma are primitive yolk sacs, the endo dermal type is more aggressive than the teratoma (which tends to be benign). Interestingly, any type of fetal tissue may be seen in these tumors, including hair, skin, muscle and teeth. An rare variant form "struma over is made up of thyroid tissue and can even cause thyroiditis!

Stromal Tumors are the final major group of ovarian cancers and make up about 5% of all cases. They include those that produce sex hormones.

Granulosa-Theca tumors (3% of ovarian tumors) produce estrogen and may have a co-existing uterus or breast cancer from this extra estrogen.

Sertoli-Leydig tumors (1 % of ovarian tumors) produce testosterone, the male sex hormone and can cause facial hair growth and voice deepening.

Non-Specialized Stromal tumors that arise from the core substance of the ovary, such as its muscle fibers or fat, ("sarcomas") or the immune cells (Illymphoma"). These are very rare. The treatment of them follows that for other areas of the body in which they are more common.

One other possibility is that the cancer did not start in the ovary, but instead spread to the ovary from somewhere else. These "metastatic" tumors are NOT considered "Primary ovarian cancer", but instead labeled according to their area of origin.

You can see that there are many types of ovarian cancer, and it confuses the physicians as well as the patient. Overall, since in older individuals over 80% are the epithelial type, are the most aggressive, and have been most thoroughly researched.

What are the Signs and Symptoms of Ovarian Cancer?

The way the patient appears when they first come to medical attention is called their "presentation". -Patients are queried about "symptoms", which are something that the patient feels (e.g. headache, fatigue). They are then examined for "signs", which means something the doctor can measure (e.g. fever, a new lump). Unfortunately, the most common signs and symptoms of ovarian cancer are nonspecific, and likely to be attributed to some benign condition by both the patient and physician. Thus, there is often a delay in diagnosis. Often no symptoms at all occur until the disease becomes advanced. Sadly, early disease is often entirely without symptoms. Most patients have disease spread past the ovary when first diagnosed.

A Mass in the Ovary or Fallopian Tube ('adenexal mass") may be felt by a doctor during a routine pelvic exam and pap smear. In a younger patient, this is much more likely a benign cyst, but in a patient over menopause is worrisome for cancer.

Vague Abdominal Complaints such as cramping and increasing abdominal girth are often misattributed to gastrointestinal problems.

Pelvic Complaints including vague pain, abnormal vaginal bleeding, pain on sexual intercourse and constipation. Eventual urinary obstruction is seen also.

Signs of Spread into the thorax including shortness of breath and pain in the lungs. General signs of spread include weight loss and fatigue. In advanced disease it can spread to lung, liver, bone and brain.

How does Ovarian Cancer Spread?

There are 4 ways ovarian cancer may spread:

Local spread through the capsule of the ovary, into the fallopian tubes and uterus, and toward the pelvic wall, eventually filling up the pelvis with cancer.

Lymphatic spread to the local lymph nodes in the pelvis, and eventually to the more distant ones in the groin ("inguinal") and abdomen ("para-aortic").

Blood-Born spread ("hemotogenous") distant spread to other body areas.

lntraperitoneal spread from the tumor escaping to the abdomen and implanting upon the linings of the gut and organ surfaces (like liver and stomach). To be detectable, both the original tumor ("primary site") and any spread must normally be 1 centimeter (-1/2 inch) or larger. Smaller spread is called "seeding" or "micrometastasis". It may (or may not) grow into large tumors in the area of spread.

How is Ovarian Cancer Diagnosed and Evaluated?

When a patient presents with symptoms which may represent a gynecological cancer, an evaluation is undertaken to prove cancer and identify location and extent.

Thorough Physical Examination with Pelvic Exam is mandatory. The doctor may detect a pelvic mass, enlarged uterus, structures that seem "fixed" (stuck together by tumor) or abnormal bleeding. He may notice enlarged lymph nodes (glands) in the groin (inguinal nodes), belly button (Sister Mary Joseph nodule), above the left collarbone ("Virchow's node") or in the left armpit lrishe's node"). The abdomen is examined for signs of liver enlargement ("hepatomegaly") or for spleen enlargement ("spienomegaly"). Any "masses" (abnormal lumps) are carefully noted, as ovarian cancer can easily escape the pelvis and grow into abdominal tumors. The abdomen is tapped upon to check for for "ascites", that means loose fluid often seen with advancing cancers. The chest is listened to ("auscultated") and tapped upon ("percussed") for"dull sounds", indicating that fluid has built up in or around the lungs ("pleural effusion") and pneumonia from blockage of lung Tubes ("bronchi") by metastatic tumor. Neurologic exam helps tell if whether the cancer has spread to the brain or other ("peripheral") nerves. Any signs of recent weight loss, skin yellowing ("jaundice") from liver problems, or paleness from lowered red blood cells counts ("anemia") are noted.

