Ovarian cancer, Part I: Biology.

The ovary is among the more complex organs of the body and its functions are achieved by numerous cell types. All of these cell types have some tendency to undergo malignant transformation, but the vast majority of ovarian cancers are believed to be the result of malignant transformation of the ovarian surface epithelium. The concept that most ovarian cancer arises from this modified peritoneal mesothelium is credited to Sir Spencer Wells in 1872. Ovarian cancer is the most frequently fatal gynecologic malignancy, and approximately 20,000 cases per year are diagnosed in the United States. Progress in understanding the biology of this disease, including factors involved in its etiology, progression, and tendency to change from a relatively chemotherapy-sensitive tumor to one with marked drug resistance, has been slow. In this review, the complex features of the normal ovarian surface epithelial cells are considered in relation to the etiology and progression of the disease. The hypothesis that incessant or repetitious ovulation contributes to the initiation of the disease is explored in detail based on experimental data, epidemiologic information, and the potential for antioncogene inactivation in this interesting cell type. Lastly, based on the experimental data available, potential mechanisms of resistance to platinum, the cornerstone of aggressive ovarian cancer therapy, are discussed, as are approaches to overcoming drug resistance. It is hoped that the reader will be left with the feeling that the pace of our understanding of the biology of ovarian cancer is increasing at such a rate that answers to the questions of etiology and why chemotherapy often fails will be known in the foreseeable future.     

Ovarian cancer, Part II: Treatment.

The death rate from epithelial ovarian cancer has only slightly decreased in the past decade. In contrast, there have been dramatic improvements in the treatment of germ cell tumors of the ovary and the majority of patients even with advanced disease is now cured because of the development of effective platinum-based combination chemotherapy. Unfortunately, most patients with ovarian cancer have the epithelial histologic type, and only one third of these patients can be cured with standard approaches. It has recently been shown that a subset of patients with early stage ovarian cancer has a greater than 90% cure rate without chemotherapy. Consequently, a major focus of current research is to develop effective screening modalities in order to diagnose epithelial tumors when they are still confined to the ovaries and pelvis. Currently, three fourths of patients are diagnosed at the time the disease has spread throughout the peritoneal cavity, and the standard approach has been cytoreductive surgery followed by combination chemotherapy. The two-drug combination of carboplatin plus cyclophosphamide has now become the treatment of choice, although it is equally effective as and less toxic than a regimen of cisplatin plus cyclophosphamide. In addition, Taxol has been identified as an extremely active agent against this disease, and new Taxol-containing combinations are under clinical investigation. Clinical trials are also in progress with hexamethylmelamine and ifosfamide combinations as well as with more dose-intense regimens based on considerable retrospective evidence that survival is correlated with the dose intensity of platinum compounds. New agents such as WR2721, IL-3, and IL-1 alpha are undergoing clinical evaluation to determine whether the toxicities of platinum compounds can be decreased and lead to further exploitation of the dose response relationship. After induction chemotherapy, approximately 50% of patients will be in a clinical complete remission. Unfortunately, 30% to 50% of these patients will have recurrent disease; clinical trials are currently in progress to determine whether any form of therapy following the initial induction regimen can prevent or delay recurrences. Based on laboratory investigations in relevant models of human ovarian cancer, clinical trials are also in progress with novel new agents that may be capable of reversing drug resistance to platinum compounds and alkylating agents. For patients with germ cell tumors of the ovary, platinum-based combination chemotherapy has produced the same dramatic effects as in testicular cancer. Clinical trials are now focused on retaining therapeutic efficacy but decreasing the toxicity of treatment in these tumors that frequently affect women in their reproductive ages.     

Ovarian cancer statistics, 2018

In 2018, there will be approximately 22,240 new cases of ovarian cancer diagnosed and 14,070 ovarian cancer deaths in the United States. Herein, the American Cancer Society provides an overview of ovarian cancer occurrence based on incidence data from nationwide population‐based cancer registries and mortality data from the National Center for Health Statistics. The status of early detection strategies is also reviewed. In the United States, the overall ovarian cancer incidence rate declined from 1985 (16.6 per 100,000) to 2014 (11.8 per 100,000) by 29% and the mortality rate declined between 1976 (10.0 per 100,000) and 2015 (6.7 per 100,000) by 33%. Ovarian cancer encompasses a heterogenous group of malignancies that vary in etiology, molecular biology, and numerous other characteristics. Ninety percent of ovarian cancers are epithelial, the most common being serous carcinoma, for which incidence is highest in non‐Hispanic whites (NHWs) (5.2 per 100,000) and lowest in non‐Hispanic blacks (NHBs) and Asians/Pacific Islanders (APIs) (3.4 per 100,000). Notably, however, APIs have the highest incidence of endometrioid and clear cell carcinomas, which occur at younger ages and help explain comparable epithelial cancer incidence for APIs and NHWs younger than 55 years. Most serous carcinomas are diagnosed at stage III (51%) or IV (29%), for which the 5‐year cause‐specific survival for patients diagnosed during 2007 through 2013 was 42% and 26%, respectively. For all stages of epithelial cancer combined, 5‐year survival is highest in APIs (57%) and lowest in NHBs (35%), who have the lowest survival for almost every stage of diagnosis across cancer subtypes. Moreover, survival has plateaued in NHBs for decades despite increasing in NHWs, from 40% for cases diagnosed during 1992 through 1994 to 47% during 2007 through 2013. Progress in reducing ovarian cancer incidence and mortality can be accelerated by reducing racial disparities and furthering knowledge of etiology and tumorigenesis to facilitate strategies for prevention and early detection. CA Cancer J Clin 2018;68:284–296 . © 2018 American Cancer Society .     

Ovarian cancer, Part II

Early diagnosis is the most effective means of reducing the currently high mortality rate associated with ovarian cancer. The palpation of what appears to be a normal size ovary in a premenopausal woman suggests an ovarian tumor in a postmenopausal woman. Also, rule out ovarian cancer in any 40-year or older woman who presents with persistent, unexplained gastrointestinal symptoms. Ninety percent of all ovarian tumors are of epithelial origin. Treatment consists of total hysterectomy, bilateral salpingo-oophorectomy, omentectomy and appendectomy. P32 instillation is optional. In Stages IIb, III and IV chemotherapy is advised, while in Stages I and IIa the use of prophylactic chemotherapy must be judged on an individual basis. Ovarian cancer in children that is beyond the localized stage is one of the most frustrating of all gynecologic diseases. Total surgical extirpation of localized disease is the only hope for cure and, as yet, early diagnosis is more chance than scientific method.     

Ovarian cancer: epidemiology, biology, and prognostic factors

Ovarian cancer varies widely in frequency among different geographic regions and ethnic groups, with a high incidence in Northern Europe and the United States, and a low incidence in Japan. The majority of cases are sporadic, and only 5% to 10% of ovarian cancers are familial. The etiology of ovarian cancer is poorly understood. Models of ovarian carcinogenesis include the theory of incessant ovulation, in which a person's age at ovulation, i.e., lifetime number of ovulatory cycles, is an index of her ovarian cancer risk. Excessive gonadotropin and androgen stimulation of the ovary have been postulated as contributing factors. Exposure of the ovaries to pelvic contaminants and carcinogens may play a role in the pathogenesis of ovarian cancer. Epidemiologic and molecular-genetic studies identify numerous risk and protective factors. The most significant risk factor is a family history of the disease. Recent advances in molecular genetics have found mutations in the BRCA1 and BRCA2 tumor suppressor genes responsible for the majority of hereditary ovarian cancer. Additional risk factors include nulliparity and refractory infertility. Protective factors include multiparity, oral contraceptives, and tubal ligation or hysterectomy. With five years of oral contraceptive use, women can cut their risk of ovarian cancer approximately in half; this also holds true for individuals with a family history. Stage at diagnosis, maximum residual disease following cytoreductive surgery, and performance status are the three major prognostic factors. Using a multimodality approach to treatment, including aggressive cytoreductive surgery and combination chemotherapy, five-year survival rates are as follows: Stage I (93%), Stage II (70%), Stage III (37%), and Stage IV (25%).     

Ovarian cancer: markers, hormones receptors, immunological status

Like other solid tumors ovarian tumors have been intensely investigated these past years to isolate specific tumoral antigens. These antigens are now used by clinical teams for post therapeutic follow-up. However, out of the 25 major antigens actually described in ovarian carcinomas, the only one that can be used today is the carcinoembryonic antigen (CEA). Moreover, an international collaborative work has demonstrated cross reacting antigenicity between these major tumoral antigens. Cellular enzymes (galactosyl transferase and sialyl-transferase) and hormonal receptors for proteinic hormones such as steroid hormones) are being studied but cannot be used as screening markers at this time.     

Epigenetic status of FBXW7 gene and its role in Ovarian cancer pathogenesis

Background: Chromatin immunoprecipitation (ChIP) analysis revealed that the FBXW7 gene and the long non-coding RNA (LINC01588) are potential candidates in epithelial ovarian cancer (EOC) pathogenesis. However, their exact role in EOC is not yet known. Thus, the present study sheds light on the impact of the mutations/ methylation status of the FBXW7 gene. Materials and Methods: We used public databases to assess the correlation between mutations/ methylation status and the FBXW7 expression. Furthermore, we performed Pearson’s correlation analysis between the FBXW7 gene and LINC01588. We performed gene panel exome sequencing and Methylation-specific PCR (MSP) in HOSE 6-3, MCAS, OVSAHO, and eight EOC patients’ samples to validate the bioinformatics results. Results: The FBXW7 gene was less expressed in EOC, particularly in stages III and IV, compared to healthy tissues. Furthermore, bioinformatics analysis, gene panel exome sequencing, and MSP revealed that the FBXW7 gene is neither mutated nor methylated in EOC cell lines and tissues, suggesting alternative mechanisms for FBXW7 gene regulation. Interestingly, Pearson’s correlation analysis showed an inverse, significant correlation between the FBXW7 gene and LINC01588  expression, suggesting a potential regulatory role of LINC01588. Conclusion: Neither mutations nor methylation is the causative mechanism for the FBXW7 downregulation in EOC, suggesting alternative means involving the lncRNA LINC01588.     

Ovarian cancer: what's new, where next?

In the last few years a number of important studies relating to the investigation and management of ovarian cancer have firmly established a pivotal role in management for CT. CT provides accurate staging information, identifying key sites of disease which influence the success of cytoreductive surgery. CT facilitates histological diagnosis from needle core biopsy when surgery is considered inappropriate. These studies have provided a strong evidence base for current practice but we are left with some uncertainties.     

Ovarian cancer

Even though cisplatin-based combination chemotherapy results in increased clinical and surgical complete remission rates and improved median survival compared with single-agent alkylating agent chemotherapy, the 5 year survival rates for stages III and IV ovarian cancer have only improved to 25-30%. New methods being evaluated to improve response rates, median survival, and 5 year survival rates include the use of high-dose carboplatin, dose intensity using platinum compounds, intraperitoneal chemotherapy, concomitant intravenous and intraperitoneal chemotherapy, and the recent discovery of new active agents against epithelial ovarian cancer--Taxol, and Ifosfamide plus mesna.     

Ovarian cancer

Ovarian cancer remains the most lethal gynecologic malignancy in women in the United States. Studies from this year's American Society of Clinical Oncology more clearly defined the role of chemotherapy in women with early stage disease and now suggest that essentially all women with invasive disease should receive chemotherapy that contains carboplatin. Studies in women with advanced disease continue to support the use of carboplatin and paclitaxel in the treatment of women with newly diagnosed disease although early data suggest that carboplatin and docetaxel might be an acceptable alternative. Platinum-resistant disease remains a therapeutic challenge. Small molecules that inhibit the function of the epidermal growth factor receptor, such as OSI-774, and novel classes of chemotherapeutic agents, including the acylfulvene MGI-114 and epothilone B and its analogue, BMS247550, all warrant further study in this disease.     

Ovarian cancer

Although surgery followed by paclitaxel/carboplatin (TJ) therapy is a standard modality for the initial treatment of ovarian cancer, 60% or more of the patients require second-line therapy. Recent studies assessed the intensification of primary chemotherapies such as 3-drug combination and/or sequential doublets, and maintenance. Moreover, the clinical studies of NAC followed by interval debulking surgery as a new treatment method are on-going. When patients are classified as having sensitive recurrent or resistant recurrent tumors, repeated chemotherapy, mainly with TJ therapy in combination with platinum therapy, is recommended for sensitive recurrent tumors. Because a response rate of 60% or more and survival for 20 months or more can be expected, therapy that actively aims at prolongation of survival is recommended for sensitive recurrent tumors. On the other hand, some drug that has no cross resistance with TJ therapy should be selected for resistant tumors. However, the response rate is only about 12-32%, and the survival duration is about 8 months. It is difficult to obtain a complete cure for such patients, and every attending physician is therefore required to be familiar with chemotherapy and palliative medicine.     

Ovarian cancer

Age-adjusted ovarian cancer deaths and mortality rates have increased annually in Japan from 1968 to 1995, with the absolute number of deaths increasing 4-fold during these years. Internationally, the mortality rates are high in North America or northern Europe, but their incidences have gradually decreased. However, the incidences of ovarian cancer have increased in France, Spain, and Japan. Risk factors for epithelial ovarian cancer include older age, being northern European or North American, family history of ovarian cancer, nulliparity, infertility, and obesity, and preventive factors include oral contraceptive use, gravidity, lactation, tubal ligation, and hysterectomy.     

Ovarian cancer

A comprehensive research effort has been focused on ovarian cancer during the past decade and this research focus has resulted in substantial improvements in accurate staging and effective treatment. On the basis of prospectively performed clinical trials in well-staged early ovarian cancer patients, a subset can be identified in whom no further therapy is necessary. Consequently, these patients can be spared the toxicities associated with long-term use of adjuvant chemotherapy. For patients with advanced disease, cisplatin-based combination chemotherapy regimens have produced higher complete response rates, prolongation of disease-free survival, and, in several large studies, a statistically significant prolongation of overall survival. In addition, recent clinical and laboratory data has confirmed the importance of dose and dose intensity in the optimum management of patients with ovarian cancer, and preliminary results of high-dose regimens are encouraging. Unfortunately, high-dose cisplatin-based chemotherapy regimens are associated with increased toxicity. However, pharmacologic techniques to decrease toxicity have been proven effective in murine models and clinical trials in patients have recently been initiated. Furthermore, the development of new cisplatin analogs may also permit further dose escalations with decreased long-term toxicities. There are also new promising clinical approaches that may be useful in treatment of patients who are left with small volume residual disease. It seems that approximately 30% of these patients can achieve disease-free status with intraperitoneal cisplatin therapy. While these results need to be confirmed in larger prospective trials, they do suggest that some patients with residual disease can be salvaged with intraperitoneal chemotherapy. Our understanding of the biology of ovarian cancer has been greatly facilitated by the development of relevant experimental model systems. These model systems have been used to help unravel the mechanisms associated with broad cross-resistance that currently limits the effectiveness of combination chemotherapy. In addition, pharmacologic techniques have already been shown to be capable of reversing resistance both in vitro and in vivo and these exciting new approaches will be entering clinical trial in the not too distant future. Finally, biological agents have also shown marked efficacy in these model systems of human ovarian cancer.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ovarian cancer

The current standard treatment for advanced ovarian cancer is primary debulking surgery (PDS) followed by postsurgical chemotherapy. We can expect a better prognosis in cases of optimal debulking (residual disease<1 cm). Unfortunately, optimal debulking in the PDS can be achieved in only about 40% of stage III/IV ovarian cancers as a rule. Neoadjuvant chemotherapy (NAC) has been recognized as an alternative treatment to primary surgical debulking for patients with apparently unresectable bulky tumors or poor performance status. Retrospective analyses revealed that overall survival was comparable between patients treated with NAC followed by interval debulking surgery (IDS) and those treated with PDS, though the former group had more advanced disease and poorer performance status.Based on these favorable results of NAC for patients with advanced disease or poor performance status, the target disease was extended to all cases of advanced disease, including patients without apparently unresectable tumors and good performance status in prospective studies. The European Organization for Research and Treatment of Cancer (EORTC) and The Japan Clinical Oncology Group (JCOG) is now conducting a phase III study comparing neoadjuvant setting treatment with standard treatment for advanced mullerian cancer, such as ovarian, tubal or peritoneal cancer. These prospective studies are expected to reveal the role of NAC for advanced müllerian cancer.     

Ovarian cancer

Early diagnosis is the most effective means of reducing the currently high mortality rate associated with ovarian cancer. The palpation of what appears to be a normal size ovary in a premenopausal woman suggests an ovarian tumor in a postmenopausal woman. Ovarian cancer should be ruled out in any woman 40 years of age or older who has persistent, unexplained GI symptoms. Ninety percent of all ovarian tumors are of epithelial origin. Treatment consists of total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and appendectomy. Instillation of P32 is optional. In stages IIb, III, and IV tumors, chemotherapy is advised; in stages I and IIa, the use of prophylactic chemotherapy must be judged on an individual basis. In children, ovarian cancer that is beyond the localized stage is one of the most frustrating of all gynecologic diseases. Total surgical extirpation of disease is the only hope for cure; for now, early diagnosis is more chance than scientific method. Thanks to better public and professional education, ovarian cancer is now being diagnosed at an earlier stage. The earlier the diagnosis, the greater the chance for cure. It is becoming obvious that ovarian cancer is a disease of the GI tract, and physicians treating ovarian cancer should be prepared to deal with bowel-associated problems. The practice of tapping women with ascites for diagnosis as well as doing an exploration merely to obtain a biopsy should be discouraged. Unless the physician is prepared to carry out the optimal surgical approach for the patient, it is crucial that the patient be referred to either a center or to a physician who is actively engaged in the day-to-day care of cancer patients. With the combined use of all the available treatment methods, patients with ovarian cancer are now living longer and more comfortably. There is also indication that their long-term survival will be increased. The one message that is important for both patients and physicians is that the gloom and doom of the 1960s and 1970s can now be replaced by a spirit of optimism.