Molecular Genetics of Type I Tumors

The most remarkable distinction between type I and type II tumors is the absence of mutations in the TP53 gene and low chromosomal instability in the former, and the near ubiquitous presence of TP53 mutations and high chromosomal instability in the latter class of tumors.32,33 In terms of well-characterized candidate genetic alterations in type I tumors, low-grade serous tumors display mutually exclusive KRAS or BRAF mutations, but the proportion of affected cases is now debated.³⁴ Recent data from a whole exome analysis of low-grade serous tumors indicate the presence of very few point mutations; 64 distinct genes were mutated in 8 tumors.³⁵ However, in a validation set, only KRAS and BRAF mutations were reproducibly found. These data support the concepts of relative genetic stability of low-grade serous tumors and that KRAS and BRAF mutations are likely important in their pathogenesis. Other types of genetic alterations, such as translocations and epigenetic alterations, have yet to be adequately explored, however, and clearly, at least 50% of low-grade serous tumors appear not to harbor KRAS or BRAF mutations. Interestingly, KRAS mutations are present in approximately 50% of mucinous carcinomas, of both the gastrointestinal and müllerian subtypes, but BRAF mutations are uniformly absent.³⁶ These molecular characteristics of low-grade serous cancers and mucinous cancers are common in borderline serous and mucinous tumors as well, supporting the hypothesized pathogenic continuum of these two tumor types.³⁷

A common molecular genetic alteration also exists in clear cell and low-grade endometrioid cancers; the ARID1A gene, encoding a key component of the SWI-SNF chromatin remodeling complex, is a tumor suppressor gene mutated in approximately half of clear cell EOCs and in approximately one-third of endometrioid EOCs.38,39 In two patients, the same ARID1A mutations were evident in cancers adjacent to atypical endometriosis, providing strong genetic evidence for a link between endometriosis and these two cases of type I cancers.³⁸ Low-grade endometrioid and clear cell cancers are also characterized by mutations in genes encoding components of the Wnt signaling pathway, including CTTNB1, PTEN, and PIK3CA.⁴⁰ Finally, the PPP2R1A gene, encoding a subunit of protein phosphatase 2A, is mutated in a small fraction of all four histologic variants of type I EOCs, but mutations are invariably absent in type II tumors.⁴¹

Thus the known molecular genetic features of type I cancers support novel emerging theories regarding their classification and pathogenesis. However, a complete understanding of their respective molecular genetic architectures, essential to develop more effective clinical approaches to prevention and treatment, will require whole genomic, transcriptomic, and epigenetic analyses of large numbers of these tumors, and presumed precursor lesions, in both a test and validation context.

Molecular Genetics of Type II Tumors

An enormous advance in our understanding of the molecular genetic landscape of type II EOCs was facilitated by the Cancer Genome Atlas Project, which analyzed more than 300 high-grade serous EOCs.³³ In addition to whole exome, genome, and comprehensive gene expression analyses, gene methylation and copy number alterations were also examined. As noted above, TP53 mutation and a high level of chromosomal instability are present in essentially all high-grade serous tumors. Germline mutation of the BRCA1 or BRCA2 genes was observed in 17% of cases, with somatic mutations in an additional 3% of tumors. Interestingly, mutations in only seven additional genes were observed in as many as 2% to 4% of cases. However, a consideration of other types of genetic aberrations, such as gene amplification, and upregulation or downregulation of gene expression, indicates the presence of oncogenic alterations in the RB pathway in 67% of cancers, alterations in the PI3K/RAS pathway in 45% of cases, and in the NOTCH pathway in 22% of cases. Additionally, defective homologous recombination-mediated DNA repair, as influenced by BRCA1/2 mutation or genetic or epigenetic alterations in additional genes with a role in this process, is present in 51% of cases. Finally, the FOXM1 signaling pathway, affecting cell cycle progression or DNA repair, is altered in 84% of high-grade serous tumors. It is likely that this type of multifaceted approach to the detection of pathogenic alterations in critical pathways, when applied to type I tumors, will yield similar insights.

Pathogenesis of High-Grade Serous Carcinoma

The most enduring theory of ovarian carcinogenesis holds that ovarian carcinomas arise from müllerian metaplasia of the ovarian surface epithelium or subcortical epithelial inclusions and develop as a function of genotoxic stimuli introduced to this epithelium during reproductive years (Fig. 89-2).⁴² Although this model supports the genesis of type I tumors, very few high-grade serous carcinomas have been encountered at a stage at which their ovarian origin can be determined with confidence and there is scant evidence for the existence of a precursor lesion in the ovarian surface epithelium or circulating immune complexes. Insight into the pathogenesis of high-grade serous carcinomas came from investigating the prevalence of occult ovarian and fallopian tube cancers in women with germline BRCA gene mutations. Inherited mutations in BRCA1 or BRCA2 are associated with familial ovarian and breast cancer syndromes and account for approximately 11% to 15% of ovarian carcinomas.^3,4,43,44 Mutations in either gene confer a 15% to 40% lifetime risk of developing ovarian cancer.⁴⁵ Many women with germline BRCA mutations elect to undergo risk-reducing bilateral salpingo-oophorectomy, after which the ovaries are thoroughly examined for evidence of occult cancer. Until recently, the fallopian tubes were not systematically examined in these cases. Consequently, early-stage tubal cancers have been rarely detected and severely underreported in BRCA mutation carriers. Recent studies suggest that the fallopian tube may harbor a cell-of-origin, the fallopian tube secretory epithelial cell (FTSEC), for high-grade serous carcinomas of the ovary. Supportive evidence for this hypothesis includes (1) ~5% to 10% of BRCA1 mutation carriers undergoing prophylactic surgery will have an early lesion, termed serous tubal intraepithelial carcinoma (STIC) in their fallopian tube fimbria; (2) >50% of women with stage III/IV pelvic serous cancer also harbor a STIC; (3) identical TP53 mutations have been identified in STICs and corresponding serous carcinomas¹²; (4) nonneoplastic FTSEC and serous carcinoma share similar morphological and immunophenotypic features; and (5) a candidate precursor lesion (the p53 signature) composed of benign-appearing FTSECs that harbor DNA damage and TP53 mutations, has been described in the fallopian tube (Fig. 89-3).^45–50 These observations suggest that pelvic serous carcinomas previously assigned to different sites of origin (ovary, fallopian tube, or peritoneum), share a common carcinogenic pathway not previously appreciated, which originates in the FTSEC.

This new model of pathogenesis is compelling and also entirely consistent with longstanding epidemiological observations. It has long been documented that lifetime ovulation is positively correlated with high-grade serous carcinoma, and that factors such as parity and birth control, which would decrease lifetime ovulation, have a protective effect.⁵¹ During ovulation, the follicular fluid surrounding the ovum is released and bathes the surrounding tissue, including the ovarian surface epithelium and fallopian tube fimbria proximal to the ovary. The composition of this fluid, known to play a critical, albeit poorly understood, role in the development of the follicle, is ill defined but contains hormones, fatty acids, reactive oxygen species, and growth factors that can have mutagenic effects on the surrounding epithelium with each successive ovulatory cycle. In fact, a recent study in a mouse model showed that ovulation causes DNA damage to tubal epithelial cells, suggesting that the distal fallopian tube is susceptible to double-strand DNA breakage during ovulation.⁵²

The shifting model of serous cancer pathogenesis is starting to impact clinical care. Sectioning and extensive examination of the fimbriated end of the fallopian tube is becoming common practice in academic tertiary care centers. Encouragingly, this has resulted in independent validation and support for the fallopian tube model of serous pathogenesis.53–56 The model is also stirring discussion about whether prophylactic surgery should be limited to the fallopian tubes, or whether one of both ovaries may be spared in BRCA mutation carriers. Salpingectomy alone carries an obvious decrease in early menopause–related morbidity and improvement in quality of life, including preservation of fertility, but evidence supporting this approach for the management of high-risk women is still very limited. A related question is whether fimbriectomy is a viable alternative to tubal ligation as a sterilization technique.⁵⁷ Arguably, sterilization practices that target the fimbria may maximize the protective effect of tubal sterilization on serous cancer prevention. However, the value of such a practice must be evaluated in the context of a clinical trial that carefully evaluates the safety and feasibility of fimbriectomy with long-term follow-up to ensure that it is effective to reducing the risk of “ovarian cancer” in an at-risk population. Nevertheless, barring the emergence of a successful chemopreventive agent or early detection strategy, removing fimbrial tissue is a provocative, albeit yet unproven, surgical approach to reducing serous malignancies.