Pap Smear occasionally has cancerous cells with ovarian cancer, but does not indicate the site of the cancer. It is more likely "positive" in advanced disease, but is routinely done to detect other gynecologic cancers (uterine and cervical).

Radiologic Tests including ultrasound to look for masses, this is now available in three dimensions. Ultrasound is good for showing when a mass has both "solid" and "cystic" (liquid) components. CT scan is basically a computerized set of multiple X-rays of the pelvis and abdomen, it will show masses greater than 1 cm. If a suspicious area is seen, the CT can be done in "thin slices" to get a better look at it. A "CT with Contrast" means a radio-opaque material is injected into an arm vein; this material will circulate through the bloodstream. When the CT pictures are taken, abnormal blood vessels or bleeding will be highlighted, and so contrast makes the scan clearer and easier to read. Insist upon "ominpaque" or equivalent contrast, it is more expensive but also more comfortable and less likely to cause kidney damage or an allergic reaction. Magnetic Resonance Imaging ("MRI") uses magnetism instead of radiation, it is better for looking at "soft tissues" (like fat and muscle) and may identify smaller tumors and their extent. MRI is about 3 times as expensive as CT scan. It can also be given with a different type of contrast ("gadolinium") to highlight blood vessels and improve accuracy. While radiology tests may detect a "mass" and even suggest that it is cancer, they do not prove cancer. Signs that a mass is probably malignant include a "complex mass" (both solid and liquid portions), nodules ("tumor implants") seen in the pelvis or abdomen, enlarging lymph glands, or very large mass. Scan results are used to justify exploratory surgery.

Blood Tests will include standard pre-operative tests of complete blood count (CBC) and blood chemistry panel (SMA). These routine tests will detect anemia and infection, as well as tell about liver and kidney function. Kidney function is important to document since ovarian tumors can grow to press upon the urine drainage system, causing backup and kidney failure ("uremia"). A special test for "epithelial" ovarian cancer is the CA-125. It is called a "Tumor Marker."

How is the Extent of Ovarian Cancer Gauged?

Like any cancer, the extent of ovarian cancer is given by the "stage". The FIGO system is most commonly used:

Stage I means "Growth Limited to the Ovaries":

IA = Only one ovary involved with it's capsule intact
IB = Both ovaries involved with their capsule's intact
IC = One or both ovaries involved with capsule ruptured, or with escape of cancer cells into the abdomen ("positive peritoneal cytology").

Stage II means growth past the ovaries, into the pelvis.

IIA = growth outside the ovaries
IIB = involvement of uterus and/or fallopian tubes
IIC = Either IIA or IIB but with "positive peritoneal cytology"

Stage III means actual growth outside the pelvis, but still within abdomen.

IIIA = microscopic growth of cancer on inner abdominal surfaces
IIIB = small (<2 cm) tumor(s) growing on inner abdominal surfaces
IIIC = larger (>2 cm) tumor(s) growing on inner abdominal surfaces, and/or spread to the lymph glands.

Stage IV means distant spread to other areas of the body, including to the liver, lungs, bone and brain. Oust liver capsule is still stage III).

What is the Survival from Ovarian Cancer?

This depends upon the stage, type, and treatment selected. In general, for the most common "epithelial" cancers, classical survival rates by stage:

What is the Conventional Treatment for Ovarian Cancer?

