Marie Lacombe • Thomas Eugène • Jean-François Chatal • Françoise Kraeber-Bodéré
Ovarian cancer is the seventh most frequent cancer in women worldwide, and is the leading cause of death from gynecologic malignancies in most Western countries. Because of insidious progression and lack of suggestive symptoms, these types of malignancies are most often discovered at an advanced stage. Hence, about 60% of ovarian cancers present an International Federation of Gynecology (FIGO) stage III or stage IV, at diagnosis. The prognosis is significantly modified depending on the spread of the disease but 5-year survival remains poor for most patients (Table 17.1).
FIVE-YEAR STAGE-SPECIFIC RELATIVE SURVIVAL RATES, ADULTS (AGES 15–99)
Initial treatment of advanced ovarian cancer consists of platinum-based cytotoxic chemotherapy after primary cytoreductive surgery. Even if the overall response rate after primary therapy is about 80%, approximately two-thirds of the patients experience disease recurrence.1,2
Ovarian cancer usually spreads to the local lymph nodes, implants on the peritoneum, and less frequently disseminates hematogenously.3 Lymph node metastases mostly involve pelvic, para-aortic, retroperitoneal, or inguinal chains. Common sites of peritoneum implantation are the pelvis, right hemidiaphragm, liver, right paracolic gutter, bowel, and omentum. Pleural effusion and parenchymal liver lesions are the most frequently observed distant metastases.4
Before the introduction of positron emission tomography (PET) imaging in routine practice conventional scintigraphy had no real place in management of this tumor. The increasing use of positron emission tomography/computed tomography using 18F-fluorodeoxyglucose (18FDG PET/CT) for more than a decade has proven to be quite useful and has become standard in the management of ovarian cancer.
INITIAL DIAGNOSIS AND STAGING
Characterization of Adnexal Masses
Adnexal masses which have benign features on imaging can undergo simple resection, or continued imaging surveillance. If a mass has malignant characteristics, however, radical cytoreductive surgery is indicated as there is evidence that it improves outcome.5 The current approach to assess an adnexal mass is based on imaging studies. Transvaginal ultrasound (TVUS) is the most widely used technique for initial evaluation because of its availability, good resolution, and safety. Many clinical studies using this technique for the detection of malignant ovarian lesions report sensitivities and specificities of 25% to 100% and 52% to 100%, respectively.6–12
MRI, used in addition to ultrasound for the characterization of an ovarian mass of unknown origin, has sensitivity and specificity for malignancy of 100% and 94%, respectively.13 Although useful in cancer detection, its value lies in its specific characterization of benign lesions.14 Indeed, MRI is useful to characterize undetermined lesions on ultrasound, such as the extraovarian cystic lesions (viz., hydrosalpinx, paratubal cysts, pseudocysts, peritoneal inclusion cysts) especially when the ipsilateral ovary is not seen and the solid component of the lesion requires further characterization (i.e., dermoid cysts, fibrothecomas). Finally, MRI is a valuable tool to characterize complex ovarian masses like endometrioma and to detect rare signs of malignant degeneration.
PET/CT provides precise localization of increased 18FDG uptake, which is particularly useful to characterize adnexal masses.
FDG PET/CT IN THE DETECTION OF OVARIAN CANCER: PRINCIPAL RESULTS FROM THE LITERATURE
In a study by Fenchel et al.,15 99 patients with a suspicious adnexal mass on ultrasound underwent an 18FDG PET/CT of the abdomen, 1 week before an exploratory laparoscopy. 18FDG PET/CT correctly detected 7 of 12 malignant ovarian lesions and 66 of 87 benign lesions. The sensitivity and specificity were 58% 76%, respectively. There were five false negatives in patients with cystadenocarcinomas, classified pT1a (tumors of low malignancy). Moderate accumulation of 18FDG in the pelvis was related to intestinal activity or benign ovarian lesions in 21 of the 27 false-positive results. In 2007, Castellucci et al.16 studied 50 patients with pelvic masses scheduled for surgical exploration based on ultrasound criteria, CA 125 serum level, and clinical examination. Focal increased 18FDG uptake with an SUVmax >3 in the ovary was classified malignant, whereas SUVmax <2.7 was classified as benign lesion. At surgery, 32 patients had a malignant lesion; the remaining 18 patients had a benign ovarian lesion. The sensitivity, specificity, NPV, PPV, and accuracy were 87%, 100%, 81%, 100%, and 92%, respectively. Two of the four false-negative results involved patients who had ovarian tumors less than 5 mm.
