Standard of Care

From Standard of Care

Women have a 1.4% lifetime risk of developing ovarian cancer.

More than 23,000 cases diagnosed each year and approximately 15,000 deaths per year in the U.S.

Epithelial cells comprise most ovarian cancers but germ cell, mixed Müllerian and ovarian stromal tumors may also occur.

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.

Lifetime risk of dying from invasive ovarian cancer is about 1 in 95.

Fifth most common cause of cancer related deaths in the U.S. among women after lung, breast, colon and pancreatic cancers.

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.

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.

Median age at diagnosis 63 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.

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.

Another risk factor for this disease includes nulliparity, each pregnancy reducing the chance of developing ovarian cancer by 10%.

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.

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.

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)

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.

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.

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).

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.

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%.

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.

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).

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 callable platinum 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 great to hypertension, 10% develop 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.

Bevacizumab single agent response 21%, with 40.3% of patients surviving progression free fot at least 6 months (Burger RA et al).

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 gentamicin 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).

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).

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.

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.

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.

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.