Surgery is the conventional method of both confirming the diagnosis and treating the patient. Surgery is optimally performed by a "gynecologic oncologist", a physician who initially trained as an OB-GYN but took extra training for this sub specialty. They are often members of groups which report their results to advance cancer care, such as the "Gynecologic Oncology Group" ("GOG"). Many classic studies in how to manage female cancers have been reported by the "GOG" in cancer journals. When a patient has an unexpected mass in the ovary, they will be treated depending upon the likely diagnosis of the mass. If they are in their reproductive years, doctors will often try hormones for a while (-6 weeks) to suppress a "cyst" in the ovary. If the cyst does not resolve, or they are older and no longer ovulating, they will have the workup detailed earlier. Then they will standardly procede to have a surgery that opens the lower abdomen ("laparotomy) for further diagnosis and possible treatment of the tumor. These operations are typically done under general anesthesia, but may be done with spinal anesthesia if the patient is a poor anesthetic risk (e.g. from lung or heart disease). It is routine to completely remove the suspicious ovary and oftentimes both of them, especially in a patient who has completed her childbearing plans. Surgical removal of an ovary is called an "oophorectomy". Unless preserving fertility is the goal, removal of both fallopian tubes and uterus by a modified procedure is standard at laparatomy, this then is a "bilateral salpingo-oophorectomy and total abdominal hysterectomy" or "TAH-BSO" for short. For the early ovarian cancer, which has not beyond these removed ("resected") organs, the "TAH-BSO" will be curative. The risks of operation include an operative death rate of 2%, an infection risk of 10%, urinary tract problems (such as dribbling) of 5% and late problems of bowel obstruction in 5% (higher if patients get extra ["adjuvant"] radiation). The recovery period from the surgery is typically one month, and patients should not lift significant weight for at least 3 weeks (at which time the tissues have healed to 75% of their former strength).

Unfortunately ovarian cancer has usually spread outside the ovary at laparotomy, often to the bowel, bladder and other pelvic and abdominal organs. Many studies have shown that patients tend to do better, have live longer and have higher cure rates if all of the evident cancer is removed at laparotomy. This may necessitate removal of bowel, bladder, or portions of liver, or even a permanent "colostomy" (drainage bags attached to the abdomen. Obviously, the side effects of these more drastic operations will depend upon their extent, the general condition of the patient and the skill of the surgeon. If obvious disease is going to be left after these drastic procedures, then patients do not appear to benefit from them. Thus, heroic attempts involving disabling surgery should only be attempted if all of the cancer can actually be removed. This is not always possible, even for the best surgeon. The surgeon must balance the need for a complete removal of the cancer against the possibility of useless surgery. If the cancer left is under 1 cm. in total dimension, the patient is said to have been "optimally debulked". These patients have a better 5 year survival rate (>70%) compared to patients who have residual disease after surgery (25%). Thus, if all the cancer can be removed as surgery, it is imperative to do so!

Radiation Therapy if effective for several types of patients with epithelial ovarian cancer, and even curative for some patients. Most commonly, it is used for palliation (symptom relief when patients have pelvic pain or bleeding, and treating symptoms from distant spread of the cancer to bone and brain. Palliative treatment is easy to receive and well tolerated, but isn't curative. Radiation kills cells when they try to divide. Commonly, cancer cells divide more quickly than surrounding normal cells, and we exploit this difference to selectively kill cancer with radiation. However, some normal cells are also bound to be killed by any effective therapy, and this limits extent and amount of radiation we can safely give. Radiation treatment is administered by a "radiation oncologist", a cancer doctor specialized in giving radiation. The radiation oncologist prescribes and monitors the treatments, and deals with side effects as they arise. It is expected that with the aggressive treatment needed to try to cure ovarian cancer ("definitive therapy") that there will be some side effects ("toxicity"), but if the treatment is given for relief ("palliative intent") the radiation dose and side effects should generally be less.

Radiation given for curative intent is not used alone, but in combination with surgery and often chemotherapy. Radiation given this way is called "adjuvant" (extra) treatment, killing the remaining cancer when it's volume is smallest. To be used for cure, the cancer can at most be stage III (no distant spread) and must be very minimal in the amount remaining after surgery. We cannot treat the whole body with enough radiation to kill ovarian cancer without fatal side-effects to the bone marrow and gut. Thus we have to balance between treating a large enough area to actually help, and not doing more harm than good. The particular type of radiation given for cure is called "whole abdominal radiation" and includes the pelvis and entire abdomen past the diaphragms. Since the upper abdomen does not tolerate as much radiation as the lower abdomen and pelvis, several techniques have been devised to deliver optimal treatment. The favored technique is called the "open field" method rather than the older "moving strip" method, since it has fewer side effects. Prior to starting treatment, the patient is "simulated". This means they are placed on a replica treatment machine and the area to be radiated is marked out. First watercolor markers, and eventually small permanent tattoos are used. During the simulation, markers are put into the vagina, and often some barium into the rectum, to locate these areas. Films are taken and the information from the simulation is put into a "treatment planning computer" which generates a "plan". This plan tells how much radiation is going to each area of the treatment field, and to normal tissues like spinal cord, bladder and kidney.