In addition to the aforementioned clinical issues that can now be addressed, this new model has sparked the development of novel fallopian tube–based experimental platforms for the discovery of biomarkers and therapeutic targets.²⁵ Coupled with a recent report from The Cancer Genome Atlas (TCGA), which provided a comprehensive, panoramic view of the genomic complexity of serous carcinomas, we are now poised to leverage these new insights for better patient management and care.

Genetics of Nonepithelial Ovarian Cancers

Nonepithelial ovarian tumors may broadly be classified into two categories: sex cord-stromal tumors and germ cell tumors. Unlike EOCs, the histogenesis and natural history of these neoplasms are relatively well understood, with little doubt as to their classification as true “ovarian” tumors.

Sex Cord-Stromal Tumors

The sex cord-stromal tumors account for approximately 7% of all ovarian neoplasms, and consist of two broad categories, granulosa-stromal cell tumors, and Sertoli-stromal cell tumors.⁵⁸ The majority of these tumors are relatively indolent and are associated with a favorable long-term prognosis. A substantial proportion of sex cord-stromal tumors is diagnosed in patients under 40 years of age; these tumors have the potential to produce steroid hormones. Remarkably, a single somatic missense mutation of the FOXL2 gene is present in the great majority of all adult-type granulosa cell tumors, rare in other granulosa cell tumors, and largely absent in EOCs or other tumor types.⁵⁹ The FOXL2 gene encodes a transcription factor known to be critical for granulosa cell development, and is likely pathognomonic for adult granulosa cell tumors. Clues to the pathogenesis of Sertoli-stromal cell tumors derive from the observation that germline truncating mutations in DICER1, which encodes an endoribonuclease in the RNase III family essential for processing microRNAs, are observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome, which includes nonepithelial ovarian tumors, including sex cord-stromal tumors.⁶⁰ Somatic missense mutations of DICER1 are found in about one-third of nonepithelial ovarian tumors, including 60% of Sertoli-Leydig cell tumors. This finding suggests a novel mechanism through which perturbation of microRNA processing may be oncogenic. Finally, women affected by the rare Peutz-Jeghers hamartomatous polyp syndrome, associated with germline mutation of the STK11 (LKB1) serine-threonine kinase gene, are susceptible to sex cord tumors with annular tubules.⁶¹

Germ Cell Tumors

Ovarian germ cell tumors are composed of seven major histologic tumor types derived from the primitive germ cells of the embryonic gonad, and account for approximately 3% of all ovarian neoplasms. Although distinct immunohistochemical features typically distinguish the various histologic types of germ cell tumors, specific genetic alterations have been described only for dysgerminomas, the most common malignant ovarian germ cell neoplasm occurring in pure form. They tend to be tetraploid, with the occasional presence of a small isochromosome, i(12p). Copy number alterations have been identified affecting gains on 12p, 12q, 21q, 22q, and loss on 13q.⁶² Missense mutation of codon 816 of the KIT oncogene occurs in approximately one-third of dysgerminomas, and is associated with advanced stage at presentation. As such, this mutation represents a potential therapeutic target.⁶³

Genetics of the BOC Syndrome

Following the original reports of genetic linkage of early-onset breast cancer families and some breast and ovarian cancer families to the BRCA1 locus on chromosome 17q,⁶⁹ the BRCA1 gene was cloned and characterized in 1994.⁷⁰ Shortly thereafter, the BRCA2 locus on chromosome 13q was defined,⁷¹ and the gene was identified in 1995.⁷² Based on a large volume of literature, a reasonable estimate is that 55% of hereditary ovarian cancers are linked to BRCA1 and 25% to BRCA2 in the context of the BOC syndrome, and 15% to the Lynch syndrome genes. Several additional genes, including RAD51C, RAD51D, and BRIP1, account for up to 5% of hereditary ovarian cancers.⁷³

The BRCA genes share remarkable similarity in both structure and function. Mutations occur throughout both genes, with more than 80% being nonsense or frameshift alterations leading to a truncated protein product; the remainder are missense and other “variants of uncertain significance,” and a very small proportion consist of large-scale gene rearrangements. Well over 1000 distinct inherited mutations in each gene have been described. The prevalence of BRCA mutations in the general population has been estimated to be as high as one in 400. This figure varies considerably among distinct populations, however. Of note, some ethnic or geographically isolated populations carry specific BRCA mutations at a high frequency, generally as a consequence of a founder effect.⁷⁴ This phenomenon is most pronounced in the Ashkenazi Jewish population, in which approximately 2.5% of individuals carry one of two distinct mutations in BRCA1 (185delAG or 5382insC) or the 6174delT mutation in BRCA2.⁷⁵ In a search for genotype-phenotype correlations, the study of BOC families revealed the presence of an “ovarian cancer cluster region” in the very large exon 11 gene of BRCA2. Emerging data suggest that a similar region exists in BRCA1, but the mechanism for these effects are not clear. Mutations of the BRCA genes are inherited in an autosomal dominant fashion; somatic loss of heterozygosity at the BRCA loci in ovarian cancers invariably affects the wild-type allele, consistent with their function as classic tumor suppressor genes.

Given the very large size and multiple functional domains within the BRCA proteins, it is not surprising that both interact physically with numerous additional proteins and participate in multiple cellular processes. Over the years, a major challenge had been to distinguish among the various functions of BRCA1/2 insofar as they relate directly to tumor suppression.⁷⁷ Based on a wealth of data from model systems, there is now strong consensus that the primary role of both proteins in this regard is in the repair of DNA double strand breaks through the process of homologous recombination; loss of this function leads to genomic instability and tumorigenesis.^80–80 The BRCA1 protein is substantially more diverse with respect to protein–protein interactions, and involvement in protein supercomplexes, playing a role in DNA replication, cell cycle checkpoint control, apoptosis, regulation of transcription, chromatin unfolding, and protein ubiquitination. Although the BRCA2 protein probably also plays a role in cell cycle checkpoint control and regulation of mitosis, its key function appears to involve serving as a scaffold for RAD51 in the repair of DNA double strand breaks, as for BRCA1, through homology-directed DNA repair.⁸¹

Ovarian Cancer Associated with the BOC Syndrome

In carriers of mutant BRCA1 or BRCA2, penetrance is high but incomplete for ovarian cancer. Numerous studies using multiple designs have proposed the lifetime risk of ovarian cancer associated with germline BRCA mutation, with estimates converging around 40% for BRCA1 and 20% for BRCA2. There is considerable evidence that these risks are affected by other genetic and environmental factors clustering in families. Data from large collaborative genomewide association studies suggest that several common alleles modify ovarian cancer risk associated with BRCA mutation carriers.⁸²

