1. GENERAL INFORMATION
1.1.1 Incidence and mortality
Ovarian cancer is the sixth most common cancer in European women (5% of all cancers) (Ferlay 1999). In Europe, estimates suggest that about 61,000 new cases are diagnosed and 39,000 deathsform ovarian cancer occur annually [GLOBCAN]. The age-adjusted incidence (World) is around 11 per 100, 000 [GLOBCAN]. The highest rates are reported in the Northern and Western Europe and North America. Low rates are found in Africa and Asia (Figure 1).
The risk of epithelial ovarian tumours increases with age, the majority of cases occurring predominately in peri- and postmenopausal women. Tumours of germinal or embryonic origin are more frequent in young adults (Figure 2) .
Overall mortality increased for many years, but then stabilised in the late 1980’s. The earlier reported increases may be artefactual due to improved death certification, but could also reflect a true increase in risk that was associated with a decline in parity. In England and Wales mortality in women under 45 was falling by more than 4% a year in the late 1980s, and mortality has been falling for successive generations born after 1930 (Coleman 1999). This decline has not been considered attributable to treatment or to prior oophorectomy for benign disease (Villard-Mackintosh 1989). In Italy, during the period 1986-1997, overall incidence and mortality rates were mostly stable. An increase in incidence did occur in the oldest age group > 65 years, whereas the incidence was stable at younger ages (Zambon 2004).
Figure 1. Age-standardised incidence rates in the world(2000)
Figure 2. Incidence rate by age for ovarian cancer(Europe, 2000)
For ovarian cancer, survival is generally low. Relative survival in Europe was 66%, 45% and 37% at one, three and five years after diagnosis, respectively (Berrino 2003). Five-year survival decreased markedly with age from 70% in the youngest (40%) was found in Iceland and Sweden, Spain, Germany and Austria (Sant 2003).
During the period 1983-94, 5-year survival increased slightly by 4%. The increase in survival may be related to the adoption of cisplatinum-containing chemotherapy regimens, which occurred at different times in different parts of Europe. Stage at diagnosis remains the main prognostic factor for ovarian cancer, and the modest increase in survival with time that has been seen is probably due largely to earlier diagnosis (Sant 2003).
Five-year survival was excellent for gonadal germ-cell tumours in girls (92%) and adolescent and young adults (90%) ( Gatta 2003). The survival data reported in this document are derived from information collected by population-based cancer registries. They provide the means by which we can measure progress against cancer (Micheli 1997).
1.2 Aetiology and risk factors
The molecular events responsible for initiation and promotion that initiate and promote the carcinogenic processof carcinogenesis in the ovarian cancer, that arises from the celomic epithelium covering the ovarian surface, are still unknown. Despite medical and surgical improvements, long-term survival rates for patients with advanced disease remain disappointing, due primarily to our inability to detect early-stage tumours. A careful understanding of risk factors for epithelial ovarian cancer may allow forfacilitate primary prevention, screening and early detection. Epidemiological factors associated with epithelial ovarian cancer include:
- AGE: epithelial ovarian cancer is a disease of older age. Incidence rates increase with each decade of life and peak in the middle to late seventies, on a type C basis. With the exception of the hereditary forms of the disease, ovarian cancer is uncommon before the age of 40 years (Yancik 1986).
- GENETIC FEATURES: approximately 5 to 10% of all epithelial ovarian cancers result from a hereditary predisposition and three distinct patterns have been identified, on a type C basis (Lynch 1993):
a) Site-specific ovarian cancer syndrome (10-15 % of all cases). The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter or sister) with the disease. Data derived from a meta-analysis of 15 observational studies (Stratton 1998) showed that women with one affected first-degree relative had a 4 to 7% lifetime chance of developing epithelial ovarian cancer by age 70 with a relative risk of 3.1 (CI 95% 2.6-3.7) on a type 3 level of evidence. The highest risk appears in women with two or more first-degree relatives with ovarian cancer, who presenthave a 7 to 15% lifetime chance of developing disease by age 70 (4-7) on a type 3 level of evidence. The risk is somewhat less for women with one first-degree and one second-degree relative (grandmother or aunt) with ovarian cancer. In most families affected, genetic linkage to BRCA 1 mutations has been found to the BRCA1 mutations ( Steichen-Gersdorf 1994).
b) Breast-ovarian cancer syndrome. Ovarian cancer in these families is characterized by multiple cases (two or more) of ovarian and breast cancer in successive generations, an earlier age of onset (usually in the premenopausal age) and evidence of both maternal and paternal transmission, on a type C basis (Easton 1993). This hereditary syndrome has been linked to the BRCA1 gene at chromosome 17q12-21 (81% of cases) and, less frequently, to the BRCA2 gene at chromosome 13q. The pattern of transmission, autosomal dominant with variable penetrance, implies that a single mutant allele is sufficient to promote breast or ovarian cancer and each child has a 50% chance of inheriting a mutant allele. The lifetime risk of breast and ovarian cancer in these families is estimated to be respectively 35 to 85% (82% by age 70 years and 50% by age 50 years) for breast cancer and 15 to 60% (Couch 1997; Whittemore 1997) for ovarian cancer, on a type 3 level of evidence. This variability is due to the wide variation (16-63%) in likelihood that these gene mutations may result in either of these cancers. Some mutations may be more specifically related to ovarian cancer risk than others. Similarly, it is possible that there is an interaction betweenwith genetic and environmental factors (high parity, pregnancy, proto-oncogene HRAS1 polymorphism, gene mutations of the androgen receptor), resulting in an increased risk for ovarian cancer in women with BRCA1/BRCA2 mutations, on a type 3 level of evidence (Narod 1995; Johannsson 1998;Phelan 1996; Levine 2001).
c) Hereditary nonpolyposis colorectal cancer (HNPCC) syndrome or Lynch syndrome II. In HNPCC the increased risk for ovarian cancer is associated with an excess of colorectal and endometrial cancers (three or more first-degree relatives affected with early age of onset) (Lynch 1998). The HNPCC syndrome arises from an inherited defect in any one of four known DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2). Data from several studies have suggested that the cumulative risk for ovarian and colorectal cancer was 12% and approximately 80% respectively, on a type 3 level of evidence (Wheeler 2000; Aarnio 1999).
Prophylactic oophorectomy. Individuals with a family history suggestive of an inherited malignancy syndrome should be offered a formal genetic counselling and testing. The potential benefits of genetic testing for the BRCA mutations include the identification of women at increased risk of development of breast or ovarian cancer, to allow maximization of the surveillance measures for early detection of disease, the possibility of offering surgical prophylaxis, the introduction of pharmacological and lifestyle interventions, on a type C basis. However, genetic testing may be associated with psychological and social adverse effects: genetic counsellors must be trained to provide psychosocial assessment and support. At present, prophylactic oophorectomy is recommended by the National Institute of Health (NIH) for women aged 35 or older who have a clear increased risk, providing childbearing is complete, on a type 3 level of evidence ( NIH 1995). In 1997, the Cancer Genetics Studies Consortium, considering the observational data available, concluded that there is insufficient evidence to make recommendations either in favour of or for or against prophylactic oophorectomy as a measure for reducing ovarian cancer risk. Women with BRCA1/BRCA2 mutations should be counselled that this is a possible therapeutic option for them on a type 3 level of evidence (Burke 1997). However,Actually the benefit of this procedure has not yet well established. Numerous reports hadve described the occurrence of primary peritoneal cancer, similar in appearance to ovarian cancer, in 1.8 to 10.7% of the patients who had undergone prophylactic oophorectomy (Tobacman 1982; Piver 1993; Struewing 1995). The first prospective study evaluating the role of bilateral prophylactic oophorectomy in 170 women aged 35 years or older with BRCA mutation was published by Kauff et al ( Kauff 2002). These women underwent either a surgical procedure (98 patients) or surveillance (72 patients), consisting in biannual gynaecologic examination, transvaginal ultrasound evaluation and serum CA125 assay. With thea mean follow up of 24.2 months, in the oophorectomy group one primary peritoneal cancer and three breast cancers were detected, one primary peritoneal cancer and three breast cancers while in the surveillance group were found four ovarian cancers, one primary peritoneal cancer and eight breast cancers were found. Bilateral prophylactic oophorectomy seems to reduce the risk of development of breast or ovarian cancer byof 75% (CI 95% 0.08-0.74), on a type 2 level of evidence. These results were supported by a large retrospective case-control study of 551 women with BRCA mutations performed by Rebbeck et al (Rebbeck 2002). Among the 259 women who had previously undergone to oophorectomy, six women were diagnosed with stage I ovarian cancer at the time of surgery and two women (0.2%) developed primary peritoneal cancer after oophorectomy. In the control group, 58 cases (19.9%) of ovarian cancer were observed. The risk reduction associated with prophylactic surgery for celomic epithelial cancer resultedwas therefore of 96% (CI 95% 0.01-0.16), on a type 3 level of evidence. Thus, bilateral prophylactic oophorectomy may provide benefit for patients at high-risk of ovarian cancer. However, this procedure is not completely protective against peritoneal cancer. Considering the relative high incidence of occult ovarian cancer at the time of surgery (2.5% of the combined surgical groups), a thorough exploration of the abdominal cavity and a frozen section pathologic analysis of the ovaries is warranted in these patients. Finally, it seems prudent also to remove also the fallopian tube at the time of bilateral oophorectomy, because of increased risk of fallopian tube cancers in these patients. Patients with HNPCC syndrome should receive a genetic counselling and should be offered a prophylactic surgery (hysterectomy and bilateral salpingo-oophorectomy) to reduce the risk of gynaecologic malignancies ( Smith 2002).
- HORMONAL FEATURES: The use of exogenous hormones for menopause-related symptoms could be associated with and increased risk of ovarian cancer incidence or mortality. Recent studies showed that prolonged periods of hormone replacement therapy (HRT) use (>=5-10 years) confer an approximately 1.5 to 2.0-fold increase in risk. The risk was elevated specifically among those women who used oestrogen unopposed by progesterone. However the Women’s Health Initiative randomised trial showed that women assigned to combined oestrogen plus progesterone HRT also experienced a higher risk (1.58) of ovarian cancer in comparison with women receiving placebo (Lukanova 2005). Several studies have shown a significantly increased prevalence of a history of infertility among patients diagnosed with ovarian cancer, on a type C basis. Most studies show no increase in the risk of invasive ovarian cancer in infertile women, but ovarian tumours of borderline malignancy are more common. In a pooled analysis of eight case-controlled studies in North America, Australia and Europe found no correlation between fertility drug use and overall risk of invasive ovarian cancer, on a type 3 level of evidence ( Ness 2002). On the other hand, in a collaborative case-control study of 2200 women (Whittemore 1992), the risk of invasive cancers associated with fertility drugs use is tripled (odds ratio= 2.8 CI 95% 1.3-6.1), in particularly there iswas a strong relationship with null igravidity (odds ratio= 27), on a type 3 level of evidence. Decreased risk of ovarian cancer follows the use of oral contraceptives (OC). Five year or more of OC use confers a 30% to 50% reduction in cancer risk (Lukanova 2005). Lactation is associated with a reduced risk: risk decreased with increasing duration of breast feeding (Lukanova 2005). The risk is possibly increased in women with polycystic ovary syndrome and endometriosis. Excess body weight possibly confers a moderate increase of risk (on average between 20% and 40%). Few studies indicated that elevated body mass index during adolescence or early adulthood may increase the risk, while in the premenopausal years it specifically increased the risk of ovarian cancer (Lukanova 2005).
- ENVIRONMENTAL FEATURES: significant geographic and ethnic variations in ovarian cancer incidence have been observed. Rates are highest for Caucasian women in the industrialized countries of North America and Europe. This difference may be partially explained by differences in reproductive patterns or an environmental component, such as diet. In support toof this hypothesis is the observation that when women migrate from countries with a low incidence of ovarian cancer to one with a high incidence, the risk of their descendants becomes that of native women, on a type C basis. Data on the relationship between dietary factors and ovarian cancer are sparse and often contradictory. A recent review (Shulz 2004) on diet and ovarian cancer found that a Western diet, which is high in meats and low in vegetables, may be positively associated with ovarian cancer incidence. Vegetable, but not fruit, consumption may be associated with beneficial effects while high meat consumption may be associated with increased risk. A protective effect rfor whole-grain food consumption as well as for consumption of low-fat milk is suggested by the results of some studies. Goodman et al. (Goodman 2002) found that women who consume higher quantities of low-fat milk, calcium or lactose were at significantly decreased risk of epithelial cancer. Exposure to talc or asbestos may represent environmental factors that could initiate or promote ovarian carcinogenesis, inducing a chronic inflammation of ovarian epithelium. Inflammation produces toxic oxidants that can cause direct damage to DNA and also leads to increased proliferation rates, which enhance the risk of mutagenesis. A pooled analysis of six studies showed an increased risk of ovarian cancer after perineal exposure to talc (odds ratio= 1.3 CI 95% 1.1-1.6) (Harlow 1992), but this evidence needs further confirmations, on a type 3 level of evidence. Several recent studies have shown increased risk of ovarian cancer with tobacco smoking overall and specifically for mucinous tumours (Terry 2003; Green 2001).
1.3 Early diagnosis
The key factor for improved outcome for ovarian cancer patients is detection of the tumour at an early stage with an effective screening programme in the general population. Over the past decade, numerous large, prospective studies using ultrasound (van Nagell 1995; De Priest 1997; Sato 2000;Hayashi 1999; Tabor 1994) or CA125 as the primary test (Jacobs 1996; Grover 1995; Adonakis 1996) have been carried out in the general population with interesting results regarding the performance of the screening tests, on a type 3 level of evidence. Due to the relatively non-invasive nature of blood sampling, the CA125 assay has been used as a first-line screening. CA125 levels were elevated in 23 to 50% of surgical stage I and in 90% of stage II ovarian carcinomas ( Zurawski 1988). However, a large range of gynaecological and non-gynecological diseases are also known to elevate CA125 levels. Clearly, additional or complementary tests are needed to make CA125 a useful component of a screening programme. Encouraging results were presented by Jacobs et al. (Jacobs 1999) from a controlled trial in which 22000 postmenopausal women were randomised to have three annual CA125 screens or no screens. Patients with abnormal CA125 levels (> 30 U/ml) underwent transvaginal ultrasound. Of 29 women referred for surgical investigation, 6 had an ovarian cancer (3 cases at stage I), yielding a positive predictive value of 20.7%. Another 10 screened women developed an ovarian cancer during the follow up. Twenty women developed an ovarian cancer in the control group. The median survival time was 72.9 months in the screened group and 41.8 months in the control group (p= 0.0112). Although this pilot study did not have the power to show an overall mortality reduction, it was the first randomised study showing a significant survival difference, on a type 2 level of evidence. Based on this promising results, two large randomised studies are currently ongoing. The National Institutes of Health Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial randomly assigned 75000 women ages 55 to 74 years between 1992 and 2001 to either screening (annual pelvic examination, transvaginal ultrasound and CA125 assay) or to no screening. The United Kingdom Trial of Ovarian Cancer Screening, started in 2001, will randomly assign 200000 postmenopausal women to one of the following arm: transvaginal ultrasound, multimodality screening and control group. These studies should give a definitive answer concerning ovarian cancer mortality reduction in screened population. Ovarian cancer screening has not yet been proven to reduce mortality in the general population and is not currently recommended, on a type C basis. Statistically, the low prevalence of ovarian cancer in the general population (0.04%) makes effective screening nearly impossible. Currently, the best strategy for screening is to identify individuals at increased risk. Two observational studies of ovarian cancer surveillance for patients with BRCA mutations have been reported. In the Gilda Radner Ovarian Cancer Detection Program, started in 1991, women with a positive familial history (one first-degree relative with ovarian, breast or colorectal cancer) underwent biannual transvaginal ultrasound and CA125 assay until 1995, when the protocol was amended to annual screening. Preliminary results, based on 1261 participants, showed an ovarian cancer incidence of 0.81% with 3 stage I ovarian carcinomas and 7 advanced primary peritoneal cancers detected ( Karlan 1999). Recently, Scheuer et al. published the outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers (Scheuer 2002). Ovarian cancer screening included six-monthly or annual gynaecological examination, six-monthly transvaginal ultrasound and CA125 determination. At a mean follow up of 17 months, 4 out of 89 women screened had been diagnosed with early stage ovarian cancer (stage I and II) and 1 with primary peritoneal carcinoma. Based on this evidence, some medical societies (Zoorob 2001) recommended surveillance for women with a hereditary ovarian cancer syndrome with transvaginal ultrasound and serum CA125 determination performed yearly, on a type C basis (NIH 1995; Burke 1997; Eisinger 1998). However, abnormal ultrasound and serum CA125 measurement often lead to unnecessary procedures, such as surgical laparoscopy or salpingo-oophorectomy. A recent study of proteomic serum analysis has focused current interest on this as a potentially useful approach ( Petricoin 2002). Nowadays, there is no evidence that screening reduces mortality, but several large randomised controlled trials are in progress.
1.3.2 Clinical diagnosis
Ovarian carcinoma does not produce specific symptoms, on a type C basis. In early stage disease, the patient may complain of urinary frequency or constipation as a consequence of tumour growth and occasionally lower abdominal distension, pressure and pain. Ovarian carcinoma may also present as a surgical emergency secondary to torsion or rupture of the ovarian mass. In advanced disease, patients most often present with symptoms related to the ascites, omental or bowel involvement, including abdominal distension, bloating, constipation, nausea, anorexia or early satiety. The most important sign is the presence of a pelvic mass on rectovaginal examination. A solid, irregular, fixed pelvic mass is highly suggestive of an ovarian malignancy. The diagnosis of a pelvic mass ultimately requires an exploratory laparotomy. The preoperative evaluation should include haematological and biochemical assessments, chest X-ray, transvaginal ultrasound and serum CA125 assay. Patients with ascites and no pelvic mass should have an abdominal and pelvic CT or MRI scan to exclude liver or pancreatic tumours. Colonoscopy and upper gastrointestinal radiological studies are indicated if a patient complains of severe anaemia and weight loss or when there is clinical evidence of bowel obstruction.
1.4 Selected reviews
- Cannistra SA. Cancer of the ovary. N Engl J Med 2004; 351(24): 2519-2529.
- Gonzales-Martin AJ. Medical treatment of epithelial ovarian cancer. Expert Rev Anticancer Ther 2004; 4(6): 1125-1143.a
2. PATHOLOGY AND BIOLOGY
2.1 Biological data
Approximately 90% of ovarian cancers are derived from the coelomic epithelium that normally covers the ovarian surface. This surface lining is multipotential and can differentiate into mullerian and other types of epithelium, including endometrial, endocervical, tubal and intestinal types, which may help explain the wide variety of epithelial tumours observed. Therefore, surface epithelial tumours are classified according to cell type and are stratified as benign, borderline and malignant based on cellular proliferation, nuclear atypia and stromal invasion. This classification is obviously crucial to plan the best therapeutic strategy and to define the prognosis of disease.
2.2 ICD-O Types
The following is a list of ovarian epithelial cancer histological classification:
- Serous benign cystadenomas [8441/0]
- Serous cystadenomas with low potential or borderline malignancy [8442/1]
- Serous cystadenocarcinomas [8441/3]Mucinous tumours (endocervical-like and intestinal types)
- Mucinous benign cystadenomas [8470/0]
- Mucinous cystadenomas with low potential or borderline malignancy [8472/1]
- Mucinous cystadenocarcinomas [8470/3]Endometrioid tumours (similar to adenocarcinomas in the endometrium)
- Endometrioid benign cysts [8380/0]
- Endometrioid tumours with low potential or borderline malignancy [8380/1]
- Endometrioid adenocarcinomas [8380/3]Clear cell (mesonephroid) tumours
- Benign clear cell tumours [8005/0]
- Clear cell tumours with low potential or borderline malignancy
- Clear cell cystadenocarcinomasTransitional cell (Brenner) tumours
- Brenner tumours benign [9000/0] or malign [9000/3]
- Brenner tumours with low potential or borderline malignancy [9000/1]
- Transitional cell carcinomas [8120/3]Mixed epithelial tumours
- Benign tumours [8010/0]
- Tumours with low potential or borderline malignancy
- Malignant tumours [8010/3]Undifferentiated carcinomas
Unclassified and miscellaneous epithelial tumours (that cannot be allotted to one of the above groups).
Several different grading systems have been used by pathologists to classify ovarian tumours, but many problems of reproducibility and consistency of grading have been documented. Despite these problems, a universal grading system has been developed (Silverberg 2000). The method combines a mitotic score (0-3), a nuclear atypia score (0-3) and an architectural score based on the dominant histological pattern (glandular=1, papillary=2, solid=3). Although it displays good reproducibility and predictive power, this system has not been widely embraced by pathologist. Nonetheless, there are highly significant relationships between histological grade, tumour stage and survival. Poorly differentiated carcinomas are most common in the advanced stages while the majority of grade 1 carcinomas are early stage. For patients with stage I disease, grading is the most important prognostic factor, followed by dense adherence and ascites (Dembo 1990 ), and its evaluation is fundamental to assessing prognosis and selection of appropriate treatment strategy. In a study of 1545 patients (Vergote 2001) with invasive epithelial ovarian cancer FIGO Stage I, the degree of differentiation was the most powerful prognostic indicator of disease-free survival, on a type 3 level of evidence. This was followed by rupture before surgery, rupture during surgery, bilateral occurrence of the tumour and age.
2.3 Pathologic diagnosis
Despite the introduction of many new techniques to investigate patients with suspected malignancy, histopathology is still the cornerstone for diagnosis and planning adequate therapy. It has been shown that patients initially referred to specialized cancer centres have better outcome, due not only to the quality of debulking surgery and staging performed by gynaecologic oncologists but also to the accuracy of frozen section diagnosis ( Junor 1994). The frozen section analysis must address the following areas: separate benign, borderline and malignant lesions, discriminate primary from metastatic tumours and identify special neoplasms (germ cell tumours, stromal tumours, lymphomas). Correct diagnosis is most important especially in young women to avoid unnecessary surgical procedures and to preserve fertility. The sensitivity rate of ovarian frozen section diagnosis is 92.5% (Rose 1994). A recent report by Lin et al. shows that the accuracy is worse in lower-grade and in borderline tumours, with a correct diagnosis in 86% of patients treated in specialized hospitals (Lin 1999). For a definitive diagnosis a careful gross description and extensive sampling by multiple sections are essential. No patients should be treated based on a report from another laboratory without confirmation at the treating institution.
3.1 Diagnostic cues
Ovarian carcinoma does not produce specific symptoms, on a type C basis. In early stage disease, the patient may complain of urinary frequency or constipation as a consequence of tumour growth and occasionally lower abdominal distension, pressure and pain. Ovarian carcinoma may also present as a surgical emergency secondary to torsion or rupture of the ovarian mass. In advanced disease, patients most often present with symptoms related to the ascitis, omental or bowel involvement, including abdominal distension, bloating, constipation, nausea, anorexia or early satiety.
The most important sign of ovarian carcinoma is the presence of a pelvic mass on physical examination. A solid, irregular, fixed, nodular, bilateral pelvic mass is highly suggestive of an ovarian malignancy. It should be noted that pelvic examination must include bidigital rectovaginal examination in order to appreciate the characteristics outlined above and to evaluate the posterior uterine surface, pouch of Douglas and cardinal ligaments. In advanced disease, distension of the abdomen, due to ascites or a large tumour, is also common. Distension may be related to partial bowel obstruction, ileus, “omental cake” (malignant infiltration of the omentum) or various combinations of these. Important positive findings can be elicited by a general physical examination in ovarian cancer patients. Supraclavicular, inguinal and even axillary nodes may be enlarged by metastases. Pulmonary examination may reveal a pleural effusion, which commonly accompanies ascites. Emaciation, leg oedema, skin metastases should also be noted.
The diagnosis of a pelvic mass ultimately requires an exploratory laparotomy. The preoperative evaluation is directed toward excluding other important non-gynecological causes of a pelvic mass, such as colonic carcinoma, diverticular disease, upper abdominal cancers with ovarian involvement and regional enteritis. Various imaging modalities have emerged as important contributors to the diagnosis of ovarian cancer. When symptoms or findings are localized to the pelvis, transvaginal ultrasonography plays a primary role to measure ovarian size and to delineate internal ovarian structure. Several investigators have shown that volume, septem thickness and papillary projections are important predictors of malignant histology. If postmenopausal patients present with a unilateral cyst of diameter less than 5 cm there is an extremely low incidence of malignancy (Goldstein 1989). Similar results have been reported by Bailey, using an upper limit of 10 cm cystic diameter as cut-off point for conservative treatment ( Bailey 1998). DePriest et al. in 1993 (DePriest 1993) presented a morphological scoring system, based on size, complexity and septal thickness of ovarian masses, which has proved useful for interpreting scans. A value of > 5 is highly predictive of malignancy in postmenopausal women, with a positive predictive value of 0.450. The introduction of colour flow Doppler imaging to evaluate vasculature and blood vessels in ovarian tumours is now accepted as improving the sensitivity of transvaginal ultrasound assessment. Malignant masses have increased blood flow during diastole resulting in lower mean values of resistance and pulsatility index (Kurjak 1991; Timor-Trisch 1993). In the first report by Kurjak et al., resistance index was found to be highly predictive of malignancy: values of 0.40 were measured in all but one of 624 benign tumours. Similarly, Timor-Trisch and co-workers measured the resistance index and pulsatility index in 115 adnexal masses scheduled for surgery and showed lower mean values for malignant lesions. However, later studies have shown that low impedance flow can also be seen in benign tumours and even in normal ovaries during ovulation; although malignant lesions tended to have higher rates of blood flow and lower resistance indices, no specific cut-off values have been yet established.
Cancer antigen (CA125) is expressed by many epithelial ovarian tumours. Bast and co-workers (Bast 1983) demonstrated that elevated CA125 levels were seen more frequently in women with ovarian carcinoma (82%) than in women from the general population (1%), women with benign disease (6%) or women with non-gynecological cancers (28.5%). CA125 levels are elevated in 23 to 50% of surgically defined stage I and in 90% stage II ovarian carcinomas (Zurawski 1988). An elevated CA125 level can confirm a suspicion of ovarian cancer in a postmenopausal woman, particularly in the presence of a pelvic mass. A normal level, however, cannot be taken as a guarantee against malignancy, since up 25% of ovarian carcinoma are marker negative (Mann 1988). Furthermore, especially in premenopausal patients, a large range of gynaecological pathological conditions are known to elevate CA125 levels. Examples include uterine leiomyomas, endometriosis and pregnancy, all of which can additionally be associated with an abnormal pelvic mass. Liver and lung disease and other malignancies can also cause elevations in CA125 levels, further limiting its use as a primary diagnostic tool. Other markers, such as CA19.9 and OVX1, are still being evaluated. Recently, the blood assay of plasma lysophosphatidic acid (LPA), that possesses mitogenic and growth factor-like activities, has been studied in ovarian cancer patients with promising results. Its specificity for ovarian cancer is 90% and, when assessed in stage I and II disease, its level was elevated in more than 90% of cases ( Bast 1998).
3.2 Diagnostic strategy
Where ovarian cancer is suspected, a pelvic examination is recommended, on a type C basis. If a palpable adnexal mass is detected in postmenopausal women an exploratory laparotomy is recommended, on a type C basis. In premenopausal patients, a period of observation is recommended, on a type C basis, only if the adnexal mass is not clinically suspicious (mobile, mostly cystic and unilateral lesion with less than 8 cm in diameter). Generally, observation should be no more than two months’ duration, during which period hormonal suppression can be employed. If the mass does not regress, or if it increases in size, surgery must be performed.
4.1 Stage classification
In the absence of extra-abdominal metastatic disease, definitive staging of ovarian cancer requires a laparotomy, on a type C basis. The role of surgery in stage IV disease remains to be established. The Federation Internationale de Ginecologie et d’Obstetrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designed staging (Shepherd 1989; UICC 2002).
- Stage IA: Tumour limited to 1 ovary; capsule intact, no tumour on ovarian surface. No malignant cells in ascites or peritoneal washings (malignant ascites is not classified. The presence of ascites does not affect staging unless malignant cells are present).
- Stage IB: Tumour limited to both ovaries; capsule intact, no tumour on ovarian surface. No malignant cells in ascites or peritoneal washings (malignant ascites is not classified. The presence of ascites does not affect staging unless malignant cells are present).
- Stage IC: Tumour limited to 1 or both ovaries with any of the following: capsule ruptured, tumour on ovarian surface, malignant cells in ascites or peritoneal washings.STAGE II
Stage II ovarian cancer is tumour involving 1 or both ovaries with pelvic extension and/or implants.
- Stage IIA: Extension and/or implants on the uterus and/or fallopian tubes. No malignant cells in ascites or peritoneal washings.
- Stage IIB: Extension and/or implants on other pelvic tissues. No malignant cells in ascites or peritoneal washings.
- Stage IIC: Pelvic extension and/or implants (stage IIA or IIB) with malignant cells in ascites or peritoneal washings.STAGE III
Stage III ovarian cancer is tumour involving 1 or both ovaries with microscopically confirmed peritoneal implants outside the pelvis. Superficial liver metastases equals stage III. Tumour is limited to the true pelvis but with histologically verified malignant extension to small bowel or omentum.
- Stage IIIA: Microscopic peritoneal metastases beyond pelvis (no macroscopic tumour).
- Stage IIIB: Macroscopic peritoneal metastases beyond pelvis 2 cm or less in greatest dimension.
- Stage IIIC: Peritoneal metastases beyond pelvis more than 2 cm in greatest dimension and/or regional lymph node metastases.STAGE IV
Stage IV ovarian cancer is a tumour involving one or both ovaries with distant metastases. If pleural effusion is present, there must be positive cytologic test results to designate a case as stage IV. Parenchymal liver metastases equals stage IV.
4.2 Staging procedure
The current stage classification requires an extensive surgical assessment performed by an experienced gynaecological oncologist, employing a laparotomy via a vertical incision to explore the entire upper abdomen. The Federation Internationale de Ginecologie et d’Obstetrique (FIGO) defined an optimal staging for ovarian cancer as inspection and palpation of all peritoneal surfaces, peritoneal washing, total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies of any suspect lesions for metastases, or blind peritoneal biopsies (right diaphragm, right and left para-colic gutter, pelvic side-walls of the ovarian fossa, bladder and cul-de-sac peritoneum) in the absence of macroscopic disease In the presence of peritoneal metastases less than 2 cm in greatest dimension sampling of iliac and para-aortic lymph nodes is recommended on a type C basis ( FIGO 1986). Adequacy of staging and consequent post-operative treatment is dependent on the skills of the operating surgeon. An optimal surgical staging is achieved in 97% of cases if surgery is performed by an experienced gynecological oncologist compared with a gynecologist (53%) or a general surgeon (35%). Five-year survival and disease-free survival for stage I-II patients surgically staged by a gynecological oncologist were significantly improved compared with patients operated upon by a non-oncologist, on a type C basis (Mayer 1992). Chest X-ray and liver function tests are recommended for assessing the presence of pleural effusion and/or liver metastases, on a type R basis.
For patients with stage I disease, classic clinical and pathological prognostic factors, such as degree of differentiation, FIGO-stage, histological type, dense adhesions, large-volume ascites, rupture before surgery, extracapsular growth, and age of the patient, have been identified by multivariate analyses as independent prognostic characteristics, on a type C basis ( Ahmed 1996; Bertelsen 1993;Dembo 1990; Finn 1992; Sevelda 1990; Sjovall 1994; Trope 2000; Vergote 1993; Young 1990). Degree of differentiation is the only factor with independent prognostic value in all published multivariate analyses. Trimbos et al (Trimbos 1991) have demonstrated an excellent prognosis in patients after adequate surgical staging for stage 1 grade 1 ovarian cancer (100% disease-free survival rate). In another report (Ahmed 1996), the 5-year overall survival rates for 194 consecutive patients with FIGO stage I ovarian cancer were 93% for stage IA, 92% for stage IB and 84% for stage IC. The 5-year disease-free survival rates according to grading were 90% for grade 1, 85% for grade 2 and 45% for grade 3 disease. Grade of differentiation is an important prognostic factor and should be used in the classification of risk and for therapeutic planning. The histological grading is, however, hampered by inter-observer and intra-observer variations. Other factors, such as bilateral occurrence, clear cell histology and positive peritoneal cytology, were of prognostic significance in some univariate analyses. Cyst rupture before surgery has been suggested as an independent prognostic factor in several studies ( Ahmed 1996; Sjovall 1994; Trope 2000; Kodama 1997) but rupture during surgery was significant only in univariate analyses (Kodama 1997; Zanetta 1998; Sainz de la Cuesta 1994; Webb 1973). In a study of 1545 patients (Vergote 2001) with invasive epithelial ovarian cancer FIGO Stage I, the degree of differentiation was the most powerful prognostic indicator of disease-free survival in stage I ovarian cancer, on a type 3 level of evidence. This was followed by rupture before surgery, rupture during surgery, bilateral distribution of the tumour and age. Patients without tumour rupture had a 5-year disease-free survival of 83% compared with 72% and 70% for patients with tumour rupture before or during surgery. This study confirmed that rupture before surgery is an important independent prognostic factor but showed that rupture during surgery has an independent unfavourable impact on disease-free survival. DNA ploidy, measured by flow cytometry, has been identified as a strong prognostic factor in epithelial ovarian cancer. Vergote et al ( Vergote 1993) in 219 stage I patients showed 5-year disease-free survival rates of 90% for patients with diploid tumours and 64% for patients with aneuploid tumours (p= 0.0001). By multivariate analysis, the degree of differentiation, DNA ploidy and FIGO substage were the only independent prognostic factors. The only way to confirm these data is to test the DNA ploidy in a large, prospective, randomised trial. In an attempt to better predict relapse in early stage ovarian cancer, a search is needed for additional prognostic factors. Several molecular biological probes, such as P53 protein, platelet-derived growth-factor (PDGF), platelet-derived growth-factor alfa-receptor (PDGFR-alfa), vascular endothelial growth factor (VEGF), B-cell leukemia/lymphoma-2 protein (BCL-2) and BCL-2-associated X protein (BAX) are under investigation. Prognosis in advanced ovarian cancer patients is influenced by several factors, but multivariate analyses suggest that the most important favourable factors include younger age, good performance status, cell type other than mucinous and clear cell, lower stage, well-differentiated tumour, absence of ascites and smaller residual tumour following primary cytoreductive surgery ( Omura 1991; van Houwelingen 1989; Neijt 1991; Hoskins 1992;Thigpen 1993). In particular, the amount of residual tumour following primary surgery is an important prognostic factor, on a type 1 level of evidence (Aure 1971; Griffiths 1978; Berek 1999). It has been well known, since the report of Griffiths (Griffiths 1978), that the survival outcome (progression-free survival and overall survival) of these patients is directly related to the amount of residual disease left after primary cytoreductive surgery. Based on information from a meta-analysis, a statistically significant positive correlation is seen between percent maximal cytoreduction and median survival time, after controlling for all other variables. In addition, each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time, on a type 1 level of evidence ( Bristow 2002). The definition of an optimal debulking ranges from a largest residual tumour mass of 2 cm to no residual tumour. Patients without residual tumour had a better survival than those with the largest residual tumour mass of less than 0.5cm. The latter group had a better prognosis than patients with 0.5 to 1.5 cm residual tumour, on a type 1 level of evidence (Hoskins 1992; Hacker 1983; Heintz 1986; Heintz 1988; Potter 1991; Neijt 1987; Redman 1986).
6.1 Early Ovarian Cancer (FIGO Stage I-II)
6.1.1 Surgical treatment
The standard surgical treatment in early ovarian cancer consists of total hysterectomy, bilateral salpingo-oophorectomy, omentectomy and peritoneal cytology, on a type C basis. Extensive staging by an experienced gynaecological oncologist, performing a laparotomy via vertical incision exploring the entire upper abdomen and the pelvic and para-aortic lymph node regions results in an upstaging of about 1/3 of patients ( Young 1983). An adequate staging procedure is also found to be an independent prognostic factor in the multivariate analysis for survival and disease-free survival (Zanetta 1998). Based on these findings, the European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) defined an optimal staging for early ovarian cancer as inspection and palpation of all peritoneal surfaces; biopsies of any suspect lesions for metastases; peritoneal washings; infra-colic omentectomy; blind biopsies of the right diaphragm and right and left para-colic gutter, pelvic side-walls of the ovarian fossa, of the bladder peritoneum and of the cul-de-sac and sampling of iliac and para-aortic lymph nodes. In 1990, the EORTC-GCG proposed a new definition of optimal, modified, minimal and inadequate surgical staging in early ovarian cancer (Trimbos 2003a) (Table 1). Staging adequacy is a statistically significant prognostic factor for overall and recurrence-free survival both in the univariate and the multivariate analyses (Young 1983; Zanetta 1998). Patients with stage I ovarian cancer should both be optimally staged (if the general condition of the patient allows this) and be treated with adjuvant platinum-based chemotherapy if they have a medium or high-risk ovarian cancer on type 1 level of evidence (Trimbos 2003a; Trimbos 2003b; Bel 2003). According to the present data there is no scientific basis to rely only on adjuvant chemotherapy or only on an optimal staging procedure in medium and high-risk stage I patients (Bel 2003; Vergote 2003). Classic clinical and pathological prognostic factors, such as degree of differentiation, FIGO-stage, histological type, dense adhesions, large-volume ascites, rupture before surgery, extracapsular growth, and age of the patient, have been identified by multivariate analyses as independent prognostic characteristics, on a type 1 level of evidence ( Ahmed 1996; Bertelsen 1993; Dembo 1990; Finn 1992; Sevelda 1990; Sjovall 1994; Trope 2000; Vergote 1993; Young 1990). Degree of differentiation is the only factor with independent prognostic value in all published multivariate analyses. Other factors, such as bilaterality, clear cell histology and positive peritoneal cytology, were of prognostic significance in some univariate analyses. Cyst rupture before surgery has been suggested as an independent prognostic factor in several studies (Ahmed 1996;Sjovall 1994; Trope 2000; Kodama 1997) but rupture during surgery was significant only in univariate analyses (Zanetta 1998; Kodama 1997; Sainz de la Cuesta 1994; Webb 1973). In a study of 1545 patients ( Vergote 2001) with invasive epithelial ovarian cancer FIGO Stage I, the degree of differentiation was the most powerful prognostic indicator of disease-free survival in Stage I ovarian cancer. This was followed by rupture before surgery, rupture during surgery and bilaterality of the tumour and age. This study confirmed that rupture before surgery was an important independent prognostic factor but showed that rupture during surgery had an independent unfavourable impact on disease-free survival. In the standard surgical treatment for early ovarian cancer cyst rupture during surgery should be avoided on type 3 level of evidence. The unfavourable prognostic effect of rupture during surgery was observed in patients who underwent laparotomy. No firm conclusions can be made for the endoscopic removal of malignant tumours confined to the ovaries. In view of the reports on rapid peritoneal spread after laparoscopic removal of ovarian cancer and our findings (Vergote 2001 ; Maiman 1991; Trimbos 1993) it is recommended that the laparoscopic removal of ovarian cysts should be restricted to patients with preoperative evidence that the cyst is benign, on a type C basis. Should an unexpected lesion be found at laparoscopy, and documented by frozen section histopathological analysis, an immediate staging laparotomy is recommended on a type C basis (Vergote 2001; Maiman 1991; Trimbos 1993; Berek 1995; Kindermann 1995; Lehner 1998; Leminen 1999).
Table 1 - Requirements for surgical staging following bilateral salpingo-oophorectomy and total abdominal hysterectomy* according to the EORTC-GCG ACTION-trial
|Surgical staging category||Staging guidelines|
|Optimal||Inspection and palpation of all peritoneal surfaces; biopsies of any suspect lesions for metastases; peritoneal washings; infra-colic omentectomy; blind biopsies of the right diaphragm and right and left para-colic gutter, pelvic side-walls of the ovarian fossa, of the bladder peritoneum and of the cul-de-sac and sampling of iliac and para-aortic lymph nodes|
|Modified||Everything between optimal and minimal staging|
|Minimal||Inspection and palpation of all peritoneal surfaces and the retroperitoneal area; biopsies of any suspect lesions for metastases; peritoneal washing; infracolic omentectomy|
|Inadequate||Less than minimal staging but at least careful inspection and palpation of all peritoneal surfaces and the retroperitoneal area; biopsies of any suspect lesions for metastases.|
|* Patients with stage Ia disease who wished to preserve fertility were permitted to have only a unilateral salpingo-oophorectomy|
6.1.2 Adjuvant treatment
The standard treatment for early-stage ovarian cancer is typically surgery on a type C basis and in patients with well differentiated FIGO stage I-IIA surgical treatment may be curative (Young 1990). However, 5-year survival rates for early ovarian cancer patients varies from 50 to 85% depending on stage and grade of tumour ( Richardson 1985). Unfortunately, about 10-30% of women with early disease will have recurrence and will eventually die of their disease. Identification of patients with a significant risk for recurrence is crucial. Adjuvant treatment, potentially useful in only a fraction of the patient population treated, must be effective in controlling micrometastatic disease and tolerable in terms of short- and long-term side effects, on a type C basis. Adjuvant platinum-based chemotherapy has been suggested as the best strategy to prevent recurrence in early ovarian cancer patients compared to observation (Bolis 1995) and to intraperitoneal instillation of radionuclides, such as phosphorus 32 (Bolis 1995; Young 1999). In all these studies, no difference was found in overall survival but a significant disease-free survival advantage was demonstrated for patients receiving cisplatin, on a type 2 level of evidence. By contrast, another large trial, comparing six courses of cisplatin with intraperitoneal phosphorus 32, failed to confirm this evidence ( Vergote 1992). The Authors, however, concluded that with no difference in efficacy and less toxicity, cisplatin was the preferred treatment, on a type 2 level of evidence. Three large prospective European trials have been conducted to determine whether adjuvant chemotherapy in poor-prognosis patients would prolong recurrence-free and long-term survival (Trope 2000; Trimbos 2003a). The first study by the Nordic Cooperative Ovarian Cancer Group (NOCOVA) was prematurely closed due to poor accrual. The analysis of 162 eligible patients (FIGO stage I – grade 2 and 3 or grade 1 aneuploid or with clear cells histotype) showed no statistically significant benefit of adjuvant chemotherapy (6 courses of carboplatin AUC=7) comparing with observation, on a type 2 level of evidence. The combined analysis of two other randomised clinical trials (International Collaborative Ovarian Neoplasm 1 – ICON1 trial and Adjuvant Chemotherapy In Ovarian Neoplasm – EORTC-ACTION trial) has been recently published ( Trimbos 2003a). Between November 1999 and January 2000, 925 patients (477 in ICON1 trail and 448 in ACTION trial) were randomly assigned to receive platinum-based adjuvant chemotherapy or observation. In the ACTION trial, patients eligible were FIGO stage IA-IB grade 2 or 3, FIGO stage IC-IIA (all grades) and clear cells carcinomas. In the ICON1 trial, by contrast, although all stages were potentially enrolled based on the opinion of the responsible clinician, most patients were stage I or II. After a median follow up of over 4 years, there is a significant advantage for the chemotherapy arm in terms of 5-year overall survival (82% versus 74% – P=0.008) and 5-year recurrence-free interval (76% versus 65% – p=0.001), on a type 1 level of evidence. This is the first evidence that immediate treatment is significantly better than treatment at relapse. The future of therapy for early-stage ovarian cancer will be guided by randomised trials investigating novel prognostic factors for patient stratification as well as new targeted therapies. No consistent data are available concerning external radiotherapy.
- Surgical treatment alone is recommended on a type C basis in patients with well differentiated FIGO stage I-IIA.
- Patients with high-risk disease should be offered platinum-based chemotherapy regimen on a type 1 level of evidence or enrolment in a clinical trial on a type C basis.
6.2 Advanced Ovarian Cancer (FIGO Stage III-IV)
6.2.1 Surgical treatment
- Primary Debulking Surgery
Initial metastatic tumour load: based on a type 3 level of evidence, patients with extensive metastatic disease prior to cytoreduction or with clinical ascites or with peritoneal carcinomatosis, have a poor prognosis even if the disease was cytoreduced to an optimal status (Hacker 1983; Heintz 1986 ; Heintz 1988). On a type 3 level of evidence the role of organ resection should be questioned when residual disease remains at the completion of the operative procedure (Potter 1991). Whether primary debulking surgery is performed in a patient with more than 1,000 g of total metastatic tumour load can be decided on an individualised basis (Eisenkop 1993; van Dam 1996; Vergote 1998).
Residual tumour load: the amount of residual tumour following primary surgery is an important prognostic factor in advanced ovarian carcinoma, on a type 3 level of evidence (Aure 1971; Griffiths 1978). Primary cytoreductive surgery should be the standard of care in advanced ovarian cancer, on type 3 level of evidence (Berek 1999). Based on information from a meta-analysis a statistically significant positive correlation is seen between percent maximal cytoreduction and median survival time, also after controlling for all other variables. In addition, each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time ( Bristow 2002). The definition of an optimal debulking ranges from a largest residual tumour mass of 2 cm to no residual tumour. Patients without residual tumour had a better survival than those with less than 0.5 cm as the largest residual tumour mass. The latter group had a better prognosis than patients with 0.5 to 1.5 cm residual tumour, on a type 3 level of evidence (Hacker 1983; Heintz 1986; Heintz 1988; Potter 1991; Hoskins 1992;Neijt 1987; Redman 1986). On a type C basis, optimal cytoreductive surgery should be defined as no macroscopic residual tumour (Vergote 1998).
Stage IV disease: the role of cytoreductive surgery in FIGO stage IV remains controversial. Whether primary debulking surgery is performed in patients with Stage IV disease can be decided on an individualised basis (Eisenkop 1993 ; van Dam 1996; Vergote 1998). During a consensus meeting in 1998 it was agreed that patients with only a pleural effusion, or a supraclavicular node or a single cutaneous metastasis could be treated as stage III disease (Berek 1999b). However, extensive primary debulking in patients with liver or lung metastases was regarded as most likely of no benefit, on a type R basis (Berek 1999b).
- Interval Debulking Surgery
Interval debulking surgery is an operation performed in patients after a short course of induction chemotherapy, usually 2 or 3 cycles of chemotherapy, to remove as much primary and metastatic disease as possible in order to facilitate response to subsequent chemotherapy and to improve survival (Berek 1999a).
Interval Debulking Surgery after suboptimal primary bebulking: interval debulking surgery after suboptimal primary debulking followed by 3 courses of platinum-based chemotherapy has been investigated in 2 prospective randomized trials ( van der Burg 1995;Rose 2002). It can be concluded that, based level of evidence 1, interval debulking surgery by an experienced gynecological oncologist improves survival in some patients who have not been optimally operated primarily (poor medical condition, inexperienced surgeon,…). On the other hand, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecological oncologist, on a type 1 level of evidence.
Interval Debulking Surgery after neoadjuvant chemotherapy: the outcome of women, treated with neoadjuvant chemotherapy followed by interval debulking surgery, is essentially the same as the outcome of patients treated with primary debulking surgery followed by chemotherapy, on a type 3 level of evidence (phase II retrospective reports, Table 2). This approach can be advocated on an individual clinical basis, especially for the treatment of Stage IV ovarian cancer (not based on positive pleural cytology) or for patients with a very high metastatic tumour load and a poor general condition. A third group of patients who can be chosen for neoadjuvant chemotherapy are those with metastases of larger than 2 cm around the superior mesenteric artery in the porta hepatis. The interval debulking surgery is performed after 3 or 4 courses of neoadjuvant chemotherapy, on a type R basis. The arguments for this timing of the interval surgery are firstly that chemotherapy induced fibrosis is less extensive after 3 than after 6 courses, secondly that more patients might be chemoresistant after 6 courses than after 3 courses and lastly that earlier studies investigating the role of debulking surgery at the time of second-look surgery after 6 courses of chemotherapy did not improve survival.
Table 2 - Retrospective studies in which patients with advanced ovarian cancer were treated with neoadjuvant chemotherapy followed by interval debulking surgery
|Lawton 1989||36||78 % IDS of which 89 % < 2 cm|
|Jacob 1991||22||Same survival as 18 matched controls|
|Lim 1993||30||NAC can make patients operable|
|Shimizu 1993||74||46 % IDS to < 2 cm|
|Onnis 1996||88||42 % IDS to < 2 cm|
|Surwit 1996||29||Median survival = 22 months (= primary debulking)|
|Vergote 1998||75||Crude survival higher when selecting about ½ of the patients for NAC|
|Schwartz 1999||59||Similar survival compared with those treated during the same time period with primary debulking|
|Ansquer 2001||54||Better survival for patients treated with NAC compared with non-debulked tumours|
|Kuhn 2001||37||Better median survival in the group treated with NAC compared with primary debulked group|
|Recchi 2001||34||Only stage IV, median survival 28 months|
|Kayikcioglu 2001||45||NAC followed by IDS does not appear to worsen prognosis|
|Ushijima 2002||65||Similar survival in NAC group compared with primary debulking group|
|Vrscaj 2002||20||Rate of optimal debulking is higher at IDB then PS|
|Fanfani 2003||73||Results similar compared with sub-optimal PS|
|Morice 2003||57||Similar survival compared with PS|
|Mazzeo 2003||45||Median survival of 29 months|
|Shibata 2003||23||No significant difference with PS|
· IDS: Interval Debulking Surgery
· NAC: Neoadjuvant chemotherapy
· PS: Primary Surgery
Laparoscopy is the preferred technique to select patients for neoadjuvant chemotherapy, on a type 3 level of evidence. Operability cannot adequately be judged based on CT findings. The proposed computerized tomographic (CT) criteria lack positive predictive value compared to laparoscopy, on a type 3 level of evidence (Nelson 1993). Both CT with peritoneography and PET scan were superior to standard CT but were still less sensitive than laparoscopy to evaluate operability, on a type 3 level of evidence (Gryspeerdt 1998; Drieskens 2003). Porta hepatis site metastases should also be completely excised at the time of primary debulking surgery or interval debulking surgery to prevent recurrence later during follow-up on a type R basis (Gryspeerdt 1998). However, there is no evidence that porta heaptis site metastases in advanced ovarian cancer are of prognostic significance.
6.2.2 Primary chemotherapy
After completion of surgical cytoreduction, patients with advanced disease will require chemotherapy. The Advanced Ovarian Cancer Trialists Group (AOCTG) conducted and published five meta-analysis incorporating data on individual patients from 45 randomized trials -including a total of nearly 10,000 patients – and helped clarify the role of cisplatin, its analogue carboplatin and the anthracycline doxorubicin in this disease. Although no firm conclusions were reached, these meta-analyses suggested that in terms of survival immediate platinum-based therapy was better than non- platinum based therapy; platinum in combination was better than single-agent platinum when used at the same dose; and there was no difference between carboplatin and cisplatin either as single agents or in combination regimens, on a type 1 level of evidence ( Aabo 1998) . Two further meta-analyses, considering the role of doxorubicin, confirmed the advantage of doxorubicin-based regimens (CAP) over non anthracycline-containing regimens in the first line treatment of women with advanced ovarian cancer, on a type 1 level of evidence (A’Hern 1995; OCMP 1991). Despite these results, a subsequent prospective randomized trial (ICON 2), with 1526 patients randomised, showed reliably that there was no difference between CAP regimen and adequate doses of carboplatin in terms of progression-free survival and overall survival (ICON 1998). The use of single-agent carboplatin at AUC 6 could represent an acceptable alternative for initial management of patients with advanced ovarian cancer, on a type 1 level of evidence. In the early 1990s the drug paclitaxel was first tested in ovarian cancer. Four randomized trials have been completed comparing the combination of paclitaxel-platinum versus a platinum-based control arm ( McGuire 1996; Piccart 2000; Muggia 2000; ICON 2002). In two of these trials – GOG 111 and OV 10 (McGuire 1996; Piccart 2000) – significant differences in outcome were observed favouring the paclitaxel+ cisplatin combination versus an identical cisplatin+ cyclophosphamide “standard arm”, on a type 1 level of evidence. By contrast, the taxane-platinum combination failed to improve both survival and disease-free survival when compared to single-agent treatments with either cisplatin, in the GOG 132 trial (Muggia 2000), or carboplatin, in ICON 3 trial (ICON 2002), on a type 1 level of evidence. ICON3 is the first and only trial comparing paclitaxel plus carboplatin against carboplatin alone or a (non-taxane) cisplatin-based control arm. ICON 3 included 2074 patients enrolled between 1995 and 1998 who were randomized to receive either single agent carboplatin (AUC6) or CAP (cyclophosphamide-adriamycin-cisplatin) against a combination of carboplatin and paclitaxel. The last analysis performed with a median follow up of 51 months showed no evidence of a difference in overall survival, with a median overall survival of 36.1 months on carboplatin and paclitaxel combination and 35.4 months on control. Progression-free survival curves showed no evidence of differences between the groups, with a median progression-free survival of 17.3 months and 16.1 months respectively. Several hypotheses have been raised to explain this discrepancy including differences in the extent and timing of crossover to taxanes in the control group, differences in the type of patients included, differences in the efficacy of research regimens or in the efficacy of the control regimens. It will be almost impossible to achieve an agreement on this explanation. Recently, a meta-analysis with individual patient data has been conducted to better clarify the issue of paclitaxel in the front line therapy of advanced ovarian cancer (Sandercock 2002). By simply pooling the results of four trials, a benefit of paclitaxel/platinum becomes apparent, which is smaller than that originally expected on the basis of GOG 111, but still statistically significant, on a type 1 level of evidence. By examining four hypotheses which have been proposed to explain heterogeneous results of the four trials the authors demonstrate that only one of the proposed explanations appears to be consistent with the data: differences in the efficacy of the control arms. However, by the time the results of ICON 3 became available, the combination of paclitaxel plus a platinum compound had already gained wide use as the standard of care. In clinical trials, the next generation of studies have all adopted paclitaxel plus carboplatin as the control arm, indicating that this regimen is the de facto standard for the research community. Main ongoing researches are focusing on the addition of a third drug to platinum/taxane in regimens consisting of triplets or sequential doublets. The phase III Gynecologic Cancer Intergroup (GCIG) trial (GOG 0182-ICON 5) includes 5 experimental arms to evaluate the addition of three new drugs (topotecan, gemcitabine, and PEG-liposomal doxorubicin) using two different strategies (sequential doublets and triplet combinations). The control arm is represented by carboplatin/paclitaxel. This 5-arm trial has recruited patients until 2004. Data on progression-free survival and overall survival are still awaited.
- Platinum should represent the standard of advanced ovarian carcinoma and should be given at adequate doses, on a type 1 level of evidence.
- Cisplatin and carboplatin are equally effective on a type 1 level of evidence.
- Neither of the following regimens has been outperformed in a randomized clinical trial:
a) Adequate dose single agent platinum on a type 1 level of evidence
b) Paclitaxel + platinum on a type 1 level of evidence.
In clinical trials, ongoing studies have adopted paclitaxel + carboplatin as the standard arm.
6.2.3 Salvage treatment
Appropriate salvage therapy is based on the timing and nature of the recurrence and the extent of prior chemotherapy. Surgical resection should be considered for patients whose relapse follows long-term remission, and especially in those with isolated recurrences and good performance status, on a type C basis. In other cases, the major aim is to deliver active second-line chemotherapy.
- Secondary cytoreductive surgery
Patients who develop progressive disease during their initial therapy should not be submitted to secondary cytoreductive surgery on a type C basis. Secondary cytoreductive surgery at the time of the completion of the primary chemotherapy has little influence on survival, on a type 3 level of evidence (Berek 1983). Based on a type 3 level of evidence, patients with advanced ovarian cancer considered to be the most suitable candidates for a secondary debulking operation are those who had an initial complete response to chemotherapy, a long treatment-free interval (i.e. longer than 12 months) before the development of clinically recurrent disease and resectable disease without peritoneal carcinomatosis (Eisenkop 2000; Janicke 1992; Meier 1993; Morris 1989; Munkarah 2001; Pecorelli 1994 ; Scarabelli 2001; Segna 1993; Tay 2002;Zang 2000) (Table 3). The longer the interval from completion of chemotherapy to clinical relapse, the more likely that a secondary resection will be associated with prolonged survival. Patients with resectable disease limited to the pelvis are more likely to have benefit from a secondary debulking surgery than those with diffuse carcinomatosis (Burke 1993). Good performance status and younger patient age correlate with a positive outcome. The variables making a patient an optimal candidate for secondary cytoreductive surgery are summarized inTable 4. The possibility of complete resection can best be evaluated prior to laparotomy using an open laparoscopy, on a type R basis.
Table 3 - Retrospective studies on secondary debulking surgery in patients relapsing after a long treatment-free interval
|AUTHOR||Pts. Nr||Optimal debulking*||Median Survival (months)|
|Janicke 1992||30||14/30 (47 %) (NoR)||18|
|Munkarah 2001||25||18/25 (72 %) ( < 2cm)||25|
|Segna 1993||100||61/100 (61 %) ( < 2 cm)||17|
|Morris 1989||30||17/30 (57 %) ( < 2 cm)||16|
|Pecorelli 1994||22||8/22 (36 %) (NoR)||20|
|Meier 1993||93||38/93 (41 %) (NoR)||24|
|Tay 2002||46||19/46 (41 %) (NoR)||23|
|Zang 2000||106||46/106 (43 %) ( < 1 cm)||20|
|Scarabelli 2001||149||104/149 (70 %) ( < 1 cm)||24|
|Eisenkop 2000||106||87/106 (82 %) (NoR)||35|
|TOTAL||707||412/707 (58 %)||16-35|
|* According to the authors definition
–> NoR = No residual disease
Table 4 - The variables making a patient an optimal candidate for secondary cytoreductive surgery
|1.||Long interval from time after complete remission (12 months or longer)|
|2.||Potential for complete resection|
|5.||No metastasis to the parenchyma of the abdominal viscera or extra-abdominal metastases|
- Palliative surgery
Palliative secondary surgery can be used to relieve intestinal obstruction in patients who have failed two or more chemotherapy regimens, as suitable for individual clinical use on a type R basis. The criteria for selection of patients for palliative surgery are categorized according to the presumptive estimate of duration of survival, the overall medical status and performance status, presence of ascites, the will to live, presence of focal disease, and a suspicion of local obstruction where a bypass or local resection might be feasible (Bais 2001). However, estimates of duration of surgery in terminal patients with ovarian cancer are often inaccurate, so the surgeon must be quite careful and take care not to overuse these prognostic factors. Palliative secondary surgery should be balanced against the use of second, third or fourth line chemotherapy, such as liposomal doxorubicin (Doxil or Caelyx), topotecan, gemcitabine, or hexamethylmelamine, which may produce relief from the intestinal obstruction in up to 40% of cases ( D’Agostino 2003). Furthermore, the use of conservative treatment options such as the placement of a gastrostomy tube, either endoscopically or by cut-down to the stomach with direct insertion (Malone 1986) or the use of octreotide should be considered. Another approach is to give minimal intravenous fluids and frequent small feedings, with avoidance of nasogastric suctioning (Baines 1985).
More critical is the distinction between patients with drug-sensitive or drug-resistant tumour at the time of relapse. In general, patients who progress during treatment or have stable disease in response to initial platinum-based therapy or who relapse within 6 months are considered to have “platinum-refractory” disease. Patients who develop recurrent disease at intervals of greater than 6 months are defined as “platinum-sensitive”, on a type C basis. Patients experiencing a durable response to platinum induction chemotherapy have a high probability of responding again to platinum-containing compounds, on a type 3 level of evidence (Markman 1991; Cantu 2002). The choice between cisplatin and carboplatin should be based on the agent used in prior therapy, its tolerability and residual toxicity. Among active combination regimens used in platinum sensitive patients, carboplatin/paclitaxel has shown interesting activity in several phase II studies with response rates up to 90% (Rose 1998; Dizon 2002). In order to determine whether the combination carboplatin/paclitaxel should be used at first relapse after platinum-based chemotherapy two pragmatic trials were designed (Parmar 2003). ICON4 (co-ordinated by Medical Research Council – MRC – and Mario Negri Institute ¡V IRFMN) – and OVAR 2.2 (Arbeitsgemeinschaft Gynaekologische Onkologie – AGO) were two parallel randomised trials comparing a minimum of 6 cycles of platinum chemotherapy versus paclitaxel plus platinum in patients relapsing with a treatment-free interval of > 6 months (MRC/AGO) or > 12 months (IRFMN). Eight hundred and two patients were randomised between January 1996 and March 2002. By October 2002, with a median follow-up of 34 months, the hazard ratio (HR) for progression was 0.77 and the HR for survival was 0.77 in favour of paclitaxel-platinum combination (p=0.006). There was no evidence that the effect is larger or smaller in any subgroups (randomising group, time to relapse, number of previous lines of chemotherapy, type of prior chemotherapy, age and performance status). These results suggest that the combination improves survival and progression-free survival in patients with “platinum-sensitive” relapsed ovarian cancer compared with platinum alone, on a type 1 level of evidence. Salvage chemotherapy in platinum-refractory patients typically results in low response rates and short survival, on a type C basis. Rechallenge with platinum-based treatments produces a response rate of about 10% ( Christian 1994; Thigpen 1993b). Drugs with demonstrated activity in paclitaxel-platinum refractory disease include topotecan, docetaxel, oral etoposide, liposome encapsulated doxorubicin, gemcitabine, ifosfamide and hexamethylmelamine (Table 5). It has been observed that durable response to salvage chemotherapy is rare and cure almost impossible. Since the main goal of salvage therapy in this group of patients is palliation, particular attention should be paid to the side effects of the drug utilized. Patients with good PS and motivated to receive further treatment should be considered for experimental trials with new drugs. Perhaps the most interesting role of second line chemotherapy is indeed to identify new potentially active drugs, which can be moved to first line.
Table 5 - Cumulative response rate of several drugs used in patients with platinum-free interval < 12 months
|Agent||Studies No||Patients No||Cumulative Response Rate|
- Paclitaxel-platinum combination represents the standard second line chemotherapy in patients with “platinum-sensitive” relapsed ovarian, on a type 1 level of evidence.
- Salvage chemotherapy in platinum-refractory patients usually results in low response rates and short survival, on a type C basis.
7. LATE SEQUELAE
Spontaneous physiological menopause has already occurred in the majority of women at the time of diagnosis of gynecological malignancy. However, in many cases, menopause may be a consequence of ovarian cancer treatment, such as oophorectomy (surgical menopause) or chemotherapy. The oestrogen deficiency may result in debilitating symptoms, including hot flushes, mood swings, emotional disorders, sleep disturbances and dyspareunia, and is often associated with an increase risk for osteoporosis, cardiovascular disease and cognitive disease, on a type C basis. Despite decades of accumulated observational evidence, the balance of risks and benefits for hormone use in healthy postmenopausal women remains uncertain. The WHI (Women’s Health Initiative) study (Rossouw 2002) was the first randomized trial to directly address whether oestrogen plus progestin has a favourable or unfavourable effect on coronary heart disease incidence and on overall risks and benefits of healthy women. Between 1993 and 1998, 16608 postmenopausal women were recruited by 40 US centres to receive placebo (low-fat dietary pattern and calcium plus vitamin D supplementation) or hormone therapy. Data from WHI, stopped early after an average 5.2 year follow-up, show that combined oestrogen plus progestin does increase the risk of breast cancer and cardiovascular disease. Endometrial cancer rates were low and were not increased by 5 years’ of hormone exposure. The reduction in colorectal cancer in the hormone group was consistent with previous observational studies, on a type 2 level of evidence. Results from the Million Women Study (Beral 2003), that enrolled 1,084,110 UK women aged 50-64 years, confirm that current and recent use of hormone-replacement therapy is associated with an increase risk and incidence of fatal breast cancer. The effect is substantially greater for oestrogen-progestagen combinations than for other types of hormone therapy, on a type 2 level of evidence. As a consequence of these trials, a marked variation in hormone therapy use in clinical practice developed. Within 3 months of WHI, hormone replacement therapy prescriptions declined from 12.5% to 9.4 % and therapy discontinuation in 2002 was statistically significant increased compared with 2001 (67% vs 53% – p < .0001) (Kim 2005). What about ovarian cancer patients? For many years there was a strong suggestion that hormone therapy in ovarian cancer patients was related to disease recurrence or progression, with an adverse impact on patient survival. However, the only two observational studies addressing the use of hormone therapy in women with a history of ovarian cancer have failed to confirm this hypothesis. In the first retrospective study including 373 ovarian cancer patients aged 50 years or younger, Eeles et al. ( Eeles 1991) showed no significant difference in survival between women receiving hormone therapy (78 patients) and those not receiving it (RR of dying= 0.73). Similar results have been reported in a group of 24 patients with diagnosis of invasive ovarian serous cystoadenocarcinoma treated with hormone therapy for an average of 24 months after primary surgical treatment, on a type 3 level of evidende (Ursic-Vrscaj 2001). The only published randomized trial of use of hormone therapy in ovarian cancer survivors was also limited by small sample size, on a type 2 level of evidende (Guidozzi 1999). Between 1987 and 1994, 130 ovarian cancer patients younger than 59 years were randomized to continuous oral conjugated equine oestrogen or to no supplementation; all patients were followed prospectively for a minimum of 48 months. A total of 32 recurrences occurred in hormone therapy group compared with 41 recurrences observed in the control group. Within each group, recurrence was related to poorly differentiated tumours, stage and suboptimal primary surgery. The differences in disease free interval (34 vs 27 months) and overall survival (44 vs 34 months) between the two groups were not statistically significant. In summary, these studies show that hormone replacement therapy is unlikely to have a detrimental effect on the prognosis of patients with ovarian cancer, but this could only be demonstrated conclusively by a large randomized controlled trial. While waiting for the definitive data, we should seek other established symptomatic interventions before considering the use of oestrogen. When oestrogen is used, it should be used in the lowest dose for the shortest duration of time and only after full and detailed patient assessment.
Follow up after primary therapy in ovarian cancer is poorly defined. It is comprised, on type C basis, of history and physical examination, including bimanual pelvic examination, serial assessment of serum CA125 level or other tumour markers, if positive at diagnosis, and occasionally one or more imaging studies (CT scan, MR and PET). In evaluating surveillance strategies for early detection of recurrent ovarian cancer, it is important to consider the anatomic sites of relapse. Epithelial ovarian cancer frequently recurs in the peritoneal cavity (diffuse carcinomatosis) and in the vaginal apex (small pelvic masses), which are difficult to detect by clinical and imaging evaluation. Vaginal apex nodularity, which can be missed by CT scans, is easily detected by physicians with experience in performing pelvic examinations. The major limitation of this procedure remains the detection of diffuse peritoneal disease. For this reason pelvic examination should be combined with a serologic marker, such as CA125. The CA125 tumour marker has been the most studied. In the majority of patients, sequential elevations of CA125 level following clinical or pathological complete remission presage clinical evidence of recurrence with an average lead time of 3 to 5 months, on type C basis (Niloff 1986; Vergote 1987; Cruickshank 1991; Gallagher 1994). CT scan and MR imaging are generally unable to detect disease less than 1 to 2 cm, on a type C basis. Data suggest that these procedures should be reserved for evaluating patients with physical findings or CA125 levels suggestive of recurrence. There has been increased interest in immunoscintigraphy and positron emission tomography (PET) as new imaging methods detecting metabolic and biochemical activity of neoplastic cells. Limited data available at this time preclude their use as a routine serial test in post-therapy surveillance. Typically, surveillance is more intensive initially and then becomes less frequent as the tumour-free interval increases, on a type C basis. Initially, patients are evaluated every 3 months during the first year and at 3 to 4-months intervals for 3 to 4 years thereafter. Each visit includes a bimanual pelvic examination and a serum CA125 assay. Imaging studies are not usually obtained unless symptoms, physical findings or elevated serum CA125 level suggests recurrence. The imaging study of choice is usually CT scan. Patients with early ovarian cancer treated with conservative surgery need transvaginal ultrasound every 6 months due to the risk of recurrence in the residual ovary. Finally the psychological impact of repeated testing must be considered.
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Prof. Frederic Amant (Author)
University Hospitals – Leuven, Belgium
Prof. Nicoletta Colombo (Reviewer)
European Institute of Oncology – Milan, Italy
Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
Dr. Gabriella Parma (Author)
European Institute of Oncology – Milan, Italy
Dr. Cristiana Sessa (Editor)
Istituto Nazionale per lo Studio e la Cura dei Tumori – Milan, Italy
Dr. Toon Van Gorp (Author)
University Hospitals – Leuven, Belgium
Prof. Ignace Vergote (Author)
University Hospitals – Leuven, Belgium
Dr. Maria Teresa Giannelli
Redazione START Fondazione IRCCS ‘quot;Istituto Nazionale dei Tumori’quot; – Milan, Italy
Dr.ssa Chiara Rossini