Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a widely used diagnostic tool in oncologic imaging. It is commonly used to evaluate malignancies including lymphoma, breast, head and neck, lung, esophageal, colorectal, and gynecologic cancers.118F-FDG PET/CT is a hybrid imaging technique that combines the metabolic information from PET with the anatomical detail from CT in a single examination. It relies on the increased glucose metabolism exhibited by cancer cells resulting in the accumulation of radiolabeled FDG and enabling the identification of tumor lesions. The combined synergistic use of PET and CT has diagnostic advantages over PET and CT alone.2 Its unique ability to visualize both functional and structural aspects of tissues allows for precision imaging with early detection, staging, and treatment planning, monitoring therapeutic response, targeted radiation therapy, and evaluation of recurrence.3 From early detection to treatment response assessment, 18F-FDG PET/CT has pivotal role in optimizing patient care and outcomes. It impacts patient management and changes the management course in about 27% of patients.1 Given the excellent soft tissue contrast and lack of ionizing radiation of magnetic resonance imaging (MRI), 18F-FDG PET/MRI has unique advantages over 18F-FDG PET/CT.4 Lymphoscintigraphy, using radiotracers such as technetium 99m (99mTc) based radiopharmaceuticals along with single photon emission computed tomography/ computed tomography (SPECT/CT), also holds a vital role in the identification of sentinel lymph nodes to minimize the surgical morbidity from extensive lymph node dissections. In addition, other novel imaging radiotracers give insight into various molecular tumor biomarkers and targets for radioligand therapies.

Gynecologic malignancies of endometrial, cervical, ovarian, vulvar, and vaginal origin pose significant diagnostic and management challenges due to their complex anatomic location and potential for rapid progression. These tumors cause substantial morbidity and mortality due to delayed diagnosis and treatment.5 An estimated 19% of newly diagnosed cancers amongst women are gynecologic in origin.6 In recent years, there has been growing evidence supporting the integration of nuclear medicine imaging modalities in the diagnostic work-up and management of gynecologic cancers.7 This article has the following aims: 1) To describe the role of nuclear medicine in the initial staging, lymph node mapping, response assessment, and recurrence/surveillance imaging of common gynecologic cancers, 2) To review the limitations of 18F-FDG PET/CT and promising applications of 18F-FDG PET/MRI in gynecologic malignancy, 3) To underscore the promising theragnostic applications of nuclear medicine, 4) To highlight the current role of nuclear medicine imaging in gynecologic cancers as per the National Comprehensive Cancer Network (NCCN), European Society of Surgical Oncology (ESGO), and European Society of Medical Oncology (ESMO) guidelines Table 1.

Endometrial cancer is the most common malignancy of the female reproductive system, comprising a substantial 56% of gynecologic malignancies and encompassing various histological subtypes such as endometrioid adenocarcinoma, mucinous adenocarcinoma, serous carcinoma, clear cell carcinoma, neuroendocrine tumors, mixed adenocarcinoma, as well as undifferentiated and dedifferentiated carcinoma.8 To combat this prevalent cancer effectively, accurate staging, and tailored treatment strategies are essential. In recent years, the integration of imaging modalities, particularly MRI and 18F-FDG PET/CT, has revolutionized the diagnosis, staging, and management of endometrial cancer.9

The cornerstone of successful endometrial cancer management lies in proper staging, enabling informed decisions about treatment approaches and risk assessment. Although the International Federation of Gynecology and Obstetrics (FIGO) staging system is primarily surgical, complementary preoperative imaging for estimating the preoperative stage adds a layer of precision to evaluate tumor size, myometrial, and cervical involvement, adnexal status, and lymph node involvement.10 This information helps in stratifying the risk of recurrence, determining optimal treatment regimens, and even predicting overall survival (OS).11 The primary treatment for endometrial cancer is hysterectomy with bilateral salpingo-oophorectomy, often accompanied by pelvic lymphadenectomy and, if necessary, para-aortic lymphadenectomy.12 Lymphadenectomy for staging purposes is usually reserved for patients with high-risk disease because of its associated perioperative complications and long-term morbidity. High-risk features in endometrial cancer are defined as high-grade histology (grade 3 endometroid adenocarcinoma and other nonendometroid subtypes such as serous carcinoma, clear cell carcinoma, and carcinosarcoma), a primary tumor larger than 2 cm, and deep (>50%) myometrial invasion or cervical stromal invasion.13