The clinical and pathological characteristics of BRCA-linked compared with sporadic ovarian cancer are distinct. The age at diagnosis for BRCA1-linked ovarian cancer patients (age 45 to 50 years) is considerably younger than for those in the general population (age 61 years). In contrast, BRCA2-linked ovarian cancer patients are diagnosed at a significantly older age (55 to 60 years) than BRCA1-linked patients.83,84 Notably, in contrast with hereditary breast cancer, BRCA-linked ovarian cancers do not occur in women under 30 years. These data have considerable implications for clinical intervention in unaffected mutation carriers. The histopathological characteristics of BRCA-associated ovarian cancers differ from the spectrum associated with their sporadic counterparts. In the BRCA population, tumors of high-grade serous histology are overrepresented, although endometrioid and clear cell tumors are also observed. Tumors of mucinous histology and borderline (low malignant potential) tumors do not occur in association with BRCA mutation. In addition, low-grade serous ovarian cancers are the result of a distinct pathogenic process, and do not occur in the BRCA population. Finally, there does not appear to be a difference between the histopathological spectrum of tumors in the BRCA1 compared with the BRCA2 population.⁸⁵

The clinical course of BRCA-linked ovarian cancer patients is dramatically different from that of sporadic ovarian cancer patients matched for all other clinical and pathological criteria of prognostic significance. Specifically, progression-free survival and overall survival are significantly improved in BRCA mutation carriers. This prognostic difference has been unequivocally demonstrated in both the Ashkenazi Jewish founder population83,86 as well as the general population,^87,88 when comparing BRCA-linked tumors with sporadic tumors. Furthermore, the improved outcome appears to be greater for BRCA2 mutation carriers compared with BRCA1 mutation carriers. The biological basis for this phenomenon is also reasonably well established based on work in vitro and in model systems in vivo. Platinum-based combination chemotherapy, the standard first-line treatment for epithelial ovarian carcinoma, is an “accidental” targeted or personalized therapy in this context. Cis(carbo)platin is known to create interstrand DNA cross links, which are repaired by the cell through creation of a double-strand break at the crosslink, which is then repaired through homologous recombination. Cells deficient in homologous recombination-mediated DNA repair are thus hypersensitive to the cytotoxic effects of platinum-based therapy (as well as other agents that act through similar mechanisms, e.g., mitomycin C).⁸⁹

Screening, Surveillance, and Risk Reduction in the High-Risk Population

The screening of individuals from the general population for hereditary predisposition to the BOC syndrome is a complex and controversial topic. Several groups have made consensus recommendations on this topic, all referencing different criteria, including the American College of Medical Genetics, the National Comprehensive Cancer Network, the American Society of Clinical Oncology, and the American College of Obstetricians and Gynecologists. In 2005, the U.S. Preventive Services Task Force published its recommendation statement. To summarize, the recommendation is against routine referral for genetic counseling or BRCA genetic testing for women whose family history is not associated with an increased risk for a deleterious BRCA mutation (grade D recommendation), whereas the recommendation for women whose family history is associated with an increased risk for deleterious BRCA mutation be referred for genetic counseling and evaluation for BRCA testing (grade B recommendation).⁹⁰

Although it is generally accepted that women with germline BRCA mutations should be routinely screened for ovarian cancers, there are no data to suggest that ovarian cancer screening leads to improved survival in the high-risk population. An evaluation of 13 ovarian cancer screening studies of high-risk women found that of 70 screen-detected tumors, only 24% were early-stage, similar to the incidence in the general population. This finding suggests that there is likely to be little difference in survival between screened and unscreened populations.⁹¹

In the context of prevention, essentially all published retrospective and prospective studies of the effect of risk-reducing bilateral salpingo-oophorectomy (RRSO) in BRCA mutation carriers demonstrate a significant reduction in the risk of ovarian cancer and, generally, breast cancer as well. Typical is the largest and most recent prospective, multicenter cohort study of 2482 women with BRCA mutations.⁹² In women undergoing RRSO, the procedure was associated with a substantially lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality. These and a wealth of similar data from the literature contribute to consensus recommendations from several professional organizations and experts in the field, including a review of the literature by the Society of Gynecologic Oncology Clinical Practice Committee, which recommends RRSO in the BRCA population.⁹³ The frequent finding of occult ovarian and tubal carcinomas following RRSO reinforce this recommendation, as well as the importance of careful pathological examination of the entire specimen following surgery (see previous section on Etiology and Biological Characteristics—High-Grade Serous Cancer). Hysterectomy is not recommended in this context because there is no evidence for an increased risk of uterine cancer in the BRCA population; however, the use of tamoxifen or estrogen replacement therapy in some patients may affect this decision. Factors such as current age, child-bearing considerations, and BRCA1 versus BRCA2 mutation status contribute to the timing of the procedure with respect to patient age at the time of RRSO, but the consensus recommendation is to perform the procedure no later than age 40 years. Cost- and comparative-effectiveness studies clearly support this recommendation in the context of cancer prevention in BRCA mutation carriers.^94,95

Also well established is the protective effect of oral contraceptives on ovarian cancer risk in the BRCA population. In a large representative study, duration of oral contraceptive use increasingly reduced the risk of ovarian cancer by 50% to 60% with up to 5 years of use.⁹⁶ Historically, use of this chemoprevention strategy has been tempered by conflicting data on an association with increased risk of breast cancer in BRCA mutation carriers. However, a recent meta-analysis of available data concludes that there is no evidence that recent oral contraceptive formulations increase breast cancer risk in BRCA carriers.⁹⁷ Nevertheless, as with most medical interventions, a discussion between women and their physicians of the benefit–risk ratio is strongly indicated.

Genetics of Lynch Syndrome

Clues to the genetic basis of Lynch syndrome first emerged in 1993, with several independent observations of somatic hypermutability of a class of DNA repetitive elements, known as microsatellites, in sporadic and familial colorectal tumors.¹⁰⁵ This observation was accompanied by reports of the genetic linkage of Lynch syndrome kindreds to two loci, one on chromosome 2p and another on chromosome 3p. Identification and cloning of the relevant genes at these loci, MSH2 on chromosome 2¹⁰⁶ and MLH1 on chromosome 3¹⁰⁷ quickly followed, together with the realization that these genes encoded human orthologs of yeast DNA mismatch repair proteins. The microsatellite instability phenotype previously observed in colorectal and other cancer types associated with the Lynch syndrome could be explained by loss of function of these DNA mismatch repair genes. In Lynch syndrome, one of these genes is inherited in a mutant form through the germline, whereas in sporadic colorectal, endometrial, and gastric carcinomas affected by microsatellite instability, somatic silencing of MLH1 through promoter hypermethylation is the primary pathogenic mechanism.¹⁰⁸ Most patients (90%) with Lynch syndrome carry a mutation in either MSH2 or MLH1, with approximately 10% of cases attributable to MSH6 mutation and a very small number to PMS2 mutation. The DNA mismatch repair genes responsible for Lynch syndrome are classical tumor suppressor genes that sustain loss of function mutations; they are inherited in an autosomal dominant fashion with somatic loss of the wild-type allele required for tumorigenesis. The basis for incomplete and variable tissue-specific penetrance of these genes remains unknown.

In women, Lynch syndrome is most frequently associated with colorectal and endometrial cancers, with a 40% to 60% lifetime risk of each.¹⁰⁹ Other cancers, especially of the gastrointestinal and genitourinary tracts, are common.¹¹⁰ The lifetime risk estimates for EOC associated with Lynch syndrome range from 6% to 20%, and the clinicopathological features of these cancers appear to be distinct compared to ovarian cancer in the general population. Although data are limited, in the two largest studies to date, the mean age at diagnosis is mid-40s, most cancers are well or moderately differentiated endometrioid, clear cell histologic types are overrepresented, and early-stage cancers are relatively common.^111,112 Additionally, synchronous endometrial cancers are observed in approximately 20% of cases. There is some evidence that MSH6 may account for a higher proportion of gynecologic, including ovarian cancers.

