Ovarian cancer-advanced

Epithelial ovarian cancer is the fifth leading cause of cancer death among women in the United States.

For women with stage 1A or IB grade one or two tumors, observation is recommended if the disease was surgically debulked and staged, as survival is more than 90% with this management.

Most women with ovarian cancer present at an advanced stage-stage III.

Standard treatment for stage III remains cytoreductive surgery followed by platinum- and taxane-based combination chemotherapy.

In women with recurrent ovarian cancer, cytoreduction surgery followed by chemotherapy resulted in longer overall survival than chemotherapy alone (Harter P).

More than 60% of women with advanced disease will develop recurrent disease.

Advanced disease is defined as stage III and IV disease.

With surgery an optimal cytoreduction may result in no gross residual disease.

There is an inverse relationship between overall survival and residual tumor size.

For every 10% increase in the proportion of patients achieving maximal cytoreduction (defined in this meta-analysis as residual disease ≤3 cm in maximal dimension), there was an approximate 5.5% improvement in length of overall survival.

The accepted Surgical Gynecologic Oncology Group definition states that optimal cytoreduction has been achieved if there is no gross residual.

Following surgery treatment options could include intraperitoneal (IP) chemotherapy, standard every 3-week chemotherapy with a taxane/platinum agent depending on the completed surgical result.

Guidelines recommend six cycles of IV combination therapy for those with stage II- IV disease.
For earlier stages guidelines recommend 3-6 cycles.

Recommended IV chemotherapy regimens include variations of paclitaxel/carboplatinum, docetaxel/carboplatinum, or carboplatinum/doxorubicin.

Intraperitoneal chemotherapy it’s not recommended for stage I or IV disease.

A neoadjuvant regimen with taxane and platinum doublet is recommended when surgery is not an initial option.

Taxane and platinum doublet is typically used when there is large-volume of intraabdominal disease, disease involving a solid organ, or significant ascites or pleural effusion.

As the majority of patients with ovarian cancer will have advanced (stage III or IV) disease at the time of diagnosis, the standard treatment for optimally cytoreduced women is intravenous (IV)/IP therapy with paclitaxel and cisplatin.

Women with optimally cytoreduced stage III ovarian cancer should be counseled about the clinical benefit associated with a combined regimen of IV and IP chemotherapy, as meta-analysis of all trials comparing IP and IV chemotherapy demonstrated a survival benefit in favor of the IP regimens.

The results of a meta-analysis of GOG 114 and GOG 172 support the long-term survival ad- vantage of IP chemotherapy: there was a significant difference in OS between the IP and IV treatment groups (61.8 months vs 51.4 months, with a 23% reduction in the risk of death, and improved survival with gross residual disease of less than 1 cm.

Factors associated with a poor survival include: clear cell/mucinous versus serous histology, gross residual versus no visible disease, and fewer cycles of IP therapy.

They combination cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide: Response rates were significantly better in the cisplatin/paclitaxel arm (73% vs 60%, and OS was significantly longer in the cisplatin/paclitaxel arm as well (38 months vs 24 months).

Paclitaxel and carboplatin are considered less toxic, easier to administer, and not inferior to cisplatin and paclitaxel and became the standard of care for treatment of advanced ovarian cancer.

ICON 3 was the largest randomized trial to com- pare carboplatin plus paclitaxel with carboplatin alone or CAP (cyclophosphamide/doxorubicin/cis- platin), with the treatment option chosen per patient/ physician prior to randomization: single carboplatin and CAP to be as effective as the combination of paclitaxel and carboplatin for first- line treatment in ovarian cancer.

The Scottish Randomized Trial in Ovarian Cancer (SCOTROC) found that the regimen of docetaxel and carboplatin is similar to paclitaxel and carboplatin in terms of survival.

In GOG 182/ICON 5, an international 5-arm, randomized trial with 5 treatment arms: included paclitaxel and carboplatin, paclitaxel and gemcitabine and carboplatin, paclitaxel and pegylated liposomal doxorubicin, and carboplatin, paclitaxel and topotecan and carboplatin and paclitaxel and gemcitabine and carboplatin.

There was no difference in PFS or OS within any of the experimental arms, and survival analysis defined by either optimal or suboptimal cytoreduction also showed no significant benefit in any subgroup.

Therefore paclitaxel and carboplatin remain the standard of treatment.

For patients who are suboptimally cytoreduced with residual cancer >1 cm IV chemotherapy with carboplatin and paclitaxel remains the treatment of choice.

In patients who are unable to undergo primary optimal cytoreductive surgery or who have unresectable disease, palliative neoadjuvant platinum- based therapy is considered.

Trials to evaluate the benefit of early intervention based on marker elevation:. The results showed no evidence of a difference in the OS between early and delayed treatment in an asymptomatic woman versus beginning treatment when symptomatic, )Median survival for the early group was 25.7 months compared with 27.1 months for those on the delayed treatment).

No survival benefit was noted with early treatment based on the rising CA-125 alone.

The routine measurement of this marker in follow-up management of patients who have attained a complete response after first-line treatment is not proven.

Debate exists over the role of secondary cytoreduction in the setting of recurrent disease given that cure is typically not an option in this group of patients.

Following the initial therapy the treatment-free interval (TFI)

is one of the most important predictors of outcome and response to further treatment.

Patients initially treated with a platinum-based therapy demonstrated that response rates to repeat platinum-based therapy is dependent on the treatment-free interval, with response rates of 27% at a TFI of 5 to 12 months, 33% at 13 to 24 months, and 59% at greater than 24 months.

Patients who have a treatment-free interval of greater than 24 months and had not received additional treatments had a 77% response rate and a 32% surgical complete response rate.

The treatment free interval typically shortens with each subsequent treatment with platinum, eventually evolving into platinum-resistant disease with decreasing overall response rates to chemotherapy, even in patients with initially platinum-sensitive disease at recurrence.

Treatment options for recurrent platinum-sensitive disease:

Single-agent therapy: cisplatin and carboplatin approved as single-agent treatments of recurrent ovarian cancer.

Response rate to these agents as single therapy in platinum- sensitive disease is up to 50%, and the degree of response rate depends on the length of the platinum-free interval.

Single-agent paclitaxel, topotecan have all demonstrated efficacy in the setting of recurrent platinum-sensitive disease, with response rates between 20% and 30%.

The OCEANS study was a randomized double- blind placebo phase 3 trial that evaluated the efficacy of bevacizumab with gemcitabine and carboplatin for treating platinum-sensitive recurrent ovarian, primary peritoneal, or fallopian tube cancer and as maintenance for those women showing response to treatment: The group receiving bevacizumab had a superior median PFS (12.4 months) compared with the group receiving chemotherapy alone (8.4 months).

The objective response rate was improved with bevacizumab, 78.5% versus 57.4%.

Chemotherapy and bevacizumab followed by bevacizumab maintenance given until progression showed statistical significance in PFS compared with the chemotherapy arm alone.

Studies to date in platinum-sensitive disease have demonstrated benefit with with a platinum doublet therapy, showing extended PFS with the addition of bevacizumab.

Platinum-resistant cancer is defined as relapse within 6 months or less from treatment.

Platinum-refractory disease is defined as disease progression while on a platinum regimen.

Both platinum-refractory and Platinum-resistant cancer carry a poor prognosis.

Single agents with efficacy for platinum refractory/resistant disease include:

Topotecan, Gemcitabine, Vinorelbine, Etoposide, Irinotecan, Pemetrexed, Docetaxel, and Ifosfamide with low response rates, short P

Poly (ADP-ribose) polymerase (PARP) is a family of nuclear proteins with enzymatic activity and ability to facilitate DNA repair.

PARP1 functions in the base excision repair system that repairs DNA damage induced by radiation and alkylating agents.

PARP1 inhibitors have cytotoxic effects on BRCA1- or BRCA2-deficient cells, which were caused by the lack of repair of single-strand DNA breaks resulting from PARP1 inhibition and the lack of double-strand break (DSB) repair because of ho- mologous recombination dysfunction due to BRCA mutation.

“BRCAness” is a phenotype that some sporadic tumors share with BRCA cancers.

BRCA-like tumors exhibit improved response and survival as seen in those women with true BRCA mutations.

BRCA-like tumors are related to dysfunction within the homologous recombination system and mutations within the BRCA1/BRCA2 genes.

BRCA-like tumor phenotype frequency is estimated to be approximately 50% in the high-grade serous ovarian cancer population.

PARP- inhibitors have single-agent activity in women with BRCA-related ovarian cancer who are platinum- sensitive as well as in women with BRCA-wild type ovarian cancer.

Patients with BRCA mutations definitely show response to a PARP inhibitor.

Low-grade serous carcinoma (LGSC) accounts for less than 20% of ovarian cancers.

Low-grade serous carcinoma (LGSC) mutations commonly found are KRAS, BRAF, and ERBB2 which can then activate the MAP kinase pathway.

Low-grade serous carcinomas are typically refractory to cytotoxic chemotherapy.

Anti-angiogenic agents, which target blood vessel growth, have demonstrated single-agent activity in ovarian cancer, with reported response rates of 16% to 21% for bevacizumab, a monoclonal anti-VEGF antibody, and 17% for cediranib, an oral tyrosine kinase inhibitor of VEGF receptor.

IGF-1 overexpression in low-grade but not high-grade serous ovarian cancer cell lines.

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