As several of the high-risk features of the primary tumor predict the likelihood of nodal metastases, preoperative imaging with MRI is often obtained to determine if lymphadenectomy will be required. MRI exhibits high sensitivity (70%-95%) and specificity (80%-95%) in assessing the depth of myometrial invasion while also accurately evaluating adnexal involvement (accuracy: 92%), cervical stromal involvement (accuracy: 90%-92%), and nodal metastases (sensitivity: 57%, specificity: 93%). Diffusion-weighted imaging (DWI) further heightens the sensitivity for lymph node identification to 87%, albeit at the expense of specificity.14 MRI is also advocated in fertility-sparing treatment planning cases due to its excellent soft tissue contrast resolution.14

The role of 18F-FDG PET/CT in the detection and local staging of endometrial cancer remains evolving. The performance of 18F-FDG PET/CT is limited in detecting the primary tumor secondary to normal physiological endometrial uptake in the pre and peri-menopausal women during menstrual and ovulatory phases of the menstrual cycle.15 A meta-analysis reported a moderate sensitivity (81.9%) and specificity (89.8%) for the detection of primary endometrial cancer in high-risk groups.16 Studies have also shown that high standardized uptake values (SUVmax) and total lesion glycolysis (TLG) of the primary tumor correlate with reduced disease-specific survival, shedding light on potential prognostic implications.17,18 The main utility of 18F-FDG PET/CT in the initial staging of endometrial cancer is its reliability in detecting metastases in pelvic and para-aortic lymph nodes.19 A systematic review and meta-analysis evaluating the role of preoperative 18F-FDG PET/CT in detecting lymph node metastases reported an overall pooled sensitivity, specificity, and accuracy of 72%, 94%, and 94%, respectively.20 According to the ACRIN 6671/GOG 0233 trial consisting of 215 patients with high-risk endometrial cancer, the sensitivity of 18F -FDG PET/CT combined with contrast-enhanced CT was superior to contrast-enhanced CT alone for the detection of lymph node metastases 65% vs 50% in the abdomen and 65% vs 48% in the pelvis, respectively. Specificities were relatively similar at 88% vs 93% in the abdomen and 93% vs 89% in the pelvis, and the diagnostic accuracy was 78% vs 74% in the abdomen and 82% vs 73% in the pelvis.21 Compared to diagnostic CT alone, the addition of PET to diagnostic CT significantly increased the sensitivity of lymph node detection in both the abdomen and pelvis while maintaining a high specificity.

Approximately 10%-15% of patients with endometrial cancer present with advanced-stage disease and harbor disease beyond the uterus and abdominopelvic lymph nodes.22 In these patients, 18F-FDG PET/CT can be considered to identify sites of distant metastatic disease that would obviate the morbidity of staging surgery (Fig. 1). In the aforementioned ACRIN 6671/GOG 0233 multicenter trial, the overall prevalence of distant metastases was 11.8% (24 of 203 patients) for endometrial cancer. In these patients, 18F-FDG PET/CT had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 64.6%, 98.6%, 86.1%, and 95.4%, respectively, for the detection of distant metastases.23 Given the high specificity and PPV, the authors recommended that 18F-FDG PET/CT be included in the staging evaluation.23 The most updated NCCN and ESMO guidelines state that 18F-FDG PET/CT can be considered in high-risk endometrial cancer cases, for staging purposes, especially when there is high suspicion for distant metastasis.24,25

Lymph node status is an important prognostic factor in endometrial cancer.26 Traditional lymphadenectomy (LAD) involves the removal of many lymph nodes in the pelvis and para-aortic regions, which can be associated with increased morbidity. Sentinel lymph node mapping (SLNM) aims to identify the first lymph nodes to receive drainage from the primary tumor site, which are more likely to harbor metastases if present. Retrospective and prospective studies suggest that SLNM could be a reliable alternative to systemic LAD for surgical staging in cases of apparent uterine-confined disease, while maintaining low false-negative rates.23,25 A multi-institutional retrospective study performed by Bogani et al.27 comparing the long-term oncologic results of SLNM, SLNM with LAD, and LAD found that there was no statistical difference between the three strategies in terms of disease-free survival (DFS) (p = .570) and OS (p = .911). Bodurtha et al.28 published a meta-analysis of 4915 patients in 55 studies. They reported an overall SLNM detection rate of 81% and a bilateral pelvic node detection rate of 50% in patients with endometrial cancer (sensitivity:96%, NPV: 99.7%).

