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Women have a 1.4% lifetime risk of developing ovarian cancer.
Second most common GYN cancer in the US, behind uterine cancer.
OC is a devastating disease with the highest mortality rate of all GYN tumors.
It is the fifth-sixth most common cause of cancer mortality in females.
It is the number one gynecological cancer in terms of mortality.
Estimated 19,880 cases diagnosed and approximately 12810 deaths in the US in 2022.
More than 310,000 patients receive a diagnosis of ovarian cancer annually worldwide and 207,000 will die.
Incidence increasing in southeast Asia, most notably, Japan in Korea and in sub-Saharan Africa.
In the US 28% of new ovarian cancer diagnoses occurred in women from non-white racial groups, of whom 18% were Asian patients, 35% Black patients and 41% Hispanics and 3% native American patients.
The mortality to incidence ratio in ovarian cancer is greater than 0.6.
Black women in the US are more likely to have delayed diagnosis and fragmented care for ovarian cancer.
Nearly 239,000 new cases of ovarian cancer and 152,000 associated deaths are reported worldwide annually.
The highest incidence rates are in north America and central and eastern Europe.
White women experienced the highest incidence at 11.3 cases per 100,000, followed by Hispanic, 10.3 cases per hundred thousand, and black women at nine per hundred thousand.
Five year survival just about 49%.
Approximately half of patients present with distant disease: uncommon types such as clear-cell and endometroid cancer more likely to be diagnosed at earlier stages.
Approximately 1/3 of recurrences occur within six months of the last platinum and are defined is platinum resistant, while the majority occur later and are potentially platinum sensitive.
Primary resistance to platinum in ovarian cancer occurs in approximately 20% of patients and secondary resistance, eventually develops, and nearly all patients with a recurrence of ovarian cancer.
More than half of women affected are older than 65 years.
Older age is associated with increased risk for disease progression and death.
With each five year increment of age after 65 years, survival diminishes; only 33% of those age 80-84 year survive one year after diagnosis.
Greater than 71% of all the diagnoses are in women age 65 and older.
For a patient with localized ovarian cancer, the five-year survival rate is 92.6%, for regional staging at initial diagnosis the survival rate is 74.8% in five years.
Poor-long-term survivorship is a function of widespread disease a presentation and eventual development of resistance to chemotherapy agents, whoch leads to recurrence in 70-90% of patients.
For patients diagnosed with metastases the survival rate is 30.2% in five years.
Ovarian cancer risk factors: age, nulliparity, early menarche, or late menopause, muliparoty, family history of breast or ovarian cancer and BRCA1 and BRCA2 sequence variations.
Or first pregnancy after age 35 years, post menopausal hormones therapy, and pelvic inflammatory disease.
About 15% of ovarian cancer patients develop early onset ovarian cancer with family history of ovarian cancer and BRCA 1/2 mutations, and with Lynch syndrome.
Additional risk factors include inherited risk and germline mutations, BRCA genes, nulliparity, infertility, endometriosis obesity and peroneal talc application.
The regular use of aspirin or nonsteroidal anti-inflammatory agents reduces the risk.
About 70% of ovarian cancer patients present with advanced disease, typically stage III.
No regular screenings are available.
Symptoms of advanced disease include swelling, pain, pelvic pressure, abdominal pressure, heavy/irregular vaginal bleeding, particularly after menopause, clear white or blood tinged vaginal discharge, gastrointestinal issues, urinary symptoms, and eating difficulties are feeling full too quickly.
More than 30 types of ovarian cancer exist.
Three major cell types: epithelial, germ cell, and stromal cell.
About 90% of ovarian cancers are epithelial.
About 70% of ovarian tumors have serous histology.
Grade 1 engrade serous tumors are considered relatively resistant to chemotherapy treatment.
The median survival has improved from 2 to 5 years with contemporary therapy.
As many as 50% of patients can live for 10 years.
Incidence and mortality have declined significantly over the past few decades.
The drop in mortality is largely due to the decline in incidence: decreased use of hormone replacement therapy and increased use of birth control helps explain reduced incidence which has dropped continuously since at least 1975.
Less than 40% of patients are cured, because more than 70% of patients are diagnosed with advanced-stage III or IV disease.
The term ovarian cancer generally refers to epithelial ovarian cancer and includes fallopian tube cancer and primary peritoneal cancer as well as ovarian cancer.
Epithelial cells comprise most ovarian cancers but germ cell, mixed Müllerian and ovarian stromal tumors may also occur.
Epithelial ovarian cancer comprises serous-high and low grade, endometrioid-high and low grade, clear-cell, and mucinous histologic subtypes.
High-grade serous carcinoma is the most commonly diagnosed subtype of ovarian cancer and frequently exhibits TP53 genes, copy number, and DNA repair gene alterations.
High-grade serous ovarian cancer accounts for 65% of the cases.
Most serous ovarian cancers originate in the fimbria of the fallopian tube.
Opportunistic salpingectomy is now recommended at the completion of childbearing for patients undergoing GYN or other surgery to prevent ovarian cancer.
Approximately 50% of high-grade serous carcinoma have homologous repair deficiency, which increases sensitivity to platinum and polyADP-ribose polymerase (PARP) inhibitors.
Low-grade endometrioid and low-grade serous carcinomas typically or indolent and respond to hormone therapies.
Low grade serous carcinoma represents less than 5% of epithelial ovarian cancers and is characterized by mild to moderate nuclear atypia, amd it up to 12 mitoses per high-powered fields, whereas high-grade serous carcinoma is characterized by marked nuclear atypia and greater than 12 mitosis per high-powered field.