Risum et al.17 studied 97 patients with a risk of malignancy index (RMI) greater than 150, based on CA 125 serum level, ultrasound, and menopausal status. 18FDG PET/CT was considered positive in 57 patients with ovarian malignancy and negative in 37 of 40 patients with benign lesions. Sensitivity and specificity were 100% and 92.5%, respectively.
In 2008, Yamamoto et al.18 conducted a prospective study on 30 patients suspected of epithelial ovarian cancer (EOC) based on morphologic (ultrasound and MRI) and biologic (elevated CA 125) data. The sensitivity and specificity of 18FDG PET/CT to differentiate malignant lesions from borderline lesions were 71.4% and 81.3%, respectively. The SUVmax of borderline lesions were lower than that of malignant lesions but not significantly different from benign lesions. In this report, the sensitivity and specificity of 18FDG PET/CT to differentiate malignant from benign lesions were 100% and 85% respectively. Three false positives were observed in two patients with a fibroma and one patient with a fibrothecoma. The four false-negative results were related to borderline lesions (Table 17.2).
Based on these results, 18FDG PET/CT should be included in the diagnostic assessment of adnexal masses, in addition to TVUS, CT, and MRI (Fig. 17.1).
Staging of Ovarian Cancer
It is widely accepted that optimal debulking surgery has a survival benefit.20–22 In 30% of cases, however, initial laparotomy underestimates the disease stage, mainly because of technical difficulties and spread of the disease outside of the pelvis.23 Although many studies have investigated the value of 18FDG PET/CT to characterize ovarian lesions, fewer studies have studied its value in the staging situation.
The first study of this indication, by Yoshida et al.24 in 2004 reported a correlation between 18FDG PET/CT staging and surgical staging in 13 of 15 patients (83%) versus 8 of 15 patients (53%) based on CT. Castellucci et al.16 in 2007 reported similar results with 18FDG PET/CT staging concordant with surgical staging in 22 of 32 patients (69%) whereas CT staging was concordant in 17 of 32 patients (53%). CT classified as stage III, four of the six patients with distant involvement and did not detect liver, pleural, or mediastinal and supraclavicular lymph node metastases, that were correctly detected by 18FDG PET/CT. Kitajima et al.,25 in 40 patients with ovarian carcinoma (OC), showed CT and 18FDG PET/CT staging concordance in 22 of 40 (55%) for surgical staging and 30 of 40 (75%) cases for 18FDG PET/CT, respectively (Table 17.3).
FIGURE 17.1. FDG PET/CT at initial staging of an ovarian serous papillary adenocarcinoma: Tumor mass of 13 cm, including both ovaries.
COMPARISON BETWEEN PET/CT AND CT STAGING VERSUS SURGICAL STAGING
18FDG PET/CT classified 27/87 (31%) patients as stage IV versus only two with surgery based on FIGO criteria.26 Extra-abdominal lymph nodes and distant metastases were found in 23 (85%) and 14 (52%) patients classified as stage IV by 18FDG PET/CT. In 2010, Nam et al.19 compared 18FDG PET/CT and CT or 18FDG PET/CT and MRI for the detection of extraovarian lesions in the abdomen and pelvis. The sensitivity, specificity, PPV, and NPV of FDG PET/CT were respectively 94.6%, 82.8%, 87.5%, and 92.3% against 94.1%, 71.4%, 94.1%, and 71.4% with CT. For the detection of locoregional lymph node metastases (bilateral pelvic lymph nodes and para-aortic), sensitivity, specificity, PPV, and NPV were 83.3%, 92.6%, 81.6%, and 93.6%, respectively for 18FDG PET/CT against 62.5%, 83.6%, 60%, and 85% for CT or MRI. In this study, the correlation of staging with 18FDG PET/CT versus surgery was also studied. A concordance was observed in 71 of 91 patients (78%). Also, 14 of 91 (15.4%) patients were overclassified by 18FDG PET/CT and 6 (6.6%) underclassified.
18FDG PET/CT may contribute to staging of OC with an impact on survival.
In total, 18FDG PET/CT is particularly useful in the accurate staging of EOC due to its high sensitivity to detect extra-abdominal spread of disease and therefore to influence therapeutic strategy.
18FDG PET/CT as a Prognostic Indicator
Three recent clinical studies have reported on the potential interest of 18FDG SUVmax to serve as a prognostic indicator.
Chung et al.27 conducted a retrospective preoperative 18FDG PET/CT study in 55 patients with disease recurrence. The distribution of SUVmax was divided into two regions, above and below the umbilicus. An SUV ratio was defined as the sum of SUVmax of lesions located above the umbilicus divided by the sum of SUVmax of lesions located below the umbilicus. In univariate analysis, an increased SUV ratio was significantly associated with recurrence risk. In multivariate analysis, increased SUV ratio was associated with histologic type and an increased risk of recurrence. In this study, stage of disease according to FIGO classification was not a significant prognostic indicator for recurrence; probably caused by the low number of patients included and the initial staging (45 patients; 55 were classified as stage III).
Nakamura et al.,28 in a prospective study including 51 patients, showed that a high SUVmax of the primary ovarian lesion was significantly associated with FIGO stage and histologic type. Survival was the shortest in patients with the highest SUVmax suggesting that a high SUVmax in the primary tumor is an important factor identifying patients at risk of poor prognosis. Risum et al.29 provides contradictory evidence on SUVmax. The prognostic value of SUVmax was determined prior to initial surgery in 60 patients with stage II or IV ovarian cancer. The prognostic value of SUVmax was determined prior to the initial surgery in 60 patients with stage III or IV ovarian cancer. There was no correlation between initial SUVmax and an incomplete cytoreduction at the time of initial surgery or survival.
At the present time, more prospective clinical studies in large numbers of patients are needed to determine the added value of 18FDG and 18FDG PET/CT as a prognostic indicator.
DETECTION OF RECURRENCE
Early detection and complete localization of relapse is important to select appropriate second-line treatment, and improve survival. Cytoreductive surgery and additional chemotherapy and radiation therapy which may prolong survival largely depend on accurate determination of the extent of disease.3,30
Recent National Comprehensive Cancer Network guidelines recommend that the disease status be monitored with regular physical and pelvic examinations, contrast-enhanced CT, magnetic resonance imaging (MRI), and measurement of serum CA-125 levels, and 18FDG PET/CT.31
CA-125: Approximately 80% of all ovarian cancers present with elevated CA-125 expression.32 In those patients, persistently rising serum CA-125 levels after first-line treatment have a high positive predictive value (>95%) for recurrent disease, but poor negative predictive value (50% to 60%).33
CT and MRI have comparable performance with sensitivity, specificity, and accuracy for CT being 40% to 67%, 93% to 100%, and 66% to 85%, respectively and 62% to 91%, 40% to 93%, and 59% to 90%, respectively for MRI.34 Those techniques are challenged by small-volume recurrence or metastasis (CT sensitivity = 25% to 50% for lesion <1 cm) and lymph node involvement (sensitivity = 40%). In addition, they have limitations for differentiating tumor recurrence from postoperative and postradiation changes.35–37
FDG PET/CT IN DETECTION OF RECURRENT OVARIAN CANCER
Several studies investigated the role of 18FDG PET/CT for posttherapy surveillance of patients (Table 17.4). In a recent meta-analysis, Gu et al.48 showed that 18FDG PET/CT had an area under the receiver operating characteristic curve of 0.96 for detection of recurrent ovarian cancer, which was the best result of all tested techniques: CT = 0.88; CA-125 = 0.92; MR = 0.8. In studies using clinical follow-up as gold standard, FDG PET/CT performance was very high with 74% to 100% sensitivity, 80% to 100% specificity, and 83% to 100% accuracy on patient-based analyses.38–43,49 However, when the gold standard was histopathology, the diagnostic accuracy of PET/CT tended to be poorer (because of the microscopic disease not visualized by any imaging modality) and sensitivity, specificity, and accuracy of patient-based analysis were 41% to 83%, 75% to 94%, and 72% to 82%, respectively.44–46 In a retrospective study of 60 patients with suspected recurrent ovarian cancer, Bilici et al.43 showed superiority of PET/CT over CT with 95.5% versus 55% sensitivity, 93.3% versus 66.6% specificity, and 95% versus 58.3% accuracy.
FIGURE 17.2. FDG PET/CT at restaging of an ovarian serous papillary adenocarcinoma: Pathologic peritoneal uptake not depicted on CT scan (red arrows).
For recurrences localized in abdomen and pelvis, 18FDG PET/CT is limited not only by physiologic uptake in the bladder and bowel loops, but also by post-treatment (i.e., surgery, radiotherapy) inflammatory changes in pelvis. Hence, sensitivity for detection of such lesions is lower than that of MRI (73% versus 93% on patient-based analysis), but PET/CT has slightly higher specificity (91% versus 86%).47 Peritoneal metastasis outside the pelvis seems to be a more favorable situation for PET, with a sensitivity, negative predictive value, and diagnostic accuracy values of PET/CT significantly better than those of MRI particularly for lesions <2 cm (Figs. 17.2 and 17.3).50
Visualization of lymph node involvement by conventional imaging may be difficult because of the inability to distinguish nodal metastases from inflammatory or fibrotic nodes. 18FDG PET/CT appears to be useful, particularly in retroperitoneal lymph nodes with high specificity and positive predictive values of 94% and 82.8%, respectively, despite a weak sensitivity of 40.7%.46 Moreover, the increasing use of PET suggested a reassessment of the classical pattern of lymphatic spread of disease by highlighting a significant number of supradiaphragmatic lesions not depicted by conventional imaging (Fig. 17.4).19,51,52
FIGURE 17.3. FDG PET/CT at restaging of an ovarian serous papillary adenocarcinoma: Obvious peritoneal metastasis on FDG PET (green arrow ) and pathologic peritoneal uptake not depicted on CT scan (red arrow).
Distant metastases are less common, even at restaging. However, the high sensitivity and whole-body examination of 18FDG PET/CT proved to be very useful to determine the correct extent of disease.
18FDG PET/CT not only contributes to the diagnosis of recurrence but also to subsequent therapeutic management in 40% to 60% of patients by depicting otherwise undetected recurrence site or guiding site-specific treatment.40,44,53–56 In a prospective study to assess the impact of 18FDG PET-CT on the management of patients with suspected recurrence and to determine the incremental information provided by PET-CT, Fulham et al.57 showed that at least 168 additional sites of disease in 61 patients (68%), not identified by conventional imaging, were identified by PET-CT. In 77% of cases, the additional lesions were located below the diaphragm and most of them were nodal or peritoneal. PET-CT changed management in 60% (49% high, 11% medium impact). In another recent study, treatment modifications induced by 18FDG PET/CT consisted in : previously unplanned chemotherapy or surgery in 61.2%, and cancellation of diagnostic or therapeutic procedures in 38.8%.43 In addition, Du et al.53 proved very recently that 18FDG PET/CT can help guide radiotherapy in treatment of recurrent ovarian by improving the delineation of gross tumor volume and potentially improve clinical outcome.
FIGURE 17.4. FDG PET/CT at restaging of an ovarian serous papillary adenocarcinoma: Pathologic lymph node, doubtful on CT scan (red arrows).
Neoadjuvant chemotherapy followed by surgical debulking seems to improve outcome but only in patients with complete or nearly complete response to neoadjuvant therapy.54 CT and MRI are limited in detecting response early after the initiation of therapy because anatomic changes take time. A few studies are available regarding the role of 18FDG PET/CT to monitor therapy.
Avril et al.55 demonstrated that after one and three cycles of chemotherapy, 18FDG PET/CT was more accurate for response evaluation to therapy than conventional clinical or CA-125 criteria. A higher rate of complete tumor resection was achieved in metabolic responders (defined as >20% reduction in SUVmax after the first cycle and >50% after the third cycle) than in nonresponders. In addition, metabolic responders had a longer median overall survival than nonresponders. With a threshold for SUVmax decrease from baseline of 20% after the first cycle, median overall survival was 38.3 months in metabolic responders, compared to 23.1 months in metabolic nonresponders. Using a threshold of 55% decrease in SUV after the third cycle, median overall survival was 38.9 months in metabolic responders, compared to 19.7 months in nonresponders. In 21 gynecologic cancer patients (uterine cancer, n = 13; ovarian cancer, n = 8), 18FDG PET/CT performed at the end of chemotherapy, SUV was significantly lower in responders than that in nonresponders.56 Based on these preliminary data, 18FDG PET/CT is promising to predict response to chemotherapy.
PITFALLS OR LIMITATIONS OF 18FDG PET/CT IN OVARIAN CANCER
18FDG PET protocols vary in multiple studies investigating this modality in ovarian cancer. Injected 18FDG activity ranged from 200 to 740 MBq.48 Patients fasted at least 4 hours (more often, 6 hours), and blood glucose level was controlled before intravenous injection. Whole-body imaging was acquired 1 hour after 18FDG injection. The early studies assessed 18FDG PET alone, whereas the most recent ones used an integrated PET/CT system. Interestingly, protocols for CT image acquisition varied much more than PET because of different system capacity and role assigned to CT (anatomic localization only or codiagnostic image).
In the majority of published studies, the main limitation of 18FDG PET/CT was the detection of small or microscopic lesions, because of the spatial resolution of 4 to 6 mm for currently available systems and insufficient 18FDG uptake in small lesions. The inability to detect lesions <1 cm led to a false-negative rate of 5% to 10%.58 However, a recent study by Sanli et al.50 showed that PET/CT was similar to conventional MRI for the detection of recurrence and even better for the detection of small-to-medium-sized (<2 cm) peritoneal implants. Further is necessary.
Other pitfalls are related to physiologic 18FDG concentrations. Normal activity in the urinary system and bladder can interfere with image interpretation in the pelvis. Thus problem can be reduced by administering 20 mg of Furosemide 20 minutes before imaging and having the patient empty her bladder just before the start of image recording. Another approach to limiting the urinary artifact is to have the patient drink 500 mL of water 1 to 2 hours prior to image acquisition and to void just before image acquisition.59
Focal activity in bowel loops and misregistration caused by bowel peristalsis may lead to over or underestimate extent of the disease. In a recent study, Kitajima et al.59 showed that contrast-enhanced CT reduces frequency of equivocal interpretations and improves confidence for assessing ovarian cancer recurrence. Oral contrast allows more accurate identification of the bowel and facilitates the interpretation of abdominal and pelvic CT studies and improves image quality.39
In the evaluation of recurrence, posttreatment inflammatory or fibrotic changes may lead to equivocal interpretations. Caution is necessary when 18FDG PET/CT is performed within 6 months of surgery. Detailed knowledge of previous treatment and other imaging results improves interpretation. False-negative 18FDG PET/CT results may also occur in patients with cystic or necrotic lesions or lesions with copious mucinous collections.60
Considering these pitfalls, careful review and correlation with the conventional imaging findings and patient’s history are required for accurate interpretation.
TARGETED RADIONUCLIDE THERAPY
The prognosis for patients with advanced disease remains poor with a 5-year survival rate of less than 40%. There is a need for innovative treatment modalities. After primary standard treatment combining debulking surgery and chemotherapy using platinum and paclitaxel, frequency of relapses is up to 50%. These relapses are generally confined to the peritoneal cavity and may be amenable to intraperitoneal (IP) therapy.
For the last 20 years, several phase I/II IP radioimmunotherapy clinical trials have been performed using different antibodies labeled with different radionuclides including iodine-131, yttrium-90, lutetium-177 and, more recently, astatine-211.61–67 Two studies were limited to evaluation of toxicity. The other phase I/II studies included a total of 92 patients.61,63,64,67 Transitory tumor regression was observed in 14 patients, in small-volume tumors of less than 5 mm.
Finally, a randomized phase III trial has been performed in 447 patients using yttrium-90-labeled anti-MUC1 antibody (HMFG1) murine antibody.68 Those patients had a macroscopically negative second-look laparoscopy and so were assumed to have a microscopic residual disease that is the optimal indication for radioimmunotherapy (RIT). Unfortunately, this large, prospective trial failed to demonstrate significant improvement in overall survival. This lack of efficacy confirmed an earlier limited phase II trial with a rigorous systematic histologic evaluation.65 The protocol included second-look surgery to assess the extent of the disease and third-look surgery to assess the response to RIT. This protocol was very demanding for patients which accounts for the limited number of six enrolled patients. There was no evidence of efficacy.
Some attempts to explain the lack of efficacy of IP RIT despite the favorable clinical status (microscopic disease) have been made. IP adhesions prevent homogeneous distribution of radiolabeled antibody in the abdominal cavity.65 This problem could be overcome if several catheters were inserted into the abdominal cavity and if treatment was performed immediately after laparotomy when it is possible to avoid leakage. Accessibility of tumor antigen for the radiolabeled antibody can be another problem, such as submesothelial location of tumor metastases.65 The activity levels may have been insufficient for an effective tumor absorbed dose. Retreatment might improve results. Finally for ovarian carcinoma, even if the bulk of tumor metastases is located within the abdominal cavity, some metastases are frequently located in retroperitoneal lymph nodes, bone marrow, and blood and are thus not accessed reached by intraperitoneally injected radiolabeled antibody.
Combined IP and IV RIT might provide a solution as well as IP RIT in combination with chemotherapy or repeated IP RIT.
Other PET Tracers
Tracers other than 18FDG have been evaluated in patients with ovarian cancer. Yoshida et al.69 evaluated whether 16α-18F-fluoro-17β-estradiol (FES)-PET could provide useful information to assess estrogen receptor status in advanced ovarian cancer. On three patients, the FES uptake was associated with ER status, particularly ER-α status. Torizuka et al.70 compared 18F-FDG PET with 11C-choline PET in 21 patients including 18 untreated patients with gynecologic malignancies and 3 with suspected relapse and found that 11C-choline PET detected lesions in a higher number of patients than 18F-FDG PET but 11C-choline did visualize small peritoneal disease in recurrence of ovarian cancer.
Aide et al.71 showed that 18F-FLT PET could be useful to monitor early response to treatment with mammalian target of rapamycin (mTOR) inhibitors in an animal model of cisplatin-resistant ovarian tumor. Expression of human epidermal growth factor receptor-2 (HER2). 18F-FLT is a potential biomarker for early response to targeted therapies. Affibody Ga-68 and Antibody Zr-89 are other promising probes for imaging HER2 expression in vivo.72,73
PET/MRI in ovarian cancer is a new hybrid imaging modality that would provide an alternative to a PET/CT scanner for whole-body imaging for the detection, staging, characterization, and functional therapy monitoring of ovarian cancers. At this time, no studies are available.
The role of nuclear medicine in ovarian cancer management is currently limited to 18FDG PET/CT. Although 18FDG PET/CT value in the characterization of adnexal masses and the initial assessment of ovarian cancer remain controversial, there is now strong evidence to support its use for early detection and restaging of recurrent disease. Its contribution is particularly important in patients with rising CA-125 levels and negative morphologic imaging results to improve treatment selection but also for patients with normal CA-125 level and abnormal CT scan to avoid unnecessary procedures. 18FDG PET/CT has to be carefully interpreted with other imaging and clinical information. 18FDG PET/MR may improve the detection and staging of ovarian cancer.
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