For patients with low-risk (ie, stage I grade 1 or 2 endometroid adenocarcinoma with tumors <2 cm with less than 50% myometrial invasion) endometrial cancer, SLNM detection methods include the use of blue dye, indocyanine green (ICG), radiotracers, carbon nanoparticle, and a combination method.26 Using a gamma probe or near-infrared imaging system, the surgeon identifies and removes the lymph nodes with the highest radioactivity or fluorescence signal. Cervical injection is the primary approach, achieving an 87% detection rate.8 ICG, the most recommended method, demonstrates a high sensitivity and negative predictive value.26 Radiopharmaceuticals, such as 99mTc radiocolloids, are also preferred due to their higher sensitivity in comparison to blue dyes, which are not recommended as standalone agents. SPECT/CT enhances the sensitivity of SLN detection from 67%-68% to 77%-84%.26 While SLNM can be applied for ultrastaging in low-risk endometrial cancers, its application in intermediate and high-risk cases is still under investigation. High-risk patients may still require more extensive lymphadenectomy. The NCCN guidelines suggest using SLNM for patients with endometrial cancer confined to the uterus, with no metastases evident on imaging or significant extrauterine disease detected.24

After initiating treatment, monitoring the tumor's response to therapy is vital. Traditional anatomical imaging, such as CT or MRI, may not capture early changes in tumor metabolism. 18F-FDG PET/CT, on the other hand, can detect alterations in glucose metabolism, which often occur before noticeable size changes are observed.

For assessing treatment response, 18F-FDG PET/CT can be performed, with changes in metabolic activity offering valuable insights into metabolic changes post-therapy.8 Several studies have investigated the utility of 18F-FDG PET/CT in response assessment for endometrial cancer. A study conducted by Nishiyama et al.29 involving 21 patients who underwent 18F-FDG PET/CT before and after chemotherapy demonstrated that alterations in FDG uptake were associated with treatment response with a sensitivity of 90% and specificity of 80% for differentiating responders from nonresponders. The extent of metabolic response on 18F-FDG PET/CT can also have prognostic implications. A more favorable metabolic response is often associated with better long-term outcomes.30 Despite this encouraging data, 18F-FDG PET/CT is not routinely recommended in response assessment of endometrial cancer by the NCCN, ESMO, and ESGO guidelines.24,25,31

The use of 18F-FDG PET/CT for the detection of recurrent endometrial cancer has been reported to have a high pooled sensitivity, specificity and accuracy of 95%, 91% and 97%, respectively in a systematic review and metanalysis involving eight studies and 378 patients by Bollineni et al.20 Another meta-analysis involving 11 studies and 541 patients found high efficacy of 18F-FDG PET/CT in detecting recurrence of endometrial cancer with a pooled sensitivity of 95.8% and pooled specificity of 92.5%. In this study, 18F-FDG PET/CT also changed management in 22%-35% of the studied patients.32

Although 18F-FDG PET/CT is sensitive in detecting metabolically active malignancy, modalities like MRI can provide superior soft tissue contrast, which can be particularly helpful in detecting local recurrence in the pelvis, lymph nodes, and peritoneum.14 The precise surveillance regimen, including the frequency of imaging and the role of 18F-FDG PET/CT, should be individualized based on the initial stage, risk factors, and other clinical considerations. As 20%-25% of patients with high-risk disease can develop recurrence within the first 2-3 years, the NCCN guidelines recommend 18F-FDG PET/CT for surveillance and detection of recurrence in high-risk patients who have completed initial treatment.24 The ESGO and ESMO guidelines also support the use of 18F-FDG PET/CT over CT for cases where recurrence is likely.25,31

Cervical cancer is the fourth most common cancer in women worldwide, comprising 13% of all gynecologic cancers.8 Most cases occur in low- and middle-income countries where access to screening and vaccination might be limited.8,33 When assessing the progression at the time of presentation, 54% of cases present with localized disease, 36% show regional spread, and 16% have distant metastases.33 The survival outcomes vary significantly depending on the stage at diagnosis. The 5-year survival rate for localized cases is 92%, however, this decreases to 58% for those with regional spread and further decreases to 18% for those with distant metastases. Squamous cell carcinoma (SCC) dominates the histological sub-types of cervical cancer, accounting for a significant 80% of all diagnosed cases.33 Early detection and treatment are crucial for a favorable outcome. When accessible, imaging techniques like CT, MRI, and 18F-FDG PET/CT are invaluable in influencing patient care and therapeutic decisions.34 Small (<4 cm) local tumors confined to cervix are treated with radical hysterectomy and bilateral salpingo-oophorectomy or trachelectomy (fertility sparing surgery) whereas tumors extending into the parametrium and beyond are treated with concurrent chemoradiotherapy.35