MAPK mutations are frequently identified in low-grade serous carcinomas but not high-grade serous carcinomas.
TP 53 mutations are generally associated with high-grade serous carcinomas but not low-grade serous carcinomas.
High-grade serous ovarian, cancer, is the most common histologic subtype, has a low mutational burden and nearly a universal mutation of TP 53, but few common gene mutations.
High grade serious, ovarian cancers have underlying defects in homologous recombination, commonly, and have led to successful implementation of PARP inhibitors.
Low-grade serous carcinomas is associated with more indolent disease and presents at a younger age than high-grade serous carcinomas.
Low-grade serous carcinomas often respond poorly to chemotherapy compared with high-grade serous carcinoma.
Patients with low grade serous carcinomas may benefit from maintenance hormone therapy following adjuvant chemotherapy in patients with stage II to IV disease.
Mucinous cancers frequently have KRAS mutations and are less sensitive to chemotherapy, while clear-cell cancers are associated with endometriosis and are less sensitive to platinum and chemotherapy and have phosphoinositode 3-kinase pathway aberrations.
There is an association of endometriosis and epithelial ovarian cancer, particularly clear cell and endometrial cancer.
Mucinous ovarian cancer accounts for 3% of all epithelial ovarian cancers.
65-80% of mucinous cancers are diagnosed and early stage-FIGO stage I.
Now believed up to 50% of such cancers arise from a genetic predisposition.
Arises from the malignant transformation of the epithelium of the ovarian surface, which is contiguous with the peritoneum and accounts for more than 85% of all ovarian neoplasms.
Metastatic ovarian tumors most commonly originate from gastric (Krukenberg tumors), colon, appendix, uterus, and breast cancers or rarely involvement by acute leukemia or lymphoma.
Risk increases from 15.7 to 54 per 100,00 as one ages from 40 to 79 years.
Rates in women less than 40 years is less than 15 per 100,00 and more than 50 per 100,000 in women older than 70 years.
2/3 of cases diagnosed in women over the age of 55 years.
About 2/3 of women are diagnosied at an advanced stage of disease.
Less than 30% of women with metastatic disease survive past 5 years.
From age 45, the incidence ovarian cancer rises rapidly until the 8th decade of life.
Incidence peaks at 54 per 100,000 in women age 75-79 compared to 3.0 per 100,000 in women under 30 years of age.
Close to half of all women with ovarian cancer are all within 65 years, but these women account for more than two thirds of cancer related death.
In 3/4 of cases it is diagnosed in stage III or IV.
Because the disease is diagnosed in advanced stages, the chance of recurrence after treatment approaches 75%.
Despite optimal treatment, including complete removal of all visible tumor deposits, advanced disease recurrence occurs in more than 80% of patients, and the peritoneal surface is the most common site of recurrence.
The average time to recurrence after primary surgery and platinum-based chemotherapy is 1-2 years.
Older women are more likely to have advanced stage disease at the time of diagnosis, and account for at least 45% of all stage III and IV disease.
Lifetime risk of dying from invasive ovarian cancer is about 1 in 95 in the general population and increases up to 60% and 30% for BRCA1 or BRCA2 carriers, respectively.
BRCA mutations confer a lifetime risk of 40 to 60% with BRCA 1 and 11 to 275 FOR BRCA2 of developing ovarian cancer.
Germline BRCA mutations can be detected in approximately 14 to 18% of women with ovarian cancer particularly the high-grade serious ovarian cancer subtypes compared with approximately 1% in the general population.
Approximately 20 to 25% of patients with ovarian cancer have a germ line genetic mutation. 80% of these germline genetic mutations are because of BRCA mutations: five times more common in Ashkenazi Jewish populations.
Ovarian cancer with germline or somatic BRCA1 or BRCA2 mutations have better responses to platinum based treatment and longer survival than non carriers.
BRCA2 mutation ovarian cancer has better survival and chemotherapy response than BRCA1 mutation cancer patients.
BRCA1 and BRCA2 mutations including both germline and somatic mutations found in 20-30% of patients with ovarian cancer.
Serous ovarian cancers are the most common histologic subtypes for both BRCA Mutation carriers.
BRIPI, RAD51C and RAD51D are ovarian cancer susceptibility genes.
Eighth most common cancer in women.
Fifth most common cause of cancer related deaths in the U.S. among women after lung, breast, colon and pancreatic cancers.
Accounts for more than 20% of all GYN malignancies and is associated worse outcome.
Women older than 60 years of age have a worse prognosis.
Women diagnosed with localized ovarian cancer have an estimated survival of 92%.
The majority of ovarian cancer cases are diagnosed with regional or distant disease with survival rates 72% and 27%, respectively.
Globally, in 2008, the seventh most common cause of cancer death in women with 225,500 and cases in 140,200 deaths, estimated (Jemal A et al).
Strongest risk factor is a familial history.
Family history of ovarian cancer or breast cancer in a first degree relative approximately triples the risk.
Women who have a first degree relative with ovarian cancer have a 2-to 6 fold higher risk of developing ovarian cancer.
Women with 1 affected relative have a 5% estimated lifetime risk of developing ovarian cancer, while women with 2 affected relatives have an estimated risk of 7%.
Mutations in hereditary susceptibility genes accounts for 11-15% of cases of epithelial cancer, and up to 20% of all ovarian cancer and Lynch syndrome comprising the majority of these cancers.
Lifetime risk of ovarian cancer in patients with the Lynch syndrome is 8% compared with 1.4% in the general population.
It is estimated that at least 5-10% of all epithelial ovarian cancers result from hereditary predisposition.
Factors associated include increased ovulation, including early menarche, late menopause, and nulliparity.
One year of ovulatory cycles increases risk of ovarian cancer by 6%.
Menopause after age 52 associated with a 46% increase in the risk of ovarian cancer vs age 45 or less at the time of menopause.
Nulliparity associated with a 60% increased risk of OC.
Angiogenesis results in increased vascular density and is associated with advanced stage of disease and poor prognosis.
About one third of women with ovarian cancer have an abnormally high platelet count at the time of diagnosis.
Studies have reported that the risk reducing salpingo-oophorectomy in BRCA carriers ranges from 12-78% and the median time is six months from learning their BRCA positive results to the surgery.
Median age at diagnosis 63 years.
Greater than 71% of all the diagnoses are in women age 65 and older.
For a patient with localized ovarian cancer, the five-year survival rate is 92.6%, for regional staging at initial diagnosis the survival rate is 74.8% in five years.
Notch signaling pathway mutations may be associated with a poor prognosis, disease recurrence and platinum resistance.
Notch ligand Jagged-1 is upregulated in ovarian cancers and Jagged-2 is an ovarian associated cancer antigen.
Average age of onset for ovarian cancers of familial origin is up to 10 years lower than that of ovarian cancer in the general population.
Consists of 5 major histologic subgroups:clear cell, endometroid, mucinous, high-grade serous and low-grade serous.
Seventy percent of epithelial ovarian cancers are high grade serous carcinomas, and almost all of such lesions have TP53 mutations.
Approximately half of high grade serous carcinomas have BRCA dysfunction with germline and somatic mutations or epigenetic silencing.
Combination of TP53 mutations and BRCA abnornmalities lead to impaired DNA repair accounting for high responsiveness of high grade serous carcinoma to chemotherapy..
Ovarian cancers occurring in BRCA mutation carriers have a better prognosis compared to cancers occurring in the general population.
FOXM1 Transcription factor network, a group of proteins controlling expression of genes involved with cell proliferation is altered in 87% of ovarian tumors.
Women with germline mutations in BRCA1, BRCA2, or both have an increased risk of ovarian cancer, particularly the most common type, invasive high-grade serous carcinoma.
BRCAness gene expression profile correlates with responsiveness to platinum based chemotherapy and poly-adenosine diphosphate polymerase (PARP) inhibitors.
About 15% of epithelial ovarian cancer patients are deficient in homologous recombination repair, owning to mutations in the BRCA1/2 gene.
The distal fallopian tube may be the site of origin of high grade serous ovarian cancer.
In patients with a BRCA gene undergoing risk reducing removal of ovaries and fallopian tubes often have pre-invasive lesions of the fallopian tubes, called serous tubal intraepithelial cancer (STIC).
Serous tubal intraepithelial cancer (STIC) lesions are often found in the fimbriae.
Up to 50% of patients with high grade serous ovarian cancer tumors, the tumor cells maybe deficient in homologous recombination as a result of germline or somatically acquired BRCA1/2 mutations, epigenetic inactivation of BRCA1, or defects in the homologous recombination pathway independent of BRCA1/2.
High-grade ovarian cancer characterized by TP 53 mutations, where is low-grade cancers typically have KRAS or BRAF mutations.
Patients with thrombocytosis have a worse outcome, with significantly faster disease progression and shorter overall survival.
Patients with thrombocytosis have more advanced ovarian cancer, a higher rate of thromboembolic complications, and a higher level of Ca125 than patients with normal platelet counts.
Patients with advanced ovarian cancer have a median overall survival of 50.3 months with intratumoral T cells versus 18 months for individuals without intratumoral T cells (Zhang L et al).
Silencing or dysfunction of BRCA1/2 related pathways gives rise to BRCA like phenotype similar to that resulting from the inherent mutations in BRCA1/2.
Transition time from stage I to stage III is not known, since it is not clear whether there is an evolution from early stage to advanced stage disease that may arise as a diffuse process in the peritoneal cavity.
Stage I treatment effective with a 5 year survival greater than 90%.
A Swedish study of 160 women with early stage disease had a shorter mean time from presentation to diagnosis with those of more advanced disease (Wikborn C et al).
A study of 1725 ovarian cancer patients found that women with advanced stage disease were more likely to ignore their symptoms, despite there being no difference between duration of symptoms or the time to diagnosis among women with FIGO stages I to II and those with FIGO stages III to IV disease (Goff BA et al).
UK study- no association between duration of symptoms, delays in refferal or diagnosis, and stage of disease at diagnosis or overall survival (Kirwan JM et al).
Patients generally have nonspecific abdominal or pelvic symptoms, but a recent study reported 94% of patients had symptoms in the year prior to diagnosis, including recurring symptoms in two thirds, while on another study all women experienced symptoms prior to diagnosis such as increased abdominal size and bloating, urinary urgency, abdominal or pelvic pain (Goff BA et al, Bankhead CR et al).
In a study of 1318 women presenting with symptoms with ovarian cancer 55% presented within 1 month, 70% in less than 2 months, and 92% within 6 months of sympton onset: no association between time to diagnosis and survival (Nagle CM et al).
30-60% decreased risk factor associated with younger age (25 years or younger) at the time of pregnancy and first birth.
Use of oral contraceptives and breast feeding reduces the risk.
Accounts for less than one third of all gynecological cancers but result in over 50% of the deaths from gynecologic cancers.
Kills more women each year than all other gynecologic cancers combined.
Women who have used older estrogen replacement therapy regimens for 10 or more years have a significantly higher risk of dying from ovarian caner than those who never used estrogen replacement therapy.
Risk factors include age, nulliparity, exposure to talc, high fat intake, and therapy with ovulation inducing drugs, family history of ovarian and breast cancer.
Study Finds No Association Between Powder Use and Ovarian Cancer
An analysis of 4 US cohorts showed no statistically significant association between use of powder in the genital area and incidence of ovarian cancer, according to a study published in JAMA.
The study analyzed data from a total of 252,745 women with a median age at baseline of 57 years.
Ovarian cancer incidence for talc users was 61 cases of 100,000 person-years, with an incidence of 55 cases of 100,000 among the never users.
There were no dose-response trends for duration and frequency of powder use in the genital area in relation to ovarian cancer risk.
Data was pooled from the Nurses’ Health Study, Nurses’ Health Study II, Sister Study and the Women’s Health Initiative Observational Study.
Pooled data from women 4 cohort studies indicated there is not a statistically significant association between the use of powder in the genital area and incidental ovarian cancer (O’Brien KM).
Hereditary predisposition to ovarian cancer is found in only about 10% of all women with the disease and 90% of cases appear to be sporadic.
Approximately 2 of every 3 women with ovarian cancer have advanced disease at the time of diagnosis.
Approximately 75% of patients have disseminated peritoneal disease at time of diagnosis.
An index of symptoms correlated with diagnosis of ovarian cancer in women 50 years of age or older reported having pelvic or abdominal pain, urinary frequency or urgency. increased abdominal size or bloating, difficulty eating or early satiety more than 12 times in a month within the previous year: with a sensitivity of 67% and specificity of 90% (Goff BA).
In the symptoms index sensitivity is lower for early stage disease at 57% and specificity is lower for younger women at 87% (Goff BA).
Only 35% of patients who present with late stage disease survive 5 years.
The most lethal gynecological, with a 5 year life expectancy of 45%.
Early stage disease is highly treatable with a 5 year survival rate over 95.3%.
Physical examination may reveal pleural effusions, which is the most common site of extra-abdominal disease, ascites, palpable umbilical mass (Sister Mary Joseph’s nodule), palpable abdominal mass, involvement of lymph nodes in the umbilical area, palpable adnexal mass or cul-de-sac nodularity.
Paraneoplastic phenomenon are rare, but may include hypercalcemia, subacute cerebellar degeneration anti-Purkinje cell antibodies, seborrheic keratoses (Leser-Trelat sign).
Transvaginal ultrasound may be useful in evaluation of patients with suspicious adnexal masses, CT scans of the abdomen and pelvis may permit findings of retroperitoneal or pelvic adenopathy, ascites, peritoneal carcinomatosis, omental involvement, and liver metastases.
CA 125, a 220-1000 kD antigen is normally expressed by cells lining fallopian tubes, endometrium, endocervix, peritoneum, pleura, pericardium, and bronchial tubes, but not by normal ovarian epithelium, is elevated in 80% of epithelial ovarian cancers and is a useful marker in disease activity or response to therapy.
Approximately 50% of women with stage I ovarian cancer have a normal CA125 test.
Up to 20% of women with metastatic ovarian or tubal cancers have a normal CA 125 level. CA 125 testing is unreliable in women with early stage disease, in pre-menopausal women, and those with epithelial subtypes of cancer other than high-grade serous adenocarcinoma.
Adjuvant melphalan chemotherapy for stage IA or IB not associated with improved 5-year disease free or overall survival (Young R).
Studies by Gruppo Interregionale Collaborativo in Ginecologia Oncologica (GICOG) with adjuvant cisplatin for stage I disease vs. surgery alone, resulted in a 5 year disease free survival of 83% for the cisplatin group and 65% for the control arm, while the overall survival was not significant at 88% vs. 82% for the control group (Bolis).
In a trial of cisplatin or P32 in stage I patients the 5 year disease free survivals were 65% in the 32P arm and 85% for the cisplatin arm with an overall survival of 79% in the P32 arm and 81% in the cisplatin arm (Bolis).
A Norwegian trial of adjuvant therapy for early stage disease with patients randomized to cisplatin vs. P32 or whole abdominal radiation: 5 year overall survival in 347 patients was 83% for P32, 81% for cisplatin, with the latter preferred with less abdominal problems (Vergote).
In an adjuvant study of stage IC and II disease and poorly differentiated stage IA and IB randomizing P32 intraperitoneal compared to cyclophosphamide (C )1 gm/m2 every 21 days for 3 cycles and cisplatin (P) 100 mg/m2 every 21 days for three cycles: the 5 year disease free survival was 66% for P32, 77% for CP with a 31% reduction in time to progression (GOG95 trial).
The value of additional treatment for patients who have no evidence of clinical disease after standard therapy with surgery and chemotherapy is such that Phase 3 studies of conventional maintenance chemotherapy, high-dose chemotherapy with stem cell rescue, IV topotecan, IV epirubicin, IV monoclonal antibodies directed at CA125, sub-cu interferon alpha, intraperitoneal Yttrium-90 labeled monoclonal antibody, intraperitoneal phosphorus 32 chromic phosphate, and whole abdomen XRT have no beneficial clinical effect by these additional treatments; i.e., they have failed to alter the progression of survival of such patients. (Pecorelli)
Early trials suggested intraperitoneal chemotherapy versus IV chemotherapy had a longer survival benefit.
GOG 252 trial failed show any advantage for intraperitoneal therapy compared with completely intravenous regimen of carboplatin Plus paclitaxel.
GOG 172 demonstrated intraperitoneal chemotherapy had a 17 months improved overall survival compared to IV chemotherapy after optimal surgical cytoreduction.
In women with recurrent ovarian cancer, cytoreduction surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone (Harter P).
Guidelines recommended IV/IP chemotherapy for those which stage III optimally debunked disease with a survival increase of 16 months using IP therapy with cis-platinum/paclitaxel compared with standard IV therapies.
The disease remains largely restricted to the abdominal cavity.
No accurate screening test are currently available and pelvic examination can only occasionally detect ovarian cancer when it is already advanced (2008).
Initial debulking followed by chemotherapy is the current treatment for Stage IIIC/IV ovarian carcinoma.
R0 resection is optimal-removing all visible tumor.
Median survival in optimally debulked patients is about 49 months compared with 37 months in patients suboptimally debulked when they receive intravenous taxanes and platinum based chemotherapy.
Ovarian cancer remission has not been prolonged with maintenance chemotherapy.
Disease control for metastatic disease has been prolonged with a combination of bevacizumab and chemotherapy in patients receiving first-line treatment and those with platinum sensitive relapsed ovarian cancer
Surgery in centers experienced in comprehensive debulking including retroperitoneal lymphadenectomy and peritoneal stripping associated with higher rates of complete debulking than other centers: this type of surgery associated with improved overall survival (Wimberger).
Pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer who have undergone intra-abdominal macroscopically complete resection and had normal lymph nodes both before and during surgery is not associated with longer overall or progression free survival than no lymphadenectomy and is associated with a higher incidence of postoperative complications (Harper P).
About 23% of the stage III patients, and 8% the stage IV patients after initial surgical cytoreduction have no gross disease left (Winter WE).
Neoadjuvant chemotherapy is retrospective reviews suggest that it may have a major effect by significantly increasing the rate of surgical cytoreduction to no visible disease.
Neoadjuvant chemotherapy shows no significant difference in progression free survival for patients treated with chemotherapy before surgery.
Neoadjuvant chemo therapy recommendations include IV taxane/carboplatin and liposomal doxorubicin/carboplatinum followed by the bulking surgery.
Optimal cytoreduction is traditionally defined as removal of all the tumor in the abdomen so that no more than 1 cm of tumor remains.
Now optimal cytoreduction requires that no gross residual tumor be present.
In a trial of patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy does not result in longer overall survival than chemotherapy alone (Coleman RL).
The DESKTOP III trial demonstrated an improved progression free interval with secondary cytoreduction , whereas GOG-0213 found no difference in progression or overall survival.
DESKTOP III found that secondary surgery improved not only the progressive free survival but also overall survival.
In a meta-analysis of studies involving 2805 patients who underwent secondary cytoreduction for platinum sensitive recurrent ovarian cancer there was a significant increase overall survival when maximum tumor resection was achieved (Black MH).
In a trial of patients with stage IIIc or IV ovarian cancer randomly assigned to primary debulking surgery followed by platinum based chemotherapy or to neoadjuvant platinum based chemotherapy followed by interval debulking surgery: After debulking surgery the largest residual tumor was 1 cm or smaller in diameter and 41.6% of patients in the primary debulking surgery group, and 80.6% of those in the neoadjuvant group with progression free and overall survival the same between the 2 arms (Vergote I et al).
Presently, it is the standard of care for patients with bulky stage IIIC or IV ovarian cancer received neoadjuvant chemotherapy followed by debulking surgery.
Diagnostic imaging, nor CA 125 levels consistently reflect the likelihood of optimum ability to debulk patients: presently, there is no absolute way to identify patients with advanced ovarian cancer who will or will not be able to be optimally cytoreduced at the time of initial surgery.
More than 50% of patients with complete pathologic response after cytoreductive surgery and standard platinum and taxane chemotherapy relapse.
Optimal tumor debulking refers to residual tumor of ≤1cm in diameter tumor and suboptimal debulking refers to residual tumor of >1.0 cm in diameter tumor.
The chance of response to a platinum based regimen is directly related the length of time between the last course of platinum chemotherapy and documented recurrence of disease, such that approximately 20-25% of patients with treatment free interval of 6-12 months achieve an objective response to reinstitution of platinum based chemotherapy, whereas the response rate is greater than 50% for women with a treatment free interval of greater then 24 months.
In a study of patients with relapsed disease based on increasing CA125 levels randomly asigned immediate treatment or treatment when symptomatic (1442 patients): resulted in no change in survival or duration of remission, and the quality of life for the immediate treatment group was worse-conclusion-second line treatment should be started when the patients become symptomatic (Rustin GJ).
In the above study the median time to treatment for symptomatic patients was 5 months later than the immediate treatment group.
When diameter of residual tumor is no more than 1 cm survival tends to be longer with those treated with a platinum analogue and paclitaxel having a median progression free survival of approximately 22 months and an overall survival of approximately 52 months compared to 14 and 26 months, respectively, among individuals with larger residual tumor.
Cytoreductive surgery in patients with advanced disease who had no residual disease associated with a 39 month average survival, with those having less than 5 mm maximum diameter residual disease have a 29 month average survival and patients with 6- 15 mm residual disease have an 18 month mean survival and individuals with more than a 1.5 cm residual disease have an 11 month mean survival (Griffiths).
If a patient undergoes cytoreductive treatment for ovarian cancer and the advanced tumor is reduced to less than 1.5 cm maximum diameter of residual disease, those patients will have the same survival as individuals who presented with less than 1.5 cm of disease at the time of the initial surgery-a 5 year survival of approximately 20% (Griffiths).
Gynecologic Oncology Group trial 52-compared optimally cytoreduced (equal or less than 1 cm) stage III ovarian cancers, all treated postoperatively with platinum based chemotherapy-patients with stage IIIA or IIIB did well, but 90% of cytoreduced stage IIIC patients died within 5 years of initial diagnosis (Hoskins).
Gynecologic Oncology Group trial 52-survival worse for those with gross omental disease, in addition to visible disease elsewhere in the abdomen, and with clear cell or mucinous histology, younger women more likely to have stage IIIA or stage IIIB with lower grade tumors (Hoskins).
Gynecologic Oncology Group trial 52: conclusion failed to confirm other studies that optimally surgically cytoreduced patents had the same survival as those with initially only miliary disease in the upper abdomen.
A randomized phase 3 trial to assess the efficacy of combination chemotherapy in chemosensitive recurrent or progressive disease with patients that are occurring more than 6 months after achieving with clinical CR, and after completing initial platinum-based therapy were randomized to receive platinum-based regimen with or without a taxane- 801 patients were randomized and patients were assigned to taxane/platinum regimen compared to carboplatinum alone: The combination treatment patients experience a response rate is 66% versus 54% in the single agent carboplatinum, and a superior progression free survival at one year 50% compared to 40% with the single agent.
Patients left with no residual diagnosis after surgery have approximately half the risk of death as those left with visible tumor, even with 1 cm or less in size.
No prospective randomized American trials have been performed confirming cytoreductive surgery as the most effective initial management of advanced disease.
In advanced ovarian cancer when paclitaxel replaced cyclophosphamide in combination with cisplatin the median progression free survival and overall survival increased by 35-40%.
No evidence that adding a third agent to platinum/taxane regimen in metastatic disease improves survival time.
First-line chemotherapy with platinum-paclitaxel q 3 weeks yields a response rate of greater than 80%, with a medium progression free survival of only 18 months.
Administration of adjuvant chemotherapy to women with high risk early stage II, or high grade
I disease increases the time until disease progression.
Administration of single dose paclitaxel on a monthly basis after a patients attains a complete remission can substantially increase time to recurrence.
Single agent treatment options for patients with recurrent disease include: paclitaxel overall response rate of 21-53%, gemcitabine overall response rate of 14-22%, pegylated doxirubicin overall response rate of 11-28%, topotecan overall response rate of 15-32%, vinorelbine overall response rate of 3-29%, oral etoposide overall response rate of18-27%, docetaxel overall response rate of 7-28%, pemetrexed v 21%, ifosfamide overall response rate of 10%, and bevacizumab 16-28%.
At least 3/4 of patients whose disease recurs have platinum sensitive relapse, that means they have recurrent disease at least six months after the patient’s final dose of platinum-based chemotherapy.
The treatment for patients with platinum sensitive relapse is another platinum doublet which generally is carboplatin plus gemcitabine, liposomal doxorubicin, or a second course of paclitaxel.
GOG 218 study suggested that he use of bevacizumab with chemotherapy for metastatic disease does not improve outcome, but using this drug with and after chemotherapy as maintenance results in improved progression free survival.
Results from a long-term clinical trial of patients with advanced ovarian cancer yielded no survival improvement in those treated with bevacizumab in addition to chemotherapy (Krishnansu S. Tewari).
GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma: included 1873 women with uncompletely resected stage III to IV disease, who were followed-up with for a median of 102.9 months.
The median OS was 42.8 months versus 32.6 months for IV bevacizumab-concurrent plus maintenance and for stage IV control, respectively.
Pazanib maintenance therapy has been shown to prolong progression free survival after initial chemotherapy for ovarian cancer.
No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone.
Bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs median progression free survival by about four months in advanced ovarian cancer (Burger RA et al): but no improvement in overall survival.
GOG 218 a randomized phase III study with three arms for women with advanced epithelial ovarian cancer stage III or IV, after maximal surgical debulking assigned to paclitaxel plus carboplatin followed by placebo, paclitaxel plus carboplatinum plus bevacizumab followed by placebo, or paclitaxel plus carboplatin plus bevacizumab followed by bevacizumab maintenance: progression free survival was 10.3 months in the PC arm, 11.2 months in the PCB arm, and 14.1 months in the PCB-B arm- at present there is no difference in overall survival among the treatment arms.
In the above GOG 218 trial 23% developed hypertension, 10% developed grades 3 to 4 hypertension and 2.3% had grade 3 or worse G.I. perforation, hemorrhage or fistula formation, indicating that toxicity of bevacizumab.
Results from a long-term clinical trial of patients with advanced ovarian cancer yielded no survival improvement in those treated with bevacizumab in addition to chemotherapy (Krishnansu S. Tewari).
GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma: included 1873 women with uncompletely resected stage III to IV disease, who were followed-up with for a median of 102.9 months.
The median OS was 42.8 months versus 32.6 months for IV bevacizumab-concurrent plus maintenance and for stage IV control, respectively.
No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone.
Bevacizumab single agent response 21%, with 40.3% of patients surviving progression free fot at least 6 months (Burger RA et al).
Bevacizumab plus chemotherapy increases response rate by about 20%.
Bevacizumab in platinum resistant ovarian cancer response rate 15.9% (Cannistra SA et al).
In a phase III trial (OCEANS) 484 patients randomly assigned to receive bevacizumab and carboplatinum and gemcitabine versus a placebo with the same chemotherapy: After a median followup of 24 months median progression free survival was 12.4 months for patients in the bevacizumab group when compared to 8.4 months for patients with chemotherapy alone, 79% of women in the bevacizumab group had significant tumor shrinkage, while 57% of women treated with chemotherapy alone did (Aghajanian C et al).
The response rate to platinum resistant recurrent ovarian cancer using single drugs is at 10-30%.
In the ICON7 study 1528 women with newly diagnosed high risk or advanced ovarian assigned to receive either chemotherapy alone or chemotherapy with bevacizumab, followed by maintenance bevacizumab for a total duration of 12 months: Bevacizumab group had a 15% overall reduction in risk of death, and specifically among women with stage III tumors larger than 1 cm after surgery and wall stage IV patients the risk of death was 36% lower.
Approximately 20% of ovarian cancers limited to ovary at presentation (stage I), while 15%, the tumor extends locally within the pelvis (stage II).
Niraparib can be used as a maintenance therapy in patients with platinum sensitive ovarian cancer, and a germline BRCA mutation improves progression free survival of 21 months versus five 5.5 months with placebo and 9.3 months in those without a germline BRCA mutation.
Niraparib Maintenance therapy prolonged progression free survival in patients with newly diagnosed advanced ovarian cancer, regardless of postoperative residual disease or biomarker status and is in effective safe first line maintenance therapy (Ning Li).
The combination of bevacizumab plus nirapib in women with relapsed platinum sensitive epithelial ovarian cancer had an objective response rate of 45%.
Rubaparib has an 80% response rate in patients with BRCA mutated ovarian cancer and is affective in a maintenance setting as other PARP inhibitors.
Olaparib PARP inhibitor improves progression free survival versus placebo in patients with germline BRCA mutation 19.1 months versus 5.5 months.
Patients with high grade ovarian cancer in a second remission following platinum based chemotherapy, after obtaining an objective response or achieving a status stable disease, utilizing this drug has statistically significant improved progression free survival of 8.4 months versus 4.8 months with placebo, and, in patients with BRCA it was a median of 11.2 months versus 4.3 months for placebo.
The use of maintenance therapy with olaparib provides is substantial benefit with regard to progression free survival among women with newly diagnosed ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo.
Today it is required the patients with newly diagnosed ovarian cancer have molecular testing for BRCA mutation upfront: so PARP inhibitors can be employed.
Oral contraceptive use reduces the risk for the development of ovarian cancer by 30-60%.
Of patients felt to have ovarian cancer confined to the ovaries 35% will have a higher stage after surgical exploration and staging.
Adequacy of staging by general surgeon 35%, by gynecologist 50% and by gynecologic oncologist 97%.
CA125, the best serum marker, is not elevated in roughly half of stage I ovarian cancers.
BRCA1 and BRCA2 strongest known genetic risk factors for ovarian cancer and are found in 6-15% of worn with ovarian cancer.
BRCAI gene 15-45% chance of developing ovarian cancer.
BRCA2 gene 10-27% chance of developing ovarian cancer.
Lifetime risk of ovarian cancer estimated to be 36-60% in BRCA1 mutations and 16-27% in BRCA2 mutations.
BRCA1 mutation carriers tend to develop ovarian cancer approximately 8 years earlier than BRCA2 mutation carriers.
Mutations in BRCA1 and BRCA2 compose 90% of hereditary ovarian cancers.
Genetic risk of ovarian cancer related to BRCA 1 and BRCA2 gene mutations, family history of ovarian/breast cancer in two or more women on the same side of the family, if familial breast cancer is diagnosed before the age of 40 years, if a family member has an ovarian and breast cancer, if a family member has bilateral breast cancer, if there is a male family member has breast cancer, or an Ashkenazi woman has one or more first-degree family members with ovarian cancer.
Carriers of BRCA2 mutation with ovarian cancer have improved overall survival and response rate to chemotherapy compared with BRCA wild-type mutation: Five-year overall survival with 60% for BRCA2 versus 25% for carriers of wild-type BRCA or BRCA1 mutations.
Patients with invasive ovarian carcinoma with BRCA1 or BRCA2 genes have improved 5 year survival, with BRCA2 patients having the best prognosis (Bolton KL et al).
Associated with BRCA1 mutation typically advanced, papillary, serous, poorly differentiated, affects younger women and with family history of breast and/or ovarian cancer.
Germline or somatic BRCA 1/2 mutations are identified in 6 to 15% of patients with ovarian cancer.
In an analysis of 3879 patients with all varying cancer with 2666 non- carriers, 909 BRCA1 mutation carriers, and 304 BRCA2 the patient areas the adjusted hazard ratios for overall mortality at 5 years of 0.73 and 0.49 for BRCA1 and BRCA2 mutation carriers, respectively compared with non-carriers(Bolton KL et al).
Serous ovarian cancer behavior driven by p53 mutation and then failure of DNA repair mechanisms.
Endometriosis associated with increased risk of ovarian cancer.
Median survival for advanced ovarian cancer is about 36 months.
Estimated 2-year survival and 5-year survival rates for patients with no intraperitoneal residual disease are 100% and 42% respectively. Estimated 2-year survival rate about 77% and 21% respectively for patients with abdominal residual disease < 1 cm.
For patients with advanced disease more favorable prognostic factors include the ability to undergo optimal debulking surgery, non-clear histology, low-grade disease, age younger than 65 years, over expression of proapoptotic proteins such associated BAX, presence of BRCA-1 mutation, and rapid drop in CA-125 from chemotherapy.
In a randomized controlled study of ovarian cancer patients with stage IIIC or IV, or with fallopian tube carcinoma, or primary peritoneal carcinoma treated with primary debulking surgery followed by platinum-based chemotherapy or to neoadjuvant platinum-based chemotherapy followed by debulking surgery: survival is similar in both groups (Vergote I, et al).
In advanced disease pleural effusion reported in 20-25% of patients and pulmonary parenchymal metastases are seen in 7-12%.
Most common site of metastases adjacent pelvic organs.
Routine screening with pelvic examination, abdominal or vaginal ultrasound or serum Ca-125 have not been helpful in reducing mortality.
Among women in the general population, simultaneous ovarian cancer screening with CA 125 and transvaginal ultrasound compared with usual care does not reduce ovarian mortality as indicated by a randomized controlled trial of 78,216 women age 55-74 years ( The Prostate, Lung, Colorectal and Ovarian Cancer Screening Randomized Controlled Trial)
5-year survival rates for women with stage III or IV disease range from less than 5% to 20%.
Hepatic metastases in about 9% of patients, subcutaneous nodules in 3.5% and CNS metastases in 2% of patients.
Majority of ovarian cancers that occur with high genetic risk are advanced stage at diagnosis, and they are commonly serous and poorly differentiated.
Approximately 70% of all ovarian cancer just occur in patients with advanced high grade serous adenocarcinoma type.
The overall survival for serous adenocarcinoma of the ovary is 31% and 96% of such patients have mutations in TP53 gene and 22% in the BRCA gene.
Intraperitoneal chemotherapy for patients with newly diagnosed stage III cancer that have been optimally debulked and treated with day 1 intravenous paclitaxel 135 mg/m2 plus day 2 intraperitoneal cisplatin 100 mg/m2 and day 8 intraperitoneal paclitaxel compared to intravenous paclitaxel 135 mg/m2 and cisplatin 75 mg/m2 resulted in improvement in progression free (median 24 vs. 18.3 months) and overall survival median 65.6 vs 49.7 months) in the intraperitoneal group(Armstrong study with 210 women in the intravenous chemotherapy only group and 205 women in the intravenous chemotherapy and intraperitoneal chemotherapy group.)
The addition of intraperitoneal chemotherapy resulted in the longest median survival time of 65.6 months among all randomized Phase III studies for advanced ovarian cancer among Gynecological Oncology Group studies.
Women who received intraperitoneal and intravenous chemotherapy had more deaths (5 vs. 4) and many more Grade 3 and 4 side effects, including neutropenia. infection, pain and fatigue than women treated with intravenous chemotherapy only.
The intraperitoneal catheter caused many problems for the intraperitoneal treated group with only 42% of women assigned to 6 planned intraperitoneal chemotherapy cycles completing such.
In patients with recurrent disease hyperthermic intraperitoneal chemotherapy after interval cytoreductive surgery may improve survival.
Over expression of VEGF associated with poor prognosis and malignant ascites also associated with high levels of VEGF in ascitic fluid.
Vascular endothelial growth factor (VEGF) is the dominant proangiogenic vascular growth factor in ovarian cancer.
VEGF levels are often increased in ovarian cancer. (Poon, RT)
VEGF and angiogenesis are important promoters of ovarian progression and both correlate with the extent of disease and inversely with progression free survival and overall survival.
Bevacizumab as a single agent in refractory disease associated with objective response rate of almost 18%.
Bevacizumab use associated with a 5-7% perforation rate and should be used in patients without bowel involvement, without bowel obstruction symptoms and with no evidence of rectosigmoid tumor involvement.
Aurelia trial showed that the addition of Bevacizumab to conventional chemotherapy prolonged median progression free survival by 3.3 months and increased the objective response rate by 15.5% compared with mono chemotherapy.
Prophylactic bilateral salpingo-oophorectomy is 95% effective to reduce the risk of ovarian cancer in women with a high genetic risk.
Generally held that women over the age of 70 years have a poorer prognosis than younger women.
Ascites accounts for one of the three most frequent reasons for hospital admissions in the last 12 months of life, with bowel obstruction and pleural effusion being the other two.
In recurrent ovarian cancer response rate to chemotherapy 10-28%.
Clear cell type lesions characterized by clear cells growing in glandular pattern as well as cells lining tubules and cysts.
Clear cell carcinoma of the ovary accounts for less than 5% of all ovarian cancers with an incidence of 3.7-12% of such lesions.
Clear cell carcinoma have a high incidence of stage I disease.
Clear cell ovarian cancer rarely presents bilaterally and frequently presents with a large pelvic mass and is often associated with endometriosis, hypercalcemia and thromboembolic phenomena.
Ca 125 tests and CT scans of the abdomen and pelvis in patients with ovarian cancer who are in clinical remission does not improve the value of cancer care, and results in poor quality of life without improving survival and should be avoided (Esselen K).
Combining nivolumab with ipilimumab led to a greater response rate and longer progression-free survival (PFS) than nivolumab alone in patients with epithelial ovarian cancer.
A total of 100 patients with measurable epithelial ovarian cancer and a platinum-free interval (PFI) <12 months who had previously received 1 to 3 regimens were include in the study.
Patients were randomized to receive nivolumab or nivolumab plus ipilimumab.
Within 6 months, 12.2% and 31.4% responses occurred in the nivolumab monotherapy and nivolumab plus ipilimumab arms, respectively.
The median PFS was 2 months and 3.9 months, respectively.
PD-L1 expression was not found to be significantly tied to response in recipients of either treatment regimen.
Compared with nivolumab alone, the combination of nivolumab and ipilimumab in epithelial ovarian cancer resulted in superior response rate and longer, albeit limited, PFS.