The patient then begins treatment. It is given Monday through Friday for 5 - 7 weeks, and takes only several minutes per day. The total dose to the pelvis is about 50 Gray (units of radiation), while to the abdomen about 30 Gray is given. The patient does not become radioactive, have holes burned in them, or lose their scalp hair. Expected side-effects of radiation treatment are divided into "acute" and "late" reactions. Acute reactions occur during the treatment period, while late reactions may occur months to years after treatment is completed. Common acute reactions with pelvic and whole abdominal radiation include skin redness, nausea, diarrhea, rectal irritation, frequent urination and fatigue. These side effects crescendo as during the treatment course as the dose to the "target area" builds up. Fortunately, they gradually abate after treatments are completed. Possible late reactions include bowel obstruction (5%), long-term bowel and urinary changes (i.e. diarrhea and frequent urination), and a risk of decreased kidney and liver function. There is a very tiny risk of spinal cord damage leading to paralysis (less than l%) and eventual (many year later) production of a second cancer from radiation. Overall, treatment is usually well tolerated. Since radiation kills cells when they try to divide, it keeps "working" to some extent after treatments are completed. There may still be some "tumor" evident of scans after treatment, which will gradually "fibrose" into scar tissue. The worry is if a mass grows after treatment, not if it stays the same or shrinks only gradually. Scans too soon after radiation (i.e. within the first 3 months) are usually useless to tell whether treatment was successful. Even taking a repeat biopsy too quickly after treatment can be confusing to the pathologist owing to "treatment artifact", and such readings are often inconclusive. The point is that after maximizing definitive (curative) therapy, the patient will have a period (of anxious waiting) to see how well it worked-- and whether the cancer wiII recur.

The results of radiation show that it is useful for patient who have no remaining visible disease in the abdomen after surgery, and small (less than 2 cm) or none in the pelvis. This is because the doses of radiation needed to treat more than this amount of cancer are too toxic to the normal tissues, For these patients getting whole abdominal pelvic radiation, survival is about 30% better at 5 years (i.e. 75% vs. 45%) than for those getting pelvis radiation only. Radiation may be combined with chemotherapy. Doctors have tried using single-drug chemotherapy (melphalan) instead of radiation, but overall results are about 15% better survival when radiation is used compared to a single chemotherapy agent. Unfortunately, no real survival benefit is seen when radiation is used for a patient who still has bulky remaining disease after surgery.

Another way to give radiation treatment is by putting a "radioactive colloid" into the abdomen with a needle, and letting it spread about. The chemical most used is Phosphorus-32, which gives about 60 Gray of radiation along the abdominal lining if the usual dose of 20 microcuries is used. While this treatment is quick, and less toxic to the kidneys and liver, this type of radiation has very poor penetration (less than O.5 cm) and will only treat the most superficial disease. It is useless for larger tumors. It's main complication is a tendency for later bowel obstruction (as high as 30%), especially when combined with regular external beam radiation treatment. It is used for patients who have evident remaining disease, to help ensure they don't relapse.

Chemotherapy remains the mainstay of treatment after surgery. It is not curative without meticulous surgical removal of the disease during surgery, but is able to prolong life for most patients. Using multiple drugs for chemotherapy has largely replaced radiation therapy for treatment of residual (microscopically small) disease in the abdomen. Also, chemotherapy is the most common form of therapy for patients with advanced disease. The type of drug used most has been the "alkylators", which are derivatives of the mustard gas used in WW1. Such drugs include melphalan, cyclophosphamide and thiotepa. The response of ovarian cancer to these drugs averages about 50%. They roughly double survival, from 10 to 20 months, in patients with advanced disease. Furthermore, about 20% of patients appear cured by this therapy. Side effects of these alkylators include lowered blood counts (causing anemia and infection), mouth sores, nausea, vomiting and diarrhea. In patients who get cured, alkylators increase the chance they will get a leukemia in the future. The next most active drug in ovarian cancer are the platinum derivatives "cisplatin" and "carboplatin". Carboplatin seems to cause less kidney damage than cisplatin, and appears just as effective. The typical response to these drugs is about 40%. Possible side-effects include lowered blood counts, nausea and vomiting, and nerve, hearing and kidney damage. Obviously, they must be given with extreme caution.

Given that single drugs showed effectiveness for many ovarian cancer patients, it was logical to try to combine drugs for greater response. This is then "combination chemotherapy" and is the type most commonly used today. It helps avoid the cancer getting resistance to the drugs, much the same as bacteria can develop resistance to antibiotics. The ideal combination combines the effectiveness of the drugs, but not the si 'de effects. While no perfect combination is known, the most popular is platinum and cyclophosphamide. Although unproven, many oncologists add doxorubicin for patients with more advanced disease. This drug causes heart and lung damage, but does slightly increase response (by under 10%). Other drugs which have been used for both initial therapy and relapsed cases are 5-Fluorouracil and Etoposide. When given for relapsed disease, they have a response rate of about 20%. Unfortunately, many responses with chemotherapy, even when given as combination drugs, are transient, as the tumors develop resistance. The basic principle remains that the smaller the cancer volume at treatment, the better chance for cure with the addition of chemotherapy or radiation.

Hormonal Treatment is mildly effective for some epithelial ovarian cancers. At the time of surgery, "estrogen and progesterone" receptors (which are commonly measured for breast cancers) can be tested for by the lab analyzing the tumor. If the receptors are present ("positive") , the tumor may show a response to hormone pills given by mouth (usually tamoxifen or megace). While the response was only about 10% and lasted an average of 8 months in a Gynecology Oncology Group study, the low side effects may make it worth a try.

What is the Latest, Effective Therapy for Ovarian Cancer?

Advancements in surgery have included doing "second-look" operations to see the effectiveness of prior therapy, and to remove any residual tumor. Unfortunately, there is no evidence that doing a second-look operation increases survival. About 40% of patients currently get a second-look surgery, and it will either show no disease or persistent disease after therapy. If no disease is seen, it still does not mean that the patient is cured, since nearly 50% of patients will still relapse even after their "negative" second look surgery. Also, about 40% of patients in whom no disease can be seen with ultrasound or CT scans will have some disease noted when a second look surgery is done, showing the poor ability of these scans to see small residual ovarian cancers. Overall, it is very difficult to tell about the effectiveness of radiation or chemotherapy without actually going in and looking at it. Just going in and removing residual tumor may be appropriate, but the data is mixed on whether it actually helps increase survival. The conclusion of the literature is that second-look surgery must be done to judge the effectiveness of new therapy in clinical trials, but it does not help current patients to live longer.

Radiation Therapy is still limited in usefulness to patients who have less than 2 cm. of disease in the pelvis, and only microscopic disease in the abdomen after surgery. It is critical to go to a competent radiation oncologist who is meticulous about the treatment field, since even small variations (such as not covering the diaphragms) can decrease survival. Complex 3-dimensional computerized treatment planning systems are now available to increase the accuracy of the radiation field, and lower the risk of late reactions to surrounding normal tissues (such as spinal cord). It takes an aggressive radiation oncologist to do whole abdominal irradiation for ovarian cancer, but it was shown to increase survival for stage 11 and stage III patients at the Princess Margaret Hospital in Toronto, Canada in trials authored by the prestigious (late) Dr. Dembo. Every gynecologic oncologist knows of these trials, they may have to convince older radiation oncologists that the therapy should be done.

Chemotherapy continues to evolve. The latest drug combination is Taxol and platinum. Taxol comes from the bark of the Western Yew tree, it is given by a continuous drip into the veins over 24 hours. Several major clinical trials are now underway using "taxanes" (taxol and its derivates) for ovarian cancer. The Bristol Myers Pharmaceutical company which makes Taxol has relied on study GOG-111 published in the New England Journal of Medicine in Jan. 1996 as well as European Gynecology Group Studies ("EORTC") to use taxol as first line treatment for ovarian cancer. Patients in the GOG-1 1 1 study were stage III and IV and got 135 milligrams of taxol "per meter squared" (most people are -1.5 square meters) over 24 hours plus cisplatin 75 milligrams "per meter squared". This was compared to a group who got an older alkylating agent, called cyclophosphamide, with their cisplatin (but no taxol). Patients who received taxol had over 60% response rate, compared to less than 50% for the cyclophosphamide group. There was an overall increase in survival for patients treated with taxol. Only 5% of patients who got the taxol treatment had to discontinue it because of side effects ("toxicity"). Now the Oncological Drug Adviso!Y Group which advises the FDA on new drug uses has recommended Taxol as first line chemotherapy (in combination with cisplatin or carboglatin) for newly diagnosed patients with egithelial ovarian cancer spread beyond the ovary. Blood counts must be carefully monitored! The combination produces over 30% response even in previously heavily treated patients. It causes lowering of blood counts and baldness. Using it in non-treated patients, in combination with other drugs, can give 80% response!