When detected at an early stage, cervical cancer has a good prognosis with high survival rates.34 While MRI offers superior soft-tissue contrast, which can be especially helpful in assessing locoregional disease and facilitating patient selection for fertility sparing surgery, 18F-FDG PET/CT consistently demonstrates superior performance than both CT and MR imaging when evaluating nodal and distant metastatic disease.17 Lymphadenopathy, now included in the 2018 FIGO staging system, is one of the major factors driving treatment planning and is one of the best indicators of prognosis.36 The degree of lymph node involvement, as discerned through 18F-FDG PET/CT, emerges as a potent predictor of disease-specific survival.

A systematic review and meta-analysis including 12 studies and 778 patients with locally advanced cervical cancer demonstrated a high pooled sensitivity (88%) and pooled specificity (93%) for pelvic lymph node detection on 18F-FDG PET/CT. Conversely, the pooled sensitivity for para-aortic lymph node detection was low at 40% while the pooled specificity remained high at 93%.37 For patients with advanced-stage cervical cancer without evident nodal metastasis on anatomic imaging, studies using histopathology as the gold-standard have also shown that 18F-FDG PET and 18F-FDG PET/CT offer a wide range of sensitivity (65%-86%) and a high specificity (94%-97%) for lymph node detection.38,39 According to the ACRIN 6671/GOG 0233 trial involving 153 patients with advanced cervical cancer, 18F-FDG PET/CT combined with contrast-enhanced CT had a better sensitivity compared to diagnostic contrast-enhanced CT alone for the detection of lymph node metastases in the abdomen (50% vs 40% respectively) with similar specificities (85% vs 89%).40 In the aforementioned ACRIN multicenter trial, the overall prevalence of distant metastases was 13.7% (21 of 153 patients) for cervical cancer.2318F-FDG PET/CT had a sensitivity, specificity, PPV, and NPV of 54.8%, 97.7%, 79.3%, and 93.1%, respectively, for the detection of distant metastases in patients with cervical cancer.23

Importantly, a preoperative 18F-FDG PET/CT also adds prognostic value in patients with cervical cancer. Primary tumors with a high SUVmax are associated with an increased risk of nodal metastasis at diagnosis, persistent disease after chemoradiotherapy, and worse overall survival.41 Other quantitative parameters derived from 18F-FDG PET/CT such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) can provide additional prognostic information. A study by Bollineni et al. reported that a high MTV on the pretreatment 18F-FDG PET/CT is an independent predictor of decreased progression/recurrence free survival.42

In summary, while 18F-FDG PET/CT has a limited role in nodal staging in early-stage cervical cancer, it continues to demonstrate high sensitivity and specificity in the detection of both nodal disease as well as distant metastases in locally advanced cervical cancer. Therefore, it is recommended by the NCCN, ESMO, and ESGO guidelines for staging locally advanced cervical cancer (Stage 1B3 to IVA disease).35,43,44

18F-FDG PET/CT is also customarily employed for radiation therapy planning. Its ability to delineate metabolically active disease can assist with targeting radiation fields more precisely, particularly in patients with positive pelvic or para-aortic lymph nodes on 18F-FDG PET.34 Combining 18F-FDG PET/CT and MRI can offer comprehensive insights, and both are frequently used in tandem for pretreatment planning and prognostication.