Screening, Surveillance, and Risk Reduction in the Lynch Syndrome Population

The prevalence of DNA mismatch repair gene mutations in the general population is estimated at 1 in 500 to 1 in 1000,⁸⁵ and the proportion of all ovarian cancers arising in the context of Lynch syndrome is estimated at 1% to 4%.¹¹³ With respect to screening tumor tissues for the possible presence of Lynch syndrome, it is necessary to incorporate the risk of endometrial cancer into guidelines for females, and numerous consensus recommendations are published. The Bethesda Guidelines are sensitive but have a low specificity, and are now less commonly used in the clinical setting. Another approach uses algorithms that incorporate the types of cancer in a family, the age of occurrence, and the relationships of family members with cancer to estimate the likelihood of an individual having Lynch syndrome; several of these computerized algorithms are available online.¹¹⁴ Recently, cost-effectiveness and other considerations have led to an emerging consensus that reflex testing of all incident colorectal, and perhaps endometrial, cancer cases, using immunohistochemistry to assess mismatch repair gene expression, is the most appropriate initial screen for Lynch syndrome.^116–116 Of note, 92% of ovarian cancers associated with germline mismatch repair gene mutation demonstrate loss of gene expression in the corresponding gene as assessed by immunohistochemistry.¹¹²

Although consensus recommendations uniformly endorse increased surveillance for colorectal cancer in this population, based on the resultant decreased mortality, evidence is lacking for an effective methodology for screening women for gynecologic malignancies. There is, however, evidence for the efficacy of prophylactic, or risk-reducing, surgery. In a retrospective cohort of 315 women with mismatch repair gene mutations, in which 61 had prophylactic hysterectomy with or without bilateral salpingo-oophorectomy, matched to women without surgery and followed for approximately 10 years, no ovarian cancers developed in those who had surgery, whereas 12 (5.5%) who did not developed ovarian cancer.¹¹⁷ Using a different approach, data from a decision analytic model that considered 10,000 theoretical women with a mismatch repair gene mutation indicated that only 28 prophylactic surgeries would be needed to prevent one ovarian cancer in this population.¹¹⁸ Risk-reducing surgery, compared with surveillance, is also the most cost-effective option from a societal healthcare cost perspective.¹¹⁹ Taken together, available data would suggest that prophylactic hysterectomy and bilateral salpingo-oophorectomy be offered to all women genetically susceptible to Lynch syndrome at the age of 35 years, or once child-bearing is complete, following a careful discussion of the risks, benefits, and limitations of this procedure.

Primary Therapy of Early-Stage Epithelial Ovarian Cancer

Approximately 25% to 30% of epithelial ovarian cancers present as stage I or II disease with an overrepresentation of nonserous histologies. The incidence varies depending upon the extent of staging because approximately 30% of patients will be upstaged when comprehensive staging surgery is performed.¹⁵⁵ Tumor grade and rupture before and during surgery are important factors in prognosis and determining whether early disease warrants adjuvant therapy. There is controversy over the prognostic importance of histologic type, with some studies but not all studies suggesting clear cell carcinoma has been overrepresented in recurrences in chemotherapy trials of early-stage disease.^156,157 In contrast, early-stage mucinous tumors likely have a slightly better prognosis.

Studies evaluating survival for observation alone after surgery for patients with stage IA or B, well-differentiated tumors have shown that the 5-year survival rate is more than 90%.¹⁵⁸ Survival approaches 100% for patients who have had comprehensive surgical staging, and no further therapy is recommended for these patients.¹⁵⁹ Patients with early disease who are considered at high risk and have been included in adjuvant trials are shown in Table 89-4.

Although both whole pelvic and whole abdominal radiotherapy have been used in the past as adjuvant therapy for early ovarian cancer, several small studies failed to show superiority to radiation over chemotherapy.160,161 Concerns regarding short- and long-term toxicity, especially radiation-induced bowel damage in patients who have undergone abdominal surgery, has caused this modality to fall out of favor. Intraperitoneal radioactive colloid has also been used in the past. Four randomized trials comparing intraperitoneal radioactive phosphorous (³²P) with chemotherapy in early ovarian cancer have been completed. None showed an overall survival advantage to ³²P; however, frequent and sometimes serious bowel complications have also resulted in this approach being largely abandoned.^{158,162–164}

There have been four randomized trials evaluating observation versus platinum-based chemotherapy in early ovarian cancer. Two small studies with limited power showed no significant difference in overall survival for patients with stage I, grade 2 or 3 disease using carboplatin or cisplatin for six cycles.163,165 A combined analysis of two other large European randomized trials (ACTION and ICON-1) showed a significant improvement in disease-free and overall survival for adjuvant platinum-based chemotherapy (Table 89-5).^166,167 However, a subset analysis with limited power failed to show a survival benefit in patients in the ACTION trial who underwent comprehensive surgical staging.¹⁶⁷ The duration of treatment that is optimal for patients with high-risk early ovarian cancer is uncertain. The GOG randomly assigned 427 patients with unfavorable early ovarian cancer to three or six cycles of carboplatin and paclitaxel. Unfavorable was defined as patients with stage IA or IB disease if their histology was grade 3 or clear cell, stage IC, and completely resected stage II. The carboplatin dose was given at an area under the curve (AUC) of 7.5 and the paclitaxel was given at 175 mg/m² over 3 hours. The 5-year survival rate was 84% for stage I and 73% for stage II and there was no significant difference between the two arms. There was a 25% lower recurrence rate for the patients receiving six cycles but the study was powered to identify only a larger difference (50%) and therefore this difference also was not statistically significant. Toxicity, in particular neurotoxicity, was expectedly greater with six courses.¹⁶⁸ The GOG has recently completed a trial randomly assigning the same patient population to three cycles of carboplatin and paclitaxel, this time at a carboplatin AUC of 6, with or without an additional 24 weeks of weekly paclitaxel at 40 mg/m². The 5-year survival for stage I disease was 88.8% and for stage II disease was 78.9%. There was no difference in recurrence or survival between regimens. As expected, there was a significant increase in toxicity, especially neuropathy, with the prolonged regimen.¹⁶⁹

Summary Recommendations for Early Disease

Patients with stage IA or stage IB ovarian cancer, with grade 1 or 2 histology, can be treated with surgery alone and a 5-year survival rate of more than 90% can be expected. Patients with stage I, grade 3, or stage IC disease and those with completely resected stage II disease of any grade should receive at least three cycles of carboplatin and paclitaxel. However, stage II disease has been included in recent European trials for advanced disease and plans are to include these patients in future GOG trials for advanced disease as well. Because these trials generally use at least six cycles of therapy, it is reasonable to consider treating all patients with stage II ovarian cancer with six cycles of chemotherapy as well. Other approaches such as dose-dense paclitaxel and intraperitoneal chemotherapy have not been studied in early ovarian cancer but may be considered in selected patients based on results seen in patients with more advanced disease.

Primary Therapy of Advanced-Stage Epithelial Ovarian Cancer

The initial approach to patients with presumed epithelial ovarian, fallopian tube, and primary peritoneal cancer usually involves cytoreductive surgery followed by platinum and taxane–based chemotherapy. Several controversies exist regarding the timing of initial surgery in relation to chemotherapy, the role of “interval cytoreduction” after suboptimal debulking surgery, the role of intraperitoneal chemotherapy, the importance of dose-intensity, and whether to incorporate newer targeted drugs such as bevacizumab into frontline therapy.¹⁷⁰

In 1986, Omura et al. reported the results of a GOG phase III randomized controlled trial establishing the superiority of adding cisplatin to doxorubicin and cyclophosphamide.¹⁷¹ Subsequent GOG trials failed to show a benefit to keeping doxorubicin in the combination, or to doubling the dose intensity of cisplatin and cyclophosphamide.^172,173 Eight cycles of cisplatin and cyclophosphamide at 50 and 500 mg/m², respectively, did not improve response or survival compared with the same drugs given for four cycles at 100 and 1000 mg/m², respectively. However, a Scottish trial that doubled the dose intensity of cisplatin from 50 to 100 mg/m² while keeping the cyclophosphamide dose stable at 750 mg/m² did show an improvement in response and survival when both regimens were given for six cycles.¹⁷⁴ This suggests that the total dose may be important once a certain dose intensity is achieved. Subsequently paclitaxel was tested in ovarian cancer and found to have significant activity in platinum-resistant disease. GOG 111, reported by Maguire et al. in 1996, demonstrated the superiority of cisplatin and paclitaxel over cisplatin and cyclophosphamide in patients with advanced, suboptimally debulked ovarian cancer. In this trial, cisplatin was given at 75 mg/m² and paclitaxel at 135 mg/m² over 24 hours. The prolonged infusion of paclitaxel reduces the incidence of hypersensitivity reactions and the severity of neurotoxicity. This is especially important when given with cisplatin. The median survival for the patients in the paclitaxel arm was 37 months versus 25 months in the cyclophosphamide group.¹⁷⁵ These results were confirmed by a European-Canadian trial (OV-10) in patients with stage IIB-IV disease. Neurotoxicity was significantly higher in that trial, however, because it used a higher dose of paclitaxel (175 mg/m²) given over 3 hours.¹⁷⁶

Contrasting these studies are two large randomized trials that did not show superiority of the platinum combination therapy over single-agent platinum chemotherapy. GOG 132 randomized patients with suboptimally debulked ovarian cancer to cisplatin at 100 mg/m² versus cisplatin/paclitaxel (75 and 135 mg/m²/24 h) versus paclitaxel (200 mg/m²/24 h). The two platinum-containing regimens had comparable survival (26 months) and were superior to single-agent paclitaxel. In the platinum arm, there was a high crossover to paclitaxel before progression, suggesting that sequential therapy may explain the equivalent survival.¹⁷⁷ ICON-3 was a large multinational trial that randomly assigned patients with stage I–IV disease to carboplatin/paclitaxel versus cisplatin/doxorubicin/cyclophosphamide or single-agent carboplatin (chosen prior to randomization). This showed no difference in progression-free or overall survival.¹⁷⁸

Since then, a series of randomized trials performed by the GOG and in Europe have established carboplatin, given at an AUC of 6 to 7.5, with paclitaxel (over 3 hours) or docetaxel as the standard treatment for advanced-stage epithelial ovarian cancer. GOG 158, which randomly assigned optimally debulked patients with stage III disease to carboplatin/paclitaxel versus cisplatin/paclitaxel (24 hour) showed no difference in median progression-free or overall survival, but a more favorable toxicity profile with the carboplatin-containing regimen. Grade 4 neutropenia, gastrointestinal, renal, and metabolic toxicities were more common in the cisplatin arm. The median progression-free and overall survival for the carboplatin/paclitaxel arm was 20.7 and 57.4 months, respectively.¹⁷⁹ Because the carboplatin-containing regimen can be given on an outpatient basis, this has become the preferred regimen used today. Two European studies showed similar results with different patient populations, but reported increased neurotoxicity with the cisplatin/paclitaxel regimen, likely because they used 3-hour infusions of paclitaxel. These trials also gave carboplatin at an AUC of 5 or 6.^180,181 Based on these studies, carboplatin (AUC 6) and paclitaxel 175 mg/m² over 3 hours given every 21 days has become the standard chemotherapy regimen for both early and advanced disease. Substituting docetaxel for paclitaxel may reduce the severity of neurotoxicity without compromising efficacy.¹⁸² However, duration of drug exposure may be critical for paclitaxel cytotoxicity. A randomized phase III trial from Japan reported a significant progression-free and 3-year survival advantage using weekly paclitaxel (80 mg/m²) and every-21-day carboplatin (AUC 6). This “dose-dense regimen” has demonstrated similar benefit in breast cancer but is associated with more myelosuppression and neurotoxicity. In the Japanese trial in ovarian cancer, fewer than half of the patients assigned to the dose-dense regimen completed the treatment according to protocol.¹⁸³ A GOG trial attempting to confirm the Japanese dose-dense study has recently been completed and the results are pending. This trial also allowed concurrent and maintenance bevacizumab.

Because there are multiple drugs with activity in ovarian cancer (Table 89-6), it is reasonable to consider adding additional agents to standard therapy. However, there does not seem to be an advantage to adding a third chemotherapeutic agent to platinum/paclitaxel based therapy. Three international randomized trials failed to demonstrate an improvement in survival with the addition of an anthracycline (doxorubicin or epirubicin) to platinum-based therapy.^184,185 Bookman et al. reported on a large international five-arm randomized trial looking at the addition of pegylated liposomal doxorubicin (PLD), topotecan, or gemcitabine to carboplatin and paclitaxel and found no difference in progression-free and overall survival (Table 89-7). The trial, led by the GOG, enrolled 4312 patients with advanced-stage ovarian cancer and included patients who were both optimally and suboptimally debulked. For patients with >1 cm residual, gross-residual ≤1cm, or microscopic residual, the median progression-free survival rates were 13, 16, and 29 months, respectively, and the median overall survival times were 33, 40, and 68 months, respectively. There was no benefit seen for the addition of a third agent to any of these subgroups.¹⁸⁶

Table 89-6

Active Agents in the Management of Ovarian Cancer

Green: high activity; yellow: modest activity; orange: very limited activity as single agent.

Maintenance Therapy

Only one trial has shown a potential benefit of maintenance therapy after complete remission. A Southwest Oncology Group (SWOG)/GOG trial randomly assigned patients to either 3 or 12 cycles of intravenous paclitaxel at 175 mg/m² every 4 weeks. The trial was halted after a planned interim efficacy analysis showed an improvement in progression-free survival (28 vs. 21 months, one sided P = 0.0035). A survival benefit could not be determined because the study was halted, at which time crossover to the paclitaxel maintenance arm occurred. Because of neurotoxicity, the dose of paclitaxel was reduced to 135 mg/m² during the trial.¹⁸⁷

Other European trials using intraperitoneal cisplatin, high-dose chemotherapy, topotecan, or epirubicin also failed to demonstrate a survival benefit when used as consolidation or maintenance therapy.188–192 The GOG is currently running a randomized trial of no further therapy versus paclitaxel (135 mg/m²) or Xyotax (paclitaxel polyglumex) every 4 weeks for 12 cycles for patients in complete remission, with the primary end point being overall survival.

Intraperitoneal (IP) Therapy

Ovarian cancer remains clinically confined to the peritoneal cavity for a large part of its clinical course. Therefore, it is logical to consider that direct administration of chemotherapy to the peritoneal cavity may produce a therapeutic advantage. Because many agents that are active in ovarian cancer have a pharmacologic advantage when given intraperitoneally, it is also possible to reach dose-intensity levels not possible with conventional administration routes. For example, both carboplatin and cisplatin have a tenfold to twentyfold higher local concentration when given intraperitoneally. In addition, because of absorption through peritoneal surfaces, systemic levels of these drugs are comparable when the drugs are given intravenously or IP (AUC although not Cmax). Paclitaxel has a 1000-fold increase in intraperitoneal exposure when given intraperitoneally due to a long intraperitoneal residence time with systemic levels (AUC) approximately 50% of that seen with intravenous dosing. Because intraperitoneal chemotherapy generally penetrates tumor nodules for only 1 to 2 mm, its use has been largely limited to patients with small-volume residual disease after primary cytoreduction.¹⁹³ In January 2006, the National Cancer Institute (NCI) of the United States issued a clinical advisory, suggesting that a combination of IV and IP chemotherapy should be considered in the front-line treatment of patients with optimally debulked ovarian cancer. This was based on a meta-analysis of eight trials that showed an average 21.6% decrease in the risk of death when IP chemotherapy was used.¹⁹⁴ Three U.S. studies were particularly influential in the analysis (Table 89-8).^197–197 Unfortunately, only one used equivalent doses of IP and IV therapy, leaving some doubt about the influence of the IP route as the most significant variable. Regardless, the most recent trial by Armstrong, using a more intensive IP regimen, reported an impressive improvement in overall survival (66 vs. 50 months, P = 0.03) for the IP arm. This improvement occurred despite the fact that only 42% of patients on the IP arm received the planned six cycles. The increased toxicity of the IP regimen used in this trial, combined with the difficulty of administering IP chemotherapy, has limited the adoption of this regimen as standard therapy.

To make the regimen used in the Armstrong study more tolerable, several modifications have been proposed. In addition, data from Fujiwara in Japan suggest that appropriately dosed IP carboplatin may be a suitable alternative to IP cisplatin.¹⁹⁸ The GOG has recently completed a phase III trial of IV carboplatin (AUC 6) with IV dose-dense paclitaxel (80 mg/m², days 1, 8, 15), versus IP carboplatin (AUC 6) with IV dose-dense paclitaxel, versus IP cisplatin (75 mg/m²), IV paclitaxel (135 mg/m² over 3 hours) and IP paclitaxel (60 mg/m², day 8). Each regimen was given on 21 day cycles for six cycles. Bevacizumab (15 mg/kg) was also given IV starting on the second cycle of each treatment and continued for 16 cycles after completing chemotherapy. It is hoped that this study will answer whether carboplatin and paclitaxel is more effective when carboplatin is given IP at equivalent doses or if a more tolerable modification of the IP regimen used in the Armstrong study is superior to either carboplatin-based regimen.

Biological Agents in Front-Line Therapy

Tumor angiogenesis appears to be an important process in epithelial ovarian cancer development. Bevacizumab is a monoclonal antibody that can neutralize vascular endothelial growth factor (VEGF), a promoter of the initiation phase of angiogenesis. Two phase III trials have been reported that have added bevacizumab to standard therapy with six cycles of carboplatin and paclitaxel. GOG 0218 and ICON 7 both showed an improved progression-free survival when bevacizumab was given concurrently and as maintenance therapy for a total of 18 cycles in ICON 7 and 22 cycles in GOG 0218. There were some differences in patient populations, with the GOG trial only including patients with stage III and IV disease and the ICON 7 allowing patients with high-risk, early disease (stage I and II). Bevacizumab was given at 15 mg/kg in the GOG study and 7.5 mg/kg in ICON 7.199–200 In GOG 0218, the progression-free survival was extended by 3.8 months (14.1 vs. 10.3 months, P < 0.001) and in ICON 7 by 1.7 months ( 24.1 vs. 22.4 months, P = 0.04). Although the final planned end point of both trials was progression-free survival, GOG 0218 was originally powered to detect a survival difference. However, during the trial it became apparent that patient and doctor request for unblinding at the time of progression, with the subsequent treatment of patients randomly assigned to placebo with bevacizumab, would make evaluation of survival as an end point infeasible. With the final survival analysis pending at the time of the reports, there was no overall survival advantage in either study. However, a preplanned analysis of ICON 7 demonstrated an overall survival benefit of almost 8 months in a high-risk group with stage IV or >1 cm residual disease (36.6 vs. 28.8 months, P = 0.002). Hypertension was the most common complication in both trials and required treatment in 20% to 25% of patients. The rate of gastrointestinal perforation was approximately double with bevacizumab, but still less than 3%.

Based on the results of these two trials, the European Medicines Agency approved the use of bevacizumab in combination with paclitaxel and carboplatin for the front-line treatment of advanced ovarian cancer in the European Union. Although the maintenance phase of bevacizumab may be the most important component in determining progression-free survival, the response rates with the addition of bevacizumab during chemotherapy were superior in both study arms. Until further evidence is available, including bevacizumab during and after chemotherapy is reasonable. It is unclear whether bevacizumab should be continued until progression or if 15 mg/kg is superior to 7.5 mg/kg. The recently completed GOG 0262 may help to answer whether maintaining bevacizumab until progression is beneficial.

Summary Recommendations for Advanced Disease

The initial management of advanced ovarian cancer should include surgical debulking for most patients, with the goal being removal of all gross disease. These recommendations also apply to serous carcinomas that arise from the fallopian tubes and peritoneum (primary peritoneal carcinoma). This surgery should be performed by a gynecologic oncologist or other surgeons skilled in both advanced pelvic surgery and upper abdominal surgery. In selected patients with diffuse carcinomatosis, advanced age, or medical comorbidities, initial treatment with chemotherapy followed by surgery if possible is an acceptable alternative. Initial chemotherapy should include carboplatin and a taxane given IV at 21-day intervals or as a dose-dense regimen with weekly taxane. Maintenance paclitaxel can be considered for 12 months after initial treatment. Strong consideration should be given for intraperitoneal chemotherapy for optimally debulked patients (≤1-cm residual nodules). The addition of bevacizumab during chemotherapy and as maintenance should be considered, especially for patients at high risk for recurrence (stage IV or >1-cm residual nodules).

Management of Women with Recurrent Epithelial Ovarian Cancer

The management of women with recurrent ovarian cancer should involve a strategy that emphasizes tumor control and effective palliation of the symptoms associated with recurrent disease. In general, most women with recurrent disease can be palliated for many months and often years through the sequential administration of a variety of antineoplastic agents. Women with recurrent or persistent disease can be divided into different categories related to the duration of response to a platinum-containing regimen and whether this represents a second or later recurrence. Patients who demonstrate progression of tumor while on platinum-based therapy are considered to have platinum-refractory disease. If tumor progression occurs during primary therapy, which is fortunately uncommon, this condition is often referred to as primary platinum refractory disease. This group of individuals fortunately represents at most 10% of the women with newly diagnosed epithelial carcinoma with this population of patients enriched for those with advanced-stage clear cell and mucinous carcinoma. It is also occasionally due to misdiagnosis, and physicians caring for such patients should consider a review of their pathology. There are no highly effective therapies in this population, although non–platinum-related agents (see later) may demonstrate modest responses in a subset of these patients. Although these women are logical candidates for recruitment into clinical studies, it is frequently the case that bowel dysfunction and declining performance status makes this impractical.

Women with evidence of tumor response followed by subsequent tumor progression within 6 months of completing platinum-containing therapy are considered to have platinum-resistant tumors. This is a relative term in that some patients with rising CA-125 occurring 6 months after platinum-based therapy will often respond well to retreatment with a platinum regimen, whereas those who have evidence of bulky recurrence weeks after completing platinum essentially never respond. Women with evidence of progressive disease more than 6 months after completing therapy are considered to have tumors that are potentially platinum sensitive. As with platinum-resistant tumors, the group of women with platinum sensitive disease have variable response rates to retreatment with platinum ranging from 30% for women with a median platinum-free interval of 6 to 12 months to >70% for women with a platinum-free interval of greater than 2 years.212–212 In addition, recurrent serous tumors and smaller tumors may demonstrate greater response to therapy at relapse compared with bulky tumors (>5 cm) or tumors of nonserous histology.²¹³

Women with platinum-refractory disease typically are symptomatic and require either prompt treatment with a nonplatinum agent or transition to best support care. For women with platinum-resistant or platinum-sensitive recurrent disease, the first question to be asked is whether the patients should have immediate therapy versus a course of careful observation until a time that tumor symptoms or bulk warrant therapy. In particular, the routine use of monitoring of patients with serial CA-125 values will often detect the recurrence of disease months to occasionally a year or more prior to the development of clinical symptoms.214–215 Furthermore, the increasing use of sophisticated imaging techniques including positron emission tomography–computed tomography (PET-CT) scans has successfully identified women with very early recurrences of disease.²¹⁶

Recently, Rustin and colleagues reported a study evaluating the role of CA-125 monitoring of patients in a first clinical remission after platinum-based therapy of advanced-stage ovarian cancer.²¹⁷ Patients had CA-125s evaluated every 3 months but half the patients (and their treating physicians) were blinded to those results and hence were not aware of a rising CA-125 (and by extension progression of subclinical recurrent disease). Women assigned to early treatment initiated treatment within 28 days of the time in which their CA-125 reached twice normal whereas those assigned to late treatment remained blinded to CA-125 and initiated therapy at clinical or symptomatic relapse. As anticipated, physicians and their patients acted on a rising CA-125 alone initiated therapy on average 4.8 months earlier than those blinded to the value. The patients and physicians randomly assigned to CA-125 disclosure received more chemotherapy but did not enjoy a longer survival (early treatment overall survival = 25.7 months vs. late treatment 27.1 months). The study has been criticized because of the limited use of paclitaxel and the failure to prescribe specific therapies in each arm at the time of relapse. Nevertheless, there is a lack of compelling data that early initiation of chemotherapy in asymptomatic patients with recurrent disease prolongs survival. Likewise, the early initiation of palliative chemotherapy in women with asymptomatic recurrent disease is unlikely to improve quality of life in the short term. Many investigators have concluded that careful observation is an appropriate strategy in asymptomatic patients with a rising CA-125.

In patients who will not accept observation, who have symptomatic disease, or who demonstrate significant tumor bulk that risks impending gastrointestinal, pulmonary, or urologic dysfunction, treatment is warranted. Figure 89-4 demonstrates a treatment approach supported by available, albeit somewhat limited, collection of randomized trials in this patient population.

Management of Platinum-Sensitive Recurrent Disease

Randomized studies looking at the value of treatment with platinum versus non–platinum-containing regimen demonstrates much improved responses and duration of response with a platinum-containing regimen.²¹⁸ In the study by Cantu, women with long platinum-free intervals were randomly assigned to single-agent paclitaxel versus cyclophosphamide, Adriamycin, and cisplatin. Despite the fact that the study randomly assigned less than 100 women, there was a statistically significant improvement in overall survival in women randomized to the platinum-containing regimen. Likewise, there are several randomized trials comparing platinum plus a second agent (either paclitaxel, epirubicin, PLD, or gemcitabine) versus single-agent platinum.^219–223 Only a few of the studies accrued large enough numbers of patients to have reasonable power to detect a modest difference in survival. The largest study, ICON 4, compared the use of either single-agent cisplatin or carboplatin versus the same drug with paclitaxel. This study, as well as the GEICO study, demonstrated superior outcomes with the paclitaxel regimen.^221–222 In ICON 4, the doublet had a superior response rate (66% compared with 54%; P = 0.06), progression-free survival at 1 year (50% compared with 40%; P = 0.001) and overall survival at 2 years (57% vs 50%; P = 0.023) compared with women assigned to single-agent cisplatin.²²¹ Likewise, similar results were seen in the randomized trial of carboplatin versus gemcitabine and carboplatin (Table 89-10).²²³ This modest-sized randomized trial of 356 patients with platinum-sensitive first recurrence of disease demonstrated that women treated with carboplatin (AUC 4) and gemcitabine (1000 mg/m² days 1 and 8) had a response rate of 47% compared with 31% in the women assigned to carboplatin dosed at an AUC = 5 (P = 0.0016). Progression-free survival likewise was superior in the doublet arm at 8.6 months compared with 5.8 months for the women on single-agent carboplatin (P = 0.0031).²²³ The study was not powered to detect a survival difference, and the overall survival in the two groups was not statistically different. Randomized trials have also explored a comparison of PLD alone with PLD and the novel marine product trabectedin. In a large trial that included women with platinum-sensitive and platinum-resistant disease, the group of women with platinum-sensitive disease had improved progression-free survival with the trabectedin containing doublet compared with PLD.^226–226 There was not a statistically significant improvement in survival. Because there was not a platinum-containing comparator arm, it is difficult to evaluate what precise role this combination might have in the management of recurrent and platinum-sensitive ovarian cancer.

Only a few randomized trials have been reported comparing platinum doublets (Table 89-11).^229–229 Of note, the recently published Calypso trial compared PLD with carboplatin to paclitaxel with platinum. In this study, neuropathy, alopecia, and allergy to platinum were more common in the paclitaxel-treated population whereas skin, mucosal, and hematologic toxicity was more common in the PLD-containing arm. Progression-free survival, but not overall survival, was slightly longer in the PLD-treated group. The remarkably lower rate of platinum allergy was also seen in the randomized trial of single carboplatin versus PLD with platinum.^220,230

A single randomized phase II of concurrent versus sequential therapy has also been reported. In the study reported by Secord and colleagues, patients were randomly assigned between docetaxel (days 1 and 8) and concurrent carboplatin versus docetaxel on days 1 and 8 of a 21-day cycle for six cycles followed by subsequent carboplatin as a single agent for six cycles. The sequential therapy demonstrated a 62% higher rate of tumor progression (hazard ratio [HR] 1.62, P = 0.02). Overall survival between the two groups appeared similar (33 months for concurrent therapy vs. 30 months for sequential therapy; not significant).²³¹

The addition of molecularly targeted agents to the treatment of women with recurrent and platinum-sensitive disease has been recently reported in the OCEANS (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease) study,²³² which evaluated the benefit of adding bevacizumab to carboplatin and gemcitabine in women with platinum-sensitive recurrent disease. In this moderate-size study of 484 patients, the non bevacizumab arm received a placebo to minimize bias and either placebo or bevacizumab was continued postchemotherapy in patients with a durable response. The objective response rate was 79% in bevacizumab arm and 57% in the placebo arm (P < 0.0001). Bevacizumab-based therapy also extended progression-free survival from 7.4 to 10.4 months (HR 0.534, 95% confidence interval [CI] 0.41 to 0.7). Although mature survival analysis for this randomized trial is still not available, to date the overall survival for the two groups is similar (median 35.2 months in the placebo arm and 33.3 months in the bevacizumab arm).

Recently, investigation in basic biological mechanisms of DNA repair have demonstrated that cells deficient in homologous recombination have defects in the repair of double-strand DNA breaks and are dependent on alternative mechanism of repair. In particular, alternative mechanisms of base excision repair require poly(ADP-ribose) polymerase (PARP) to locate at sites of DNA damage as an integral part of the DNA repair. Tumors deficient in BRCA1 or BRCA2 have defects in homologous recombination and thus are dependent on PARP and by extension are exquisitely sensitive to PARP inhibition.235–235

Several PARP inhibitors are currently in clinical trials, with the greatest experience currently reported with olaparib. Early phase I and II studies of this agent demonstrated activity in both platinum-sensitive and platinum-resistant disease.234,236 In addition, armed with the knowledge that a significant portion of women with high-grade serous cancer have defects in the homologous DNA end joining and rely on the base excision repair pathway, two groups have conducted randomized phase II studies evaluating the value of a PARP inhibitor as a maintenance strategy in women entering second partial or complete response after retreatment with platinum-based therapy in the setting of recurrent and potentially platinum-sensitive disease.²³⁷ The “study 19” trial evaluated olaparib versus placebo as maintenance therapy in women with high-grade serous carcinoma who had just successfully achieved at least a partial response to platinum-based therapy. Women assigned to olaparib had an 8.4-month progression-free survival compared with 4.8 months for women on placebo (HR 0.35, 95% CI, 0.25 to 0.49, P < 0.00001). Early survival data reveal no difference although the study was modest in size and these data are not mature.⁵¹ It is not yet known what portion of these patients had germline or somatic mutations in BRCA1 or BRCA2 and whether that subgroup experienced greater benefit than women without the BRCA mutation.

The second study had similar eligibility with a slightly different design: the PARP inhibitor was added to carboplatin and paclitaxel during treatment for women assigned to the active treatment arm. The women on the experimental treatment arm received carboplatin at an AUC of 4 compared with those on the control arm who received carboplatin at an AUC of 6. Women on the experimental treatment arm continued on single-agent olaparib as maintenance at the conclusion of their paclitaxel and carboplatin therapy if they had demonstrated a tumor response. Progression-free survival, the primary end point of the study, was prolonged on the olaparib arm at 12.2 versus 9.6 months for the control arm (HR 0.51, P = 0.0012). Survival data are not yet available.²³⁸ From these studies, it is clear that olaparib has activity in women in high-grade serous carcinoma. Much but not all of this activity is likely in the population with germline or somatic mutations in BRCA 1 or 2. Other individuals may also have a BRCA-deficient phenotype because of alteration in expression or structure of the many BRCA-related proteins. A cell’s ability to perform homologous repair of DNA damage has recently been referred to as BRCAness.^239,240 Determining predictive markers for BRCAness remains an area of intense research interest. Currently, there are no FDA-approved PARP inhibitors, and bevacizumab is not approved for the treatment of ovarian cancer at this time.

Treatment of Recurrent Platinum Resistant Epithelial Ovarian Cancer

Women who have clinical evidence of progressive ovarian cancer within 6 months of their last dose of platinum or platinum-based combination therapy are typically defined as having platinum-resistant disease and retreatment with platinum is expected to have a less than 10% chance of having a significant and clinically meaningful response. A variety of drugs with variable mechanisms of action have demonstrated activity in ovarian cancer, including taxanes (paclitaxel, docetaxel, nab-paclitaxel), topoisomerase 1 and 2 inhibitors (topotecan and liposomal doxorubicin and etoposide), epothilones (ixabepilone and ZK-EPO), alkylators (hexamethymelamine, ifosfamide), and antimetabolites (pemetrexed, gemcitabine) (see Table 89-6).^241–261

Typically, the management of women with recurrent disease includes the delivery of single agents in sequence. Essentially all the chemotherapeutic agents listed above have response rates in range of 10% to 20%, with time to progression typically 3 to 4 months. Because almost all these studies are single-arm studies, it is difficult to determine the relative activity for these agents.241–261 Randomized comparisons of one palliative strategy versus an alternative strategy are limited in platinum-resistant disease and are reviewed in Table 89-12. For example, a comparison of every-3-week paclitaxel to standard topotecan resulted in similar response rates and progression-free survival.²⁶² Likewise, randomized comparisons of topotecan to PLD demonstrated no significant differences in women with platinum-resistant disease.²⁶³ A similar study comparing gemcitabine with PLD demonstrated no significant difference in response rate or progression-free survival although there was a borderline improvement in overall survival favoring the PLD arm; however, it is notable that some of these patients would be classified as platinum-sensitive recurrent disease.²⁶⁴ In addition, schedules have also been evaluated such as day 1 through 5 topotecan versus weekly topotecan (5-day topotecan modestly superior)^265,266 or every 3-week paclitaxel versus weekly paclitaxel (equivalent).²⁶⁷

Studies of doublet versus single-agent chemotherapy demonstrated greater toxicity with doublets but no improvement in survival.225,226,268–270 For example, trabectedin and PLD versus PLD and, in a separate study, canfosfamide and liposomal doxorubicin versus liposomal doxorubicin, failed to demonstrate superior clinical outcome with the doublet.⁴⁹ Trials of topotecan either as a single agent or compared with combinations with either etoposide or gemcitabine demonstrated no additional benefit to addition of the second agent, and the doublets increased the risk of thrombocytopenia.

Biological or targeted therapies date back to tamoxifen therapy to target estrogen receptors, but in the last decade a collection of new targeted therapies have been explored,271–285 including EGFR inhibitors (gefitinib, erlotinib, trastuzumab, EMD7200, lapatinib), VEGF inhibitors (bevacizumab, pazopanib, cediranib), and a host of tyrosine kinase inhibitors (dasatinib, imatinib, sunitinib, sorafenib). A partial list of active agents are listed in Table 89-6. Although not yet FDA approved for the treatment of women with ovarian cancer, a large body of literature is accumulating on the efficacy of bevacizumab in platinum-resistant ovarian cancer.^275,286,287 Several studies have demonstrated that a large portion of ovarian tumors are rich in VEGF expression, and high levels of VEGF are typically found in the serum and especially in malignant ascites. In a study by Burger, single-agent bevacizumab demonstrated a response rate of 21% with a 6-month progression-free survival rate of 40%.²⁷⁵ Notable in this and other phase II studies was the dramatic resolution of ascites and/or pleural effusions within weeks of initiating therapy. Similar data have also been seen with aflibercept (a VEGF decoy receptor) and catumaxomab (a trifunctional antibody that binds T cells and EpCAM).^286,287 The drug has been well tolerated, with the principal toxicity being manageable hypertension, especially in women on prolonged therapy. More dire complications, such as bowel perforation, have been reported in as many as 10% of patients with bulky recurrent disease and/or evidence of partial bowel obstruction. Similar toxicities have been reported with aflibercept, strongly suggesting it is a class effect of VEGF inhibition.^286,288 Perforation rates are much lower in women with small-volume disease and on primary treatment.

There have been numerous studies evaluating the combination of bevacizumab with a variety of standard cytotoxic agents including platinum, paclitaxel, cyclophosphamide, topotecan, and liposomal doxorubicin.284,285 In a variety of phase II trials, the addition of bevacizumab has generated both significant response rates and progression-free survival that seemed to be superior to the single-agent drug. This led to the recently reported Aurelia study that compared bevacizumab and standard therapy with a variety of single agents in women with platinum-resistant ovarian cancer. In this trial, women with recurrent and platinum-resistant disease were randomly assigned to bevacizumab with chemotherapy or just chemotherapy. Physicians were allowed to select paclitaxel, liposomal doxorubicin, or topotecan as the palliative chemotherapy arm. In the randomized phase II study, the time to progression on the bevacizumab plus chemotherapy arm was 6.7 months as compared with 3.4 months (HR 0.48, P < 0.001).²⁸⁹ Overall survival data are not yet available. Perforation rates were 1.7% in the bevacizumab arm compared with 0% in the nonbevacizumab arm.

There is literature that reports retrospective experiences from high-volume surgical centers that demonstrate that patients who undergo aggressive surgical cytoreduction at the time of disease recurrence do better than those who do not have surgical procedures.292–292 In particular patients with platinum-sensitive disease with a limited number of discrete lesions who undergo successful complete surgical cytoreduction of tumor have a superior survival rate compared with those who have partial resections or, alternatively, are not offered surgical exploration. The major flaw in these studies is the significant risk of selection bias because often only the healthiest patients with modest burden of disease are offered surgery, and surgical resectability may be a predictive marker for more favorable biology or chemosensitivity. A randomized trial looking at the value of surgery and chemotherapy versus chemotherapy alone is currently open and accruing patients slowly. Until the time that we have better-quality data, it is appropriate to counsel patients on the uncertain benefits of surgical resection in this clinic setting.