Ovarian Cancer
This article is designed to provide an expanded viewpoint on ovarian cancer, from risks to diagnosis and the current approach to oncologic treatment. it also will offer brief specific integrative support modalities and a recommendation to find more detailed information at the resource section of the site.
Ovarian cancer is the second most common gynecologic cancer in the world, first in affluent countries. It is the leading cause of gynecologic deaths in the US as it is often diagnosed in advanced stages, as diagnosis is elusive. Often it progresses with few to mild symptoms, often digestive and can mimic benign gynecologic problems. As a result, only about one fifth are at an early stage when discovered. Another difficulty is that there is no absolute in diagnostic blood testing that will reveal early disease. Unlike many cancers, specific markers that can be used for early diagnosis are unreliable as they may not be elevated in ovarian cancer, and they can also be elevated for other reasons than cancer
Older women, starting in the mid-sixties, have the highest risk of disease, and a five-year survival of 30%. Younger women, < 65 have a survival rate of approximately twice their older counterparts. However, African American women have lower survival rates compared to white women in the same age ranges. But overall five-year survival for all types is only 50%. In 2023, twenty thousand women were newly diagnosed.
In many primary and gynecologic practices older women are seen less frequently and often as they are menopausal pelvic examinations are infrequent. If you have a family or personal history
Of breast, colon or uterine cancer regular evaluation and exam is important.
There are also genetic blood panels for ovarian cancer that can indicate if there might be other uncommonly tested markers that increase ovarian cancer risk.
Cancer of the ovary, fallopian tube and membrane lining cells of the abdomen, the peritoneum, are microscopically so similar in appearance that they are universally called ovarian cancer. It is also now believed that ovarian cancer originates from the fallopian tube and implants on the ovary. In BRCA mutations, the precursor lesion has been found to be in the fallopian tube itself.
Ninety percent of ovarian/fallopian tube cancers develop from the epithelial or surface cells. Of this type of cancer, 80% are considered high grade serous carcinoma (HGSC) occurring in 75% of women, and 10% are low grade serous carcinoma (LGSC). While both are called serous, they develop from different alterations in DNA with HGSC and tending to grow quickly and spread more rapidly.
Risk Factors for Ovarian Cancer
High risk if there is a strong family history of breast or ovarian cancer
Age is the most important risk factor, with the incidence of ovarian cancer increasing after menopause. 69% of all ovarian cancer occurs in women over 55.
The known genetic conditions associated with ovarian cancer include:
BRCA1 & 2:
These are genes that produce proteins to repair DNA damage. Mutations in these genes are associated an increased risk for ovarian and breast cancer in women, and breast and prostate cancer in men. A BRCA 1 mutation conveys a 40% lifetime risk of ovarian/fallopian tube cancer while BRCA 2 conveys a 10-20%risk. BRAC gene mutations are commonly inherited within families, but in ovarian/fallopian cancer, 40% of women with no family history have BRCA mutations.Therefore, women with ovarian/fallopian tube cancer, especially those 65 or younger, should be tested, as standard treatments are different for BRCA woman than for those without it.
Lynch Syndrome
This is an inherited cancer mutation syndrome that is associated with several different mutations that increase the risk of not only ovarian/fallopian tube cancer but endometrial, stomach, urinary tract, and bile duct cancers. With a family history of any of these cancers, genetic testing is indicated so if Lynch syndrome is diagnosed, surveillance can potentially diagnosis ovarian disease or other related cancers at an early stage.
Peutz -Jeghers Syndrome
This is an inherited syndrome presenting as large colon polyps and brown, blue and black pigmented freckles on the skin. It is associated with increased risk of several GI cancers, breast, and Ovarian/fallopian tube cancers
Nevoid Basal Cell Carcinoma Syndrome, also called Gorlin’s syndrome, is a rare genetic disorder often with developmental abnormalities but increasing the risk of basal cell cancer and to a lesser extent ovarian/fallopian cancer.
Somatic DNA Testing
Can also be performed when the primary tumor is removed, and is often covered by insurance.This is testing of the tumor DNA to look for spontaneous mutations that potentially offer advanced available treatments.
One example is a marker for the folate receptor on the tumor, which allows a specific treatment for women with platinum chemotherapy resistant disease (see below in treatments), with a 43% response rate.
Another is testing can be for a HRD+ marker, homologous recombination score which distinguishes people as candidates for PARP therapies that block tumor DNA repair.
Lifestyle Risk Factors
Obesity occurring at a younger age have an increased association with ovarian cancer and a lower survival rate.
Hypertension
Diabetes
Lack of exercise
Gynecologic factors:
Increased risk- no children or infertility
Hormone Therapy, long -term unopposed estrogen therapy (no progesterone) but decreased risk associated with the use of oral contraceptives
Pelvic Masses
Up to twenty percent of women will be diagnosed with a pelvic mass over the course of their lifetime. In the evaluation of an adnexal mass (defined as the ovary, fallopian tube, and the supporting ligaments) while many are benign, cancer must be ruled out as a cause. This can sometimes be difficult as the symptoms and signs of benign or malignant conditions present in a similar manner clinically, and laboratory markers can be normal even in cancer.
The types of masses commonly diagnosed are:
Benign Masses
Ectopic pregnancy
Polycystic ovaries
Post-ovulation or functional cysts
Endometriosis
Fibroids
Torquing of the ovary (Ovarian torsion)
Malignant Masses
Epithelial cancers
The outer surface cells covering the ovary and fallopian tube. These cancers make up the majority of ovarian/fallopian tube cancers, but include different epithelial types including:
High Grade Serous (HGSC) is associated with a mutation of P53, a tumor suppressor gene which is altered, allowing damaged or mutated cells to escape apoptosis or cell death and continue growing,
Mucinous
Clear Cell Ovarian cancer, is believed to arise from uterine implants associated with endometriosis and responds poorly to conventional ovarian cancer chemotherapies.
Endometroid
Low-Grade Serous (LGSC) is associated with gene mutations, KRAS (Kirsten rat sarcoma viral oncogene homolog) or BRAF (B-raf proto-oncogene) that are oncogenes that transform normal cells into tumor cells.
Each of these types has unique characteristics that reflect different risks of progression and treatment therapies that offer the most benefit.
Stromal ovarian cancer represents a less common cancer, 8%, and is often associated with BRCA mutations. These tumors can be benign or malignant. These cells are stimulated by hormones that act on granulosa cells to produce progesterone after ovulation and theca cells that produce androgens.
Germ Cell ovarian cancers arise from cells that can become eggs or sperm and occur most commonly from early adolescence to the late twenties. There are several different types. Many are benign but 1-2% are malignant but the majority are curable. It is also one of the few solid cancers that have specific biochemical markers, human chorionic gonadotropin (HGG) and alfa fetal protein (AFP).
Symptoms and Signs of malignancy are similar in benign conditions also.
Abdominal pain that can present as sharp, dull, sudden, or gradual
Bloating
Change in bowel habits, often constipation
Abdominal pressure and pain
Diminished appetite
Also:
Pelvic pain
Pain with intercourse
Changes in menstruation
Vaginal discharge
Urinary urgency, frequency, and incontinence
Testing
In acute, possibly life-threatening, situations early imaging with CT scan is necessary to rule out an ectopic pregnancy or twisted fallopian tube. However, even in non-acute but persistent symptoms lasting for several or more days, even with treatment, further evaluation is indicated.
Imaging
When a mass is palpated, or symptoms are persistent, radiologic imaging with a noninvasive transvaginal ultrasound is the first choice. If a concerning mass is found evaluation of adjacent structures with CT or MRI is indicated and a PET scan (positron emission tomography) can be considered if distant spread is suspected.
If findings are discovered on imaging, laparoscopic surgery will be the next step to obtain a biopsy to determine if the mass is benign or malignant.
Ca 125 protein
There is the desire to find a biomarker for early ovarian cancer and often patients request a Ca -125 level. It is not sensitive to pick up all disease. It will be positive in 80% of epithelial cancers, yet in half of the patients with early stage 1 disease, it is negative. The Ca -125 also has a high rate of false positives in patients having obesity, pelvic infections, during menstruation, endometriosis, and pregnancy. It also can be positive in lung disease, heart failure, liver cirrhosis and other cancers.
HE4
When the Ca -125 is negative, another marker called the human epididymis protein 4 (HE4) is elevated in 50% of ovarian cancer. It also is elevated in endometriosis and Lynch syndrome. However, since the normal range is vague, it is often measured and compared to previous levels in recurrent or progressive disease.
Currently there are ongoing programs which include the HE4 integrated with other biomarkers, symptoms, and ultrasound to create a malignancy risk algorithm to provide relevant information in decision making using all the available information from these sources.
For perimenopausal women, age 41-50, benign conditions are most common, and evaluation should be using a transvaginal ultrasound and Ca -125.
For menopausal women, evaluation can be similar, but oncology follow up is required for a mass larger than 10cm and a Ca -125 greater than 35, commonly prompting biopsy to uncover possible cancer.
Germline Testing
Is recommended for all women with epithelial ovarian cancers to assess for familial ovarian cancer associated syndromes. Germline cells are those inherited from your parents and are universal in all cells in the body, and testing can help other family members make choices based on the results. It is however not done in all oncology settings with less than one third of patients with epithelial ovarian cancer being tested.
Laboratory Testing
In premenopausal women with an adnexal mass, initial evaluation requires a pregnancy test, and complete blood count to determine possible infectious causes.
CA19-9 tumor marker
Is a marker for clear cell and mucinous epithelial cancer detection.
Risk of Malignancy Index (RMI) uses a scoring system to provide an assessment of the potential for ovarian cancer. If the Ca- 125 is > 35 then an ultrasound (US) should be performed.
The scoring system includes 3 points for menopause, Ultrasound; 0 for no findings, 1 point for one finding and 3 for more than two findings
RMI = Ca -125 score X menopausal score X US score. If it is >200 referral to a specialist is indicated.
Genetic Testing is recommended for all women with epithelial ovarian cancers to assess for familial ovarian cancer associated syndromes.
BRCA 1& 2, Breast Cancer Susceptibility Gene Carriers
These hereditary genes are associated, in women, with both breast cancer and ovarian cancer. Testing for these genes in epithelial ovarian cancer (EOC) is important, first because a significant percentage of women have this gene in ovarian cancer but no family history association. Second, if the testing is positive, treatment for recurrent disease benefits using the PARP inhibitor drugs (see below).DNA Mismatch Repair Deficiency Genes are found in Lynch Syndrome which is associated with ovarian cancer, 15% of certain colon cancers, and other cancers. It relates to an aberrant mechanism of DNA repair that creates a large number of mutations. Its importance in EOC as having these markers allow for targeted treatments with immune checkpoint inhibitors that can unleash the immune system on this cancer. These drugs are only indicated for Lynch Syndrome but are not indicated in typical EOC.
Somatic DNA Testing
This is testing of the tumor DNA to look for spontaneous mutations that potentially offer advanced available treatments. It can also be performed at the primary tumor removal and is often covered by insurance.
One example is a marker for the folate receptor which now has a specific treatment for women with platinum chemotherapy resistant disease (see below in treatments), with a 43% response rate.
Another is testing can be for a HRD+ marker, homologous recombination score which distinguishes people as candidates for PARP therapies that block tumor DNA repair. This is now offered as part of initial treatment when the mutation is present after first line chemotherapy.
Clinical Staging
Clinical Staging is based on examination with laboratory testing and radiologic imaging. It provides:
Location of disease
Size of the tumor
Area of local spread
All of which can offer prognostic information
Surgery is the initial treatment performed in all women who are able to tolerate surgery to remove as much tumor bulk as possible. Studies show that patients have better outcomes with an expert in gynecologic cancer surgeon as well as the removal of as much visible tumor as possible, both of which improve survival.
Early-Stage Ovarian Cancer
Stage 1, confined to the ovary
Stage 2, confined to the pelvis
Stage 1
Cancer is found in one or both ovaries or fallopian tubes but there is no spread to other areas
This situation is encountered in 20% of women.
Stage 1A: cancer is confined within one ovary or confined within one fallopian tube
Stage 1B: cancer is found in both ovaries or fallopian tubes but has not penetrated the surfaces
Stage 1C; cancer is found in one or both ovaries or fallopian tubes with the other findings of:
Stage 1C2: the cancer is found on the outer surface of the ovary or fallopian tube
Stage 1C3: cancer is found in fluid in the abdomen or pelvis
Treatment of Stage 1
Treatment is the surgical removal of the uterus/cervix, ovaries, and fallopian tubes. In addition, the fat layer covering the abdominal organs is removed, and biopsies of the lymph nodes and pelvis are performed. If the cancer is verified as stage 1A or 1B or pathology shows cells very similar to normal ovarian cells, there is a 90% five-year survival, and no further treatment is indicated.
Chemotherapy is recommended in Early-Stage Disease
In the following circumstances, as the 5 year disease free survival is significantly reduced when:
There is Stage 1C disease
High grade or aggressive tumor cells are found making progression more likely
Diagnosis of a clear cell ovarian cancer
Washing of fluid from the abdomen ,during surgery, reveal tumor cells
Stage 2
Cancer is found in one or both ovaries or fallopian tubes and has spread too other
organs in the pelvis.
Stage 2A: cancer involves the uterus or surrounding tissue
Stage 2B: cancer has spread within the pelvis but not beyond it
Treatment of Stage 2
Treatment requires the removal of the uterus, ovaries, and fallopian tubes, with biopsies of local lymph nodes and pelvic tissues and in addition the removal of as much tumor tissue as possible. Continued treatment will be necessary with chemotherapy.
The five-year survival is approximately 70%.
Stage 3
Involves cancer that has spread to the peritoneal cavity (the abdominal and pelvic cavity) and or involves the lymph nodes.
Stage 3A1: involves the ovaries, fallopian tubes or the abdominal lining and the pelvic nodes or nodes adjacent to the aorta. It has not spread to other pelvic or abdominal areas.
Stage 3A2: Involves one or both ovaries and fallopian tubes or is primary peritoneal cancer, and biopsy revels microscopic foci of cancer outside the pelvis. The cancer may also involve the pelvic and para-aortic lymph nodes.
Stage 3B: Involves one or both ovaries and fallopian tubes or is primary peritoneal cancer and has visibly spread to organs outside the pelvis but lesions are < 2cm in size. The cancer may also involve the pelvic and para-aortic lymph nodes.
Stage 3C: Involves one or both ovaries and fallopian tubes or is primary peritoneal cancer and has visibly to organs outside the pelvis but lesions are >2cm in size. The cancer may also involve the pelvic and para-aortic lymph nodes.
Five-year survival at this stage is 40%
Treatment of Stage 3
Treatment will require surgery to remove the uterus, both tubes and ovaries and the removal of as much tumor as possible, along with chemotherapy.
In addition, tissue or lymph nodes that are suspect in the pelvis and abdomen will be removed.
Depending on locations seen on imaging, chemotherapy may be advised prior to surgery, to shrink the disease, but is definitely indicated after surgery.
Stage 4
A diagnosis of Stage 4 cancer means the cancer has spread to distant sites, the liver or the lung, or is in fluid in the pleural space (lining around the lung) of the lung.
Stage 4A: Cancer cells are found in the pleural fluid but not in other organs of the abdomen such as the liver or spleen and no spread to lymph nodes outside the abdomen.
Stage4B: Cancer cells are found in the liver and lung and in lymph nodes outside the abdomen.
Five-year survival at stage four is 30-40%.
At the time of diagnosis 75% of women will already be in Stage 3 or Stage 4 disease.
Treatment of Stage 3 and Stage 4
The initial optimal treatment approach is surgery to remove as much tumor as possible followed by systemic chemotherapy. If the amount of residual tumor is <1cm after surgery, then IV therapy alone can be chosen or in combination with chemotherapy instilled in the abdomen, IP therapy (intraperitoneal chemotherapy).
The option of intraperitoneal chemotherapy is not an option if post-surgery there is still > 1cm of residual tumor l, as the intraperitoneal drugs will not penetrate the tumor adequately.
In women with a large tumor volume or have health issues that exclude surgery because of the amount of tumor and required length of surgery needed, then neoadjuvant chemotherapy, or chemotherapy given before surgery, may reduce tumor size which might then allow these women to have surgery and chemotherapy. If a woman is too fragile even for this option, then chemotherapy alone is given.
The Initial Choice of Treatment for Epithelial Ovarian Cancer
First Line Is a combination of a Platinum Drug and a Taxane Drug, Regardless of whether surgery has been optimal or suboptimal.
Platinum Drugs- These drugs activate inside the cancer cell and binds to DNA linkages, causing damage to the DNA and inducing self-destruction and cell death. The two used are:
Cisplatin
Major Side effects include:
>40% up to 80% peripheral neuropathy, drug manufacture sites 0%
28% Kidney dysfunction
31% Hearing loss
30% Marrow suppression
or
Carboplatin
Major side effects include:
5% Peripheral neuropathy
10% Nephrotoxicity
93% Nausea
84% Vomiting
44% Pain
Follow up after first line therapy
Follow up clinically after completion of treatment involves regular visits to the oncologist, which include evaluation of symptoms and a pelvic exam.
Two approaches for surveillance include :
Clinical evaluation along with Ca -125 and when indicated CT imaging
Clinical evaluation along with Ca -125 and regular CT scanning throughout at specific intervals.
Prediction of Overall Survival
Recent studies indicate that after the completion of treatment, the 3-month Ca- 125 is the best predictor of overall survival at two, three, and four years. A Ca -125 is >35 indicates lowered survival at both 24 months it is 50% and 60 it is months 79% .
Taxane Drugs-These drugs interfere with normal cell division inducing death
The two used are:
Taxotere (Docetaxel) is 2x as potent as Taxol
Major side effects:
98% Low white blood cell count
94% Anemia
98% Hair loss
60% Fluid retention
54% Rash
Or
Taxol (Paclitaxel)
Major side effects include:
90% Low white count
87% Hair Loss
78% Anemia
60% Peripheral Neuropathy and Muscle Pain
58% nausea and Vomiting
In women at higher risk of recurrence based on the presence of fluid around the Lung or abdominal fluid (ascites) the recommendation is to add Avastin and continue it as a maintenance therapy after the first line therapies are completed
Avastin (Bevacizumab)
Targets Vascular Endothelial Growth Factor (VEGF) and blocks the growth of new blood vessels that would supply nutrition and oxygen to growing cancer cells.
Major side effects include: (the company classifies these as up to %)
80% Fatigue
62% Abdominal Pain
34% High Blood Pressure
47% Upper Respiratory Infection
37% Low White Count
31% hair Loss or Coughing Up Blood
Increased risk of Bowel Obstruction, low <2%
The chemotherapy side effects listed are only the largest % of people affected, but many other potential side effects can occur.
Gemcitabine
Induces cell death during replication, by blocking their ability to move from G1 phase, cell growth, into S phase, replication.
Major side effects include:
69% Nausea and Vomiting
63% Low White Counts
68% Anemia
68% Elevated Liver Enzymes
45% Protein in the Urine
40% Fever
Recurrent Disease
The likelihood of relapse after the initial treatment of ovarian cancer is 68% for all stages. For women in Stage 3 or 4 the relapse rate is higher.
Recurrent treatments with Platinum Sensitive Women
A woman needs to be off the platinum drug a minimum of six months and preferably longer to be considered platinum sensitive. If that is the case, the plan is to use a platinum drug again as there is a likely hood of response.
If less than 6 months a woman is considered, platinum resistant.
If a platinum drug can be reused, it is combined with another chemotherapeutic agent
These include:
Carboplatin and Paclitaxel, with or without Bevacizumab
Carboplatin and Gemcitabine, with or without Bevacizumab
Carboplatin and Pegylated Liposomal Doxorubicin, with or without Bevacizumab
Pegylated Liposomal Doxorubicin is the chemotherapy drug packed inside spheres of lipid so that it remains in the blood to be transported to areas where the cancer cells are.
Major side effects are many, but often frequencies are not given, these include:
60-80% Low White Blood Cell Counts
80% Stomatitis
20-85% Nausea
1-10% Myocardial Damage, Heart Failure, Abnormal Rhythm
1-10% secondary acute myelogenous leukemia or myelodysplastic syndrome
Adriamycin (Doxorubicin) inserts within the DNA, in the lipid layers, and prevents DNA replication
Recurrent Disease in Platinum Resistant Disease
Despite treatment, many women will relapse and require additional treatment. The chemotherapy that is offered depends on the interval of time since the completion of their first line of treatment with a platinum drug.
If the time interval is < 6months or if progression occurs while on the platinum drug their disease is considered platinum resistant.
If a woman has not specifically been treated for platinum resistant disease, then the decisions for available therapies are divided into two categories:
1. Positive Folate Receptor alpha
Folate Receptor alpha +, indicates an overexpression of the folate expression. Newer treatments can target this receptor.
Ovarian cancer is composed of many diverse and dissimilar populations of cells that are implicated in chemotherapy resistance and disease recurrence. 50% of ovarian cancer cells possess a surface protein with a high affinity for folate, vitamin B9. These ovarian cancer cells commandeer normal folate metabolism and use it for their own cell growth and replication.
This marker can be measured in the blood from EOC tumor cells where if overexpressed at a percentage of > than 80% off the tumor cells, treatment with the antibody drug conjugate Elahere (Mirvetuximet Sorvatansine-) can be used. This combination drug has been described as a trojan horse. It attaches specifically to the ovarian cancer cell folate receptor and releases a concentrated chemotherapy or a targeted therapy to the cell. Its advantage over conventional chemotherapy is that it targets just the cancer cells, and while chemotherapies travel via the blood to kill cancer cells, chemo also damages normal cells that are rapidly growing too.
In a recent study, the Miravol study, with Folate Receptor Positive, Platinum Resistant Ovarian Cancer meeting the criteria for treatment, using Elahere resulted in a significant survival of 33%. It also is being offered when there are lower percentages of folate receptor measured but it has been shown to be effective but to a lesser degree.
Elahere (Mirvetuximet Sorvatansine-) This agent is a chimeric antibody (derived from 2 or more different organisms) combined with a chemotherapy drug. Elahere targets the folate receptor on the ovarian cancer cell and carries the chemotherapy directly to the target also.
Major Side effects include:
49% fatigue
36% Abdominal pain
33% Peripheral Neuropathy
27% Dry Eye
20% Constipation
Serious Effects,31% possible Intestinal obstruction, Fluid Accumulation in Abdomen or Lungs, or Infection
2. Negative Folate Receptor alpha
This marker is not present, and Mirvetuximet Sorvatansine cannot be used to target ovarian cancer cells in treatment.
Treatments Available for Folate Receptor Alpha Negative Testing include the following conventional chemotherapies:
Being platinum resistant and having not been treated for recurrence the choice is commonly to choose a single agent:
Paclitaxel is the first line drug in platinum resistant recurrence, unless previously there have been serious side effects with this drug, specifically peripheral neuropathy or sustained bone marrow suppression.
If the disease has progressed on paclitaxel or side effects restrict its use, then the next choices are:
Pegylated Liposomal Doxorubicin
Bevacizumab
Gemcitabine
Topotecan
Topotecan
The drug causes breaks in strands of DNA preventing replication
Major Side effects include:
97% Low White Blood Cell Counts
64% Nausea
45% Diarrhea
49% Hair loss or other dermatologic reactions
43% Infection
Recurrent Disease, but without Symptoms are situations in which:
Rising Ca 125, without symptoms or changes on imaging.
If this occurs within six months of completing treatment it is suggestive of progression of disease. Currently, gynecologic oncologists recommend surveillance rather than initiating another regime of chemotherapy, as treatment data shows no survival benefit when comparisons are made between early treatment versus treatment that is initiated when clinical or radiologic evidence of progression is observed.
Asymptomatic recurrent progression
Occurs when Radiologic Imaging shows progression, but there are few or no symptoms, in recurrent EOC.
In this situation, women can be offered hormone therapy as forty to eighty percent of ovarian cancers have estrogen receptors. Treatment with Tamoxifen, a selective estrogen receptor moderator, prevents estrogen from binding to its receptors and stimulating cancer growth.
In this situation, studies have shown when it is compared to treatment with either paclitaxel or pegylated liposomal doxorubicin, tamoxifen overall produced fewer severe side effects, but overall survival was similar.
Faslodex (Fulvestrant) is another hormone blocker that is an option for asymptomatic recurrent cancer, but studies have demonstrated that the median time to progression of disease was 60 days.
Tamoxifen:
Side effects:
The most common side effects include:
64% experience flushing
32% experience fluid retention,
30% experience vaginal discharge
30% experience Irregular cycles
26% nausea
19% experience skin changes,
Serious side effects that occur less commonly are blood clots, cataracts and in premenopausal women diminished bone density.
Tamoxifen has a serious risk of uterine cancer
Integrated support while on tamoxifen
EGCG enhances the effectiveness of tamoxifen.
It is also necessary to avoid Curcumin and DIM(Diindolylmethane) as they can reduce the effectiveness of tamoxifen.
Menopausal symptoms can be extremely bothersome and can be successfully addressed by practitioners of Chinese medicine.
Summary Points
Ovarian/ Fallopian Tube Cancers are described together as Epithelial ovarian cancer
Greater than 90% of ovarian cancer develops from the surface epithelial cells on the surface of the tissue.
It is the second most common gynecologic cancer, but often diagnosed in advanced stages due to subtle symptoms that are associated with many other abdominal or gynecologic conditions.
Survival diminishes with age at diagnosis for caucasian women, but for women of African American descent, survival is less than caucasian women at all ages.
Risks include several hereditary genetic mutations, many of which have markers that can be used to assess the potential risk of disease in other family members.There are also tumors that are measured from the tumor tissue that can impact treatments that improve survival.
Other risks involve lifestyle choices including, obesity,diabetes, lack of physical activity and hormone replacement with estrogen only.
Diagnosis can be difficult as laboratory markers for disease are often normal.
Ultrasound imaging usually reveals similar changes in both benign and malignant disease, often requiring CT or PET scanning, and even a surgical biopsy is often needed to confirm the diagnosis.
Staging is based on the extent of local, adjacent or distant spread.When confined to the fallopian tubes and/or ovary, surgical removal is performed to remove both.
If the peritoneum and lymph nodes are involved,considered stage 3, surgical removal of these tissues in addition to the tubes and ovaries is performed, to remove as much of the cancer as possible followed by chemotherapy.
75% of women will be initially diagnosed at stage 3 or stage 4 or distant metastasis.
Treatment, except for very early stage disease, in which the cancer cells appear almost normal, consistently requires chemotherapy or targeted therapies
Treatment of Patients with BRCA Gene Related Ovarian Cancer
Epithelial ovarian cancer (EOC) is related to germline mutations in almost 20% of cases. These are primarily related to the BRCA 1 & 2 (Breast Cancer Susceptibility Genes) and commonly associated with aggressive serous disease.
Germline mutations can only be transmitted to the children of a parent who passes the mutation via the sperm or in the egg at the time of fertilization.
Laboratory testing should be performed in woman with epithelial ovarian cancer, before treatment is initiated, to search for BRCA mutations and other mutations that might influence treatment. Also, if a woman has a BRCA mutation, communicating that information to family members can alert them to the need for their own testing and surveillance.
More than just an academic exercise, having a BRCA gene provides the possibility of immunotherapies which are not indicated in non-genetic cancer causation. It also offers the option of having a salpingo oophorectomy as a preventive measure.
Surgery
Initial treatment consists of surgery to remove as much tumor as possible followed by systemic chemotherapy. In women with a large tumor volume or have health issues that exclude surgery then neoadjuvant chemotherapy, or chemotherapy before surgery, may reduce tumor size that allows these women can then have surgery and chemotherapy. If a woman is too fragile even for this option, then chemotherapy alone is given.
Otherwise, the optimal approach is to remove as much tumor as possible. And If the residual tumor is <1cm after surgery, then IV therapy alone can be chosen or IV therapy with intraperitoneal chemotherapy (IP) instilled in the abdomen. The option of intraperitoneal chemotherapy is not an option if post-surgery there is > 1cm of tumor residual as the intraperitoneal drugs will not penetrate the tumor adequately.
First Line Chemotherapy
As with all EOC, the initial treatment is a Platinum drug combined with a Taxane drug. If disease has advanced to causing fluid in the abdomen or lungs, then Avastin (Bevacizumab) is added to first line therapy. It is however continued after Platinum/Taxane therapy is completed as maintenance treatment.
Maintenance Therapy - In situations where a woman with a BRCA mutation is responsive to first line therapy, because these mutations are associated with a higher risk of recurrence, maintenance therapy can be used to extent progression free survival. Currently the drugs used are PARP inhibitors or an angiogenesis inhibitor.
PARP Inhibitor- Poly (ADP-Ribose) Polymerase Inhibitor
The DNA needed for replication requires two strands. These drugs block the repair of damage to one of those strands resulting in cell death.
The current choice for PARP Inhibitor are:
Lynparza (Olaparib) for a partial or complete response with or without Bevacizumab
This is used in in BRCA related advanced epithelial ovarian cancer who have had complete or partial response to first line platinum-based therapy.
Side Effects listed are common, but others not listed are possible
Side Effects of Olaparib include:
60%, nausea
55%, fatigue
36%, anemia
20-30%, digestive issues
Zejula (Niraparib)
Higher percentage side effects include:
82% low red cell count
66%Low White
74%nausea
40% constipation
27% Insomnia
Recurrent BRCA ovarian cancers are divided into two categories:
Platinum sensitive woman who has been off platinum drugs for six months or longer while
Platinum resistant means a woman has been off for an interval of less than six months.
Platinum Sensitive Relapse in BRCA Carriers
In first line treatment, as discussed, women can be treated with continued maintenance using Avastin following this therapy plan. The decision for the next step in recurrence is:
Retreat with a platinum-based regime as there is a likelihood of benefit
or
Change to PARP Inhibitor, especially if significant side effects from the Platinum treatment occurred.
Platinum Resistant Relapse in BRCA Carriers
Chemotherapy is the preferred treatment, and the same chemotherapies are used as in platinum resistance relapse who do not have a BRCA
Integrative Supportive Therapies
The suggestions made for integrative supportive care of ovarian cancer are not treatments for cancer but potentially for support of western oncologic therapies.The information is not based on random controlled studies and should be interpreted with caution. The information is from reviewed data or laboratory research and hopefully will one day have confirmation. Please consult a qualified licensed health practitioner for advice. For supportive care in Ovarian Cancer the following recommendations come from studies as to the scientific effects of these supplements, and more information is available from their specific monographs on the site.
EGCG, Epigallocatechin Gallate
It supports pathways that inhibit ovarian tumor growth and replication and the development of new blood supplies of ovarian cancer cells.
Suppresses pathways by inhibiting metastasis
Induces ovarian cancer cell death
This molecule is one of several catechin polyphenol molecules found in green tea. It offers over twenty promising approaches to controlling cancer with applicability to Ovarian cancer.
Please see references below.
Modified Citrus Pectin (Pectasol-C)
A form of powdered citrus peel has been studied related to the protein, galactic -3 (GAL-3) which stimulates cancer progression of epithelial ovarian cancer (EOC). Paclitaxel as a chemotherapy drug works to disrupt cancer cell proliferation or replication. It does not affect Gal-3. When combined with Pectasol -C there was an increase in the cytotoxic effects, or destruction, of EOC specific cell type suggesting a role for its inclusion in EOC therapy with Paclitaxel.
Vitamin D status is associated with ovarian cancer survival. Higher levels are significantly associated with prolonged survival
I3C, Indole -3 -Carbinol is a chemical substance, glucobrassicin, found in the cruciferous vegetables, broccoli, cauliflower, and kale.
A recent study involved a clinical trial with I-3-C and EGCG which demonstrated results suggesting that these supplements were used in maintenance therapy in advanced ovarian cancer, compared to standard care.
Overall survival improved almost one and a half times more
Median Progression free survival almost doubled
Ovarian cancer relapse with ascites decreased from 60% to 9%
Given pre-surgery, 805 of patients had complete cyto- reduction at surgery which is extremely impactful in progression if residual tumor is present
CA-125 was statistically significantly lower if started before surgery and after combined treatment compared to combined chemotherapy
No toxicity was demonstrated
Stress Hormone Elevation
Evidence suggests an association between elevated levels of the stress adrenal hormones, occurring at night, and ovarian cancer progression. High levels are also intimately connected to disruptive sleep patterns, fatigue, and low energy.
Please see the article on sleep and fatigue.
Selenomethionine is a specific form of selenium
Women with BRCA 1 mutations are at increased risk of ovarian and breast cancer. BRCA 1 mutations inhibit DNA repair and increase susceptibility to these cancers. Selenomethionine increases the induction of DNA repair of BRCA1 suggesting its potential benefit in this genetic mutation.
Honokiol: Magnolia bark, known as Hou Pu in Chinese medicine, has a history of 2000 years of use. It is a component of distinct recipes of Chinese herbal formulas commonly used for GI disorders and to calm the mood. One component of magnolia bark, a polyphenolic compound, honokiol, has been studied in the laboratory on living cells and in biochemical research, and a study this year, 2024, demonstrated it can inhibit progression, invasion and survival of ovarian cancer cells by inducing ferroptosis. Ferroptosis is a recently recognized form of cell death associated with iron metabolism and ROS, reactive oxygen species.
For an in depth discussion, please review the article on the website, and specific reference to ovarian cancer listed below.
Chinese Herb Research in Ovarian Cancer
The use of Chinese herbal therapies
In 2020, a Chinese Biomedical Research group studied many Chinese Herbs and their analysis associated 12 specific herbs with greater survival times as an independent factor in ovarian cancer. These are available to licensed practitioners of Chinese medicine for treatment.
(Ling Zhi) Reishi Mushrooms (Ganoderma) Are able to inhibit the growth of ovarian cancer cells by inhibiting VEGF, vascular endothelial growth factor that allows new blood growth for spread and to gain access to nutrients. Practitioner advice on dosing is essential.