Lymph node status is a crucial factor for prognosis in cervical cancer, much like in endometrial cancer. Traditional LAD, which involves removing lymph nodes in both pelvic and para-aortic regions, can increase morbidity. Therefore, SLNM is often employed as a technique and has been rapidly adopted in managing early-stage cervical cancer due to its potential to provide accurate nodal staging with reduced morbidity. A study of 103 patients with early-stage cervical cancer who underwent SLN mapping using 99mTc nanocolloid +/- methylene blue reported an overall detection rate of 100%, bilateral detection rate of 83%, and NPV of 100%. No pelvic or para-aortic lymph node recurrences occurred with a median follow-up of 53 months.45

Various detection methods for SLN mapping are available, including blue dye, indocyanine green (ICG), radiocolloids, carbon nanoparticles, and a combination of these agents. Among these, ICG is highly recommended due to its excellent sensitivity and negative predictive value.46,47 Most centers currently in United States utilize the optical tracer method. When 99mTc radiocolloids are used, then an intraoperative portable gamma probe is used to localize the SLN. When available, portable gamma cameras offer better localization of SLNs and the ability to discriminate physiologic activity. Cervical injection is the primary method of introducing these agents, consisting of 0.5-1 mL injections into the submucosal layer of the cervix at the 3, 6, 9, and 12 o'clock positions.

A meta-analysis by Wang et al. described that in early-stage cervical cancer, the combined overall detection rate using blue dye with 99mTc, 99mTc alone, and ICG for SLN mapping was 95%, with a bilateral detection rate of 72%. The overall detection rate of SLN was 96% for blue dye with 99mTc, 95% for 99mTc alone, and 98% for the ICG technique. The bilateral detection rate of SLN was 76% for blue dye with 99mTc, 63% for 99mTc, and 85% for the ICG technique.48

Preoperative SPECT/CT provides three-dimensional images with better contrast and spatial resolution than planar images alone, resulting in precise anatomic localization of the SLN, depiction of lymph nodes closer to the radiocolloid injection site, and detection of SLNs in unexpected or uncommon locations such as the para-aortic and presacral regions. SPECT/CT also assists with the visualization of bilateral lymphatic drainage and reduces the false-positive findings such as focal radiocolloid activity in enlarged lymphatic vessels.49 According to the NCCN guidelines, considering SLNM for early-stage cervical cancer cases measuring <2 cm, and FIGO stages IA1 (with lymphovascular space invasion), IA2, IB1, IB2, and IIA1 is advised.35,50 This approach can aid in minimizing the need for lymph node dissection in early stages of cervical cancer.

The management and monitoring of patients undergoing treatment for cervical cancer, especially those receiving concurrent chemoradiotherapy (CCRT), are crucial for optimizing outcomes. In this context, advanced imaging modalities like MRI and 18F-FDG PET/CT play a pivotal role in gauging treatment response and predicting prognosis.51

MRI is particularly recommended for patients set to undergo CCRT.14 Its ability to provide a detailed anatomical visualization helps to assess the extent of disease and potential treatment-related changes. On the other hand, while 18F-FDG PET/CT is an invaluable tool in the post-treatment setting, it is recommended that its use be deferred until 3-6 months after treatment.8,14 This primarily prevents false-positive results arising from post-treatment inflammatory changes that can mimic disease recurrence.52

The prognostic value of post-treatment 18F-FDG PET/CT scans has been emphasized in a study by Grigsby et al. involving 152 patients who underwent pre and post-treatment scans. In this study, the 114 patients with no residual abnormal FDG uptake post-treatment had an encouraging 5-year survival rate of 92%. Conversely, those with persistent or new FDG uptake faced significantly poorer outcomes with 5-year survival rates of 46% and 0%, respectively.52 As such, patients with a complete metabolic response on post-therapy 18F-FDG PET/CT have lower recurrence rates and higher overall survival compared to those with a partial metabolic response or progressive disease.

These above findings solidify the idea that 18F-FDG PET/CT's role in the post-therapy evaluation of cervical carcinoma extends beyond assessing treatment response to also being a predictor of survival outcomes. Incorporating these imaging modalities into cervical cancer treatment and monitoring algorithms can significantly enhance patient management. As recommended by the NCCN, ESMO, and ESGO guidelines, standard practice involves conducting 18F-FDG PET/CT both at the baseline and then again 3 months post-treatment. 43,44,50 Such a regimen provides insights into the initial disease status and the efficacy of the treatment received (Fig. 2). The international guidelines recommend considering repeat imaging in 3 months if the first post-treatment 18F-FDG PET/CT is indeterminate.50