"Clinical Trials" and Research "Protocols"

Some therapies are in standard use, others recently approved as "efficacious" (they may actually work) by the Food and Drug Administration, and yet others are only offered at Major University Academic Medical Centers in the context of "Clinical Trials". These trials are first designed to show how toxic a new treatment is ("Phase I" studies), whether is works at all ("Phase 11" studies), and if so just how well it works and is tolerated ("Phase III and IV" studies). The National Cancer Institute has protocols using immune therapies that are available at the Major University Medical Centers. Also, Major Medical Centers often have their own "In House" trials designed and run by their own faculty. If one wishes to join a Clinical Trial, there are "entrance criteria" (usually ensuring that the patient is in otherwise good health, and that they are NOT receiving any other therapy which could skew the Trial results) "disqualification factors" (for eliminating those who become too sick during the trial), and "early closure" factors (if it is obvious that the treatment either does or does not work). A patient may or may not be "accepted" into the Trial, and if they are then they are "randomized" to a particular "arm" (treatment), usually in a "double-blind" fashion (neither the patient nor the investigator knows if they are getting the new drug or a fake-- "Placebo"). Obviously if a major surgery or radiation is involved in one arm but not another, the Study physicians and patients will know which treatments they are getting, but the initial "randomization" will still determine what patients will receive. Patients who do not wish to give up the autonomy for how they are treated should not enter Clinical Trials.

If the drugs or treatment being used in a Clinical Trial are already approved by the FDA for some other condition, then they can be prescribed by any physician for any condition. This is called "off label" prescribing, and is a common practice. Thus, if the drug used in a Trial is already on the market for anything, the patient may ask to be treated with it "off protocol", the difference being the know they are actually getting it. Doctors at Major Universities are more likely than at Community Clinics or HMO's to agree to treat patients "off protocol", especially if an actual protocol is being offered at their Institution and the patient does not meet all the "entrance criteria". Generally, doctors DO want to offer the patient anything they feel has a good chance of working.

Symptom Relief

When ovarian cancer is advanced, with spread throughout the body, relief of symptoms ("palliation") becomes our primary objective. The patient should always be made as comfortable as possible, and narcotic medicines like morphine (which Osler called 'G-d's own medicine) should never be withheld for fear of causing "addiction". Using "Fentanyl Patches" applied to the skin helps give a continuous amount of narcotic, eliminating the problems of forgotten doses, "loss" of narcotics, and smoothing out the dosing for less disturbing "highs and lows". Importantly, Radiation Treatment (if it has not been given priorly) can help with pelvic pain, bleeding, and bone pain in over 80% of patients. It is also useful for reducing the symptoms, and perhaps extending survival, in patients with spread to the brain. Sometimes radiation therapy is used as an emergency measure when the cancer spreads down to the spinal column and threatens to cause paralysis by pressing upon the spinal cord. Any gatient with ovarian cancer who experiences new weakness of the extremities, numbness, or loss of bowel or bladder function must be brought into the Eme[genc-y Room immediately to see whether the tumor is compressing the spinal cord causing these symptoms. Up to 60% of new back pain in a cancer patient is caused by spread of cancer there. The patient is given a painless Magnetic Resonance Imaging (MRI) scan to check for "epidural spinal cord compression". If this is caught early, and treatment is given, permanent paralysis may be prevented. It is unfortunately uncommon to reverse symptoms of paralysis once they are set in, so quick recognition is essential.

Over three-quarters of patients experience satisfactory relief with pain ("analgesic") medication and/or radiation therapy. If insufficient relief is gotten from medications or radiation, neurosurgical techniques to cut sensory nerves to the pelvis, or injecting alcohol into nerve bundles ("ganglia") can nearly always afford relief. Committing suicide because of unrelieved pain should NEVER be necessary with pain science today. CancerAnswers has an In Depth Understanding of Symptom Relief Transcript available through our website.

Conclusion

In dealing with a newly diagnosed ovarian cancer problem, the patient should not rely on any single method, such as a surgery or ray, but instead take a "combination" approach for the best chance at cure. This means seeking out and sticking by the best available conventional treatment, and always getting a second (or third) opinion if warranted, from expert gynecological oncologists and radiation oncologists. The patient should embark on a program of nutritional therapy, exercise, spirituality and "mind over cancer'. Positive mental attitude has clearly been shown to be correlated with better outcomes for cancer patients. Furthermore, the patient should select an Alternative therapy that does not interfere with their other therapy and that they can believe in. CancerAnswers offers an Alternative Therapy Transcript on Cancer available through our Website. Our conclusion is that the improving conventional approaches and new chemotherapy and biological modifiers to prevent further growth are giving better and safer survival than ever before for every known type of ovarian cancer.