It also inhibits cell growth in chemotherapy sensitive and resistant cells
Enhances the effect of cisplatin in epithelial ovarian cancer
Resources
Therapeutic Effects of Ten Commonly Used Chinese Herbs and Their Bioactive Compounds on Cancers Wei Liu, Binbin Yang, Lu Yang, Jasmine Kaur, Calvin Jessop, Rushdi Fadhil, David Good, Guoying Ni, Xiaosong Liu, Tamim Mosaiab, Zhengjun Yi, Ming Q. Wei First published: 15 September 2019 https://doi.org/10.1155/2019/6057837
Guizhi Fuling Wan (Cinnamon and Hoelen), a Traditional Chinese Herbal Formula, Sensitizes Cisplatin-Resistant Human Ovarian Cancer Cells through Inactivation of the PI3K/AKT/mTOR Pathway Li Han, Xiaojuan Guo, Hua Bian, Lei Yang, Zhong Chen, Wenhua Zang, Jingke Yang 18 May 2016 https://doi.org/10.1155/2016/4651949
Efficacy and Safety of Chinese Herbal Medicine on Ovarian Cancer After Reduction Surgery and Adjuvant Chemotherapy: A Systematic Review and Meta-Analysis. Wang R, Sun Q, Wang F, Liu Y, Li X, Chen T, Wu X, Tang H, Zhou M, Zhang S, Xiao Y, Huang W, Wang CC, Li L Front Oncol. 2019 Aug 16;9:730. doi: 10.3389/fonc.2019.00730. PMID: 31475101; PMCID: PMC6706872.
Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate Anna L. Greenshields, Trevor G. Shepherd, David W. Hoskin First published: 15 February 2016 https://doi.org/10.1002/mc.22474
Honokiol induces ferroptosis in ovarian cancer cells through the regulation of YAP by OTUB2 Fang Liu, Yufang Zhang, Xinyi Xia, Jing Han, Linyan Cao First published: 13 March 2024 https://doi.org/10.1111/jog.15922
Dziaman T, Huzarski T, Gackowski D, Rozalski R, Siomek A, Szpila A, Guz J, Lubinski J, Wasowicz W, Roszkowski K, Olinski R. Selenium supplementation reduced oxidative DNA damage in adnexectomized BRCA1 mutations carriers.
Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):2923-8. doi: 10.1158/1055-9965.EPI-09-0529. Epub 2009 Oct 20. PMID: 19843683.
Hossein G, Halvaei S, Heidarian Y, Dehghani-Ghobadi Z, Hassani M, Hosseini H, Naderi N, Sheikh Hassani S. Pectasol-C Modified Citrus Pectin targets Galectin-3-induced STAT3 activation and synergize paclitaxel cytotoxic effect on ovarian cancer spheroids. Cancer Med. 2019 Aug;8(9):4315-4329. doi: 10.1002/cam4.2334. Epub 2019 Jun 13. PMID: 31197964; PMCID: PMC6675724.
Medical References
A new promising way of maintenance therapy in advanced ovarian cancer: a comparative clinical study Vsevolod I Kiselev 1, Levon A Ashrafyan 2, Ekaterina L Muyzhnek 3, Evgeniya V Gerfanova 2, Irina B Antonova 2, Olga I Aleshikova 2, Fazlul H Sarkar 4 PMID: https://pubmed.ncbi.nlm.nih.gov/?term=Antonova+IB&cauthor_id=3023607930236079 PMCID: PMC6148762 DOI: 10.1186/s12885-018-4792-9
Sun J, Liu J, Liu D, Wu X. Network Pharmacology-Based and Clinically Relevant Prediction of the Potential Targets of Chinese Herbs in Ovarian Cancer Patients. Biomed Res Int. 2020 Oct 8;2020:8965459. doi: 10.1155/2020/8965459. PMID: 33150184; PMCID: PMC7603558.
Desai A, Xu J, Aysola K, Qin Y, Okoli C, Hariprasad R, Chinemerem U, Gates C, Reddy A, Danner O, Franklin G, Ngozi A, Cantuaria G, Singh K, Grizzle W, Landen C, Partridge EE, Rice VM, Reddy ES, Rao VN.
Epithelial ovarian cancer: An overview. World J Transl Med. 2014 Apr 12;3(1):1-8. doi: 10.5528/wjtm.v3.i1.1. PMID: 25525571; PMCID: PMC4267287. January 16, 2023 Oncology Live®Vol. 24/No. 1 Volume 24 Issue 1
Targeting FRα Enters a New Era in Ovarian Cancer and Beyond Author(s): Anita T. Shaffer
Matei D, Fang F, Shen C, Schilder J, Arnold A, Zeng Y, Berry WA, Huang T, Nephew KP. Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 2012 May 1;72(9):2197-205. doi: 10.1158/0008-5472.CAN-11-3909. PMID: 22549947; PMCID: PMC3700422.