Cervical cancer recurrence poses a significant diagnostic challenge, often due to the changes induced by treatments such as surgery, radiation, and chemotherapy. Recurrence occurs in approximately a third of patients within 2 years posttreatment.8 Given the high rate of recurrence, an accurate diagnosis of recurrence is crucial. MRI is commonly employed to evaluate known or suspected locoregional recurrence.14 It provides an accurate diagnosis in identification of site and extent of local recurrence and guide further treatment, including predicting likelihood of achieving complete surgical resection. In cases where CT or MRI are equivocal, especially in symptomatic patients with suspected recurrence or high risk of recurrent disease, 18F-FDG PET/CT is generally the next step for further evaluation.17 In addition, 18F-FDG PET/CT is recommended when considering patients for salvage therapy and is invaluable in radiation therapy planning and surgical planning during pelvic exenteration.53 A systematic review and meta-analysis including 20 studies evaluating the role of 18F-FDG PET/CT in detecting cervical cancer recurrence showed a pooled sensitivity of 82% and pooled specificity of 98% for the detection of distant metastases.54 In a study by Chong et al.55 involving 32 patients with tumor markers including carcinoembryonic antigen (CEA) or squamous cell carcinoma antigen (SCC-Ag) unexplained by conventional imaging, 18F-FDG PET/CT was an invaluable tool with a 100% sensitivity and 100% NPV. 18F-FDG PET/CT also has been shown to have implications on prognosis and treatment decisions. A study by Peng et al.56 suggested that the MTV and TLG derived from 18F-FDG PET/CT were associated with high-risk features and could serve as a prognostic biomarker of survival in patients with recurrent cervical cancer. In another study by Chung et al.57 involving 276 patients, those with a negative PET/CT result exhibited enhanced progression-free survival (PFS) and OS. Furthermore, the study highlighted that posttreatment 18F-FDG PET/CT influenced the alteration of treatment strategies in approximately 24.2% of the examined patients. In summary, 18F-FDG PET/CT plays a crucial role in evaluating patients with suspected recurrence, particularly when CT and MRI are equivocal, as well as in monitoring of patients at high risk of disease recurrence. The NCCN and ESMO guidelines recommend 18F-FDG PET/CT surveillance imaging at 3-6 months after completion of treatment.43,50

Ovarian cancer is the fifth most common cause of cancer deaths in women, comprising 20% of all gynecologic cancers.8,58 Epithelial ovarian cancer is the most predominant subtype, constituting around 90% of all ovarian cancers.8 Within the epithelial category, high-grade serous is the most common, followed by endometrioid, clear cell, low-grade serous, and mucinous tumors.8 Despite advances in treatment, ovarian cancer continues to be the most lethal among gynecological cancers.59 This is primarily because of lack of appropriate screening tests and nonspecific symptoms, leading to late-stage diagnoses.60 However, this statistic varies significantly based on the stage of diagnosis. Early-stage ovarian cancer has a much more favorable prognosis with a 5-year survival rate of 87% whereas late-stage disease has a poor 5-year survival rate, at just 11%. Overall, the 5-year survival rate is 50%.60 The discrepancy in survival rates underscores the importance of early detection and intervention in improving outcomes for those diagnosed with ovarian cancer.

The stage at initial diagnosis is a main prognostic factor in ovarian cancer.59 Imaging for preoperative staging in ovarian cancer is essential for evaluating the extent of disease and determining the feasibility of either primary cytoreductive surgery or adjuvant platinum-based chemotherapy followed by cytoreductive surgery.61 Typically, the first-line imaging modality for the detection and characterization of an adnexal mass is a transvaginal ultrasound with MRI recommended next if results are inconclusive.8 MRI demonstrates superior accuracy compared to CT for characterization of an adnexal mass as well as identification of serosal and peritoneal implants.14,61 The use of 18F-FDG PET/CT is not well established in initial detection and staging of ovarian cancer.61,62 Although there are several studies which have demonstrated similar or higher sensitivities and specificities of 18F-FDG PET/CT compared to transvaginal ultrasound in differentiating between benign and malignant tumors, it generally is limited in its ability to differentiate reliably between benign and borderline adnexal tumors.63, 64, 65 Contrast-enhanced CT is the current standard of care in preoperative ovarian cancer staging and is widely used with an accuracy ranging between 70%-90%.14,61 Kitajima et al.66 evaluated 40 patients who underwent preoperative staging with integrated 18F-FDG PET/CT and intravenous contrast-enhanced CT in comparison to enhanced-CT alone and found an improved sensitivity (from 37.6% to 69.4%), improved accuracy(from 97.1% to 97.5%), and similar specificity (97.1% vs 97.5%) with integrated 18F-FDG PET/CT and intravenous contrast-enhanced CT. Another potential role in this context is to clarify or further investigate ambiguous findings on CT scans that might elevate the cancer staging and change management. A study by Nam et al.63 involving 133 women with suspected ovarian cancer reported a concordance of 78% between 18F-FDG PET/CT and final pathologic staging. Additionally, 18F-FDG PET/CT findings of unexpected extra-abdominal lymph node metastases were reported in 15 of 95 patients with confirmed ovarian cancer. Some studies have even suggested that 18F-FDG PET/CT also provides quantitative prognostic information by demonstrating TLG as an independent factor for PFS in patients with epithelial ovarian cancer.67,68 Despite these promising results, 18F-FDG PET/CT alone is not sensitive enough to replace surgical staging. 18F-FDG PET/CT, however, is useful in patients with suspected advanced disease at initial staging for detecting distant metastases including extra-abdominal lesions and lesions that may contradict primary cytoreduction.8

Historically, SLN mapping has not been a standard approach for ovarian cancer staging, mainly because ovarian cancer has a tendency for transperitoneal spread rather than predominantly lymphatic dissemination like cervical or endometrial cancer.69 Tumors diagnosed in the initial stage (stage I–II) require complete staging surgery to histologically assess the possible existence of peritoneal or lymph node disease.8 There has been increasing interest in applying SLN techniques in ovarian cancer, particularly for early-stage disease. The hope is that it may offer a less morbid alternative to comprehensive lymphadenectomy by reducing surgical complications. In a systematic review including 14 studies, the detection rate of the SLN was influenced by factors such as the type of tracer and injection site, resulting in an overall pooled detection rate of 86%.70 Although there are clinical trials exploring the role of SLN mapping in early-stage ovarian cancer, comprehensive lymphadenectomy, when indicated, remains the gold standard in the staging of ovarian cancer.71

The primary treatment for advanced ovarian cancer includes cytoreductive surgery and platinum or taxane-based chemotherapy.72 For monitoring treatment response, CT and MRI are conventionally used due to their superior anatomic detail. Anatomical responses such as the reduction in tumor size often take time to manifest, making it a delayed indicator of treatment effectiveness.73 Despite increasing interest in utilizing 18F-FDG PET/CT to assess the treatment response in ovarian cancer, current data is limited. One promising use of 18F-FDG PET/CT is in the early identification of responders vs nonresponders by gauging their metabolic changes post-therapy.74 A study by Vallius et al.75 showed that an omental SUVmax reduction of less than 57% correlated with histopathological non-responders in patients receiving neo-adjuvant chemotherapy before primary debulking surgery. 18F-FDG PET/CT can also be a prognostic marker during disease monitoring. A study of 168 patients by Caobelli et al. demonstrated that a negative restaging 18F-FDG PET/CT conducted at least 6 months after the primary surgery and completion of adjuvant treatment correlated with significantly higher PFS and higher OS after 4 years of follow-up compared to patients with positive 18F-FDG PET/CT at the end of treatment.76 A recent ancillary PET study from the CHIVA trial showed that 18F-FDG PET/CT using the European Organization for Research and Treatment of Cancer (EORTC) criteria or the PET Response Criteria in Solid Tumors (PERCIST) helped evaluate early tumor response and predict second-look surgery outcomes including PFS and OS.77 However, neither metabolic active tumor volume (MATV) nor TLG helped predict survival. More research is needed to fully elucidate and validate the role of 18F-FDG PET/CT in the context of treatment monitoring in advanced ovarian cancer. Nonetheless, the NCCN guidelines recommend considering 18F-FDG PET/CT for monitoring treatment response after primary chemotherapy or adjuvant chemotherapy.71

18F-FDG PET/CT has emerged as a significant tool in evaluating and managing suspected recurrent ovarian cancer.74 One utility of 18F-FDG PET/CT is in patients with a rising CA-125 level and negative or inconclusive findings on CT or MRI (Fig. 3).14 A systematic review and metanalysis including 34 studies showed that 18F-FDG PET/CT had the highest pooled sensitivity of 91% and highest diagnostic accuracy (AUC 0.9555) in detecting recurrent ovarian cancer when compared to CA-125 (AUC 0.9219), PET alone (AUC 0.9297), CT (AUC 0.8845), and MRI (AUC 0.7955).78 One retrospective study by Iagaru et al. including 43 patients reported a sensitivity of 88% and specificity of 88% for the detection of recurrent ovarian cancer with a statistically significant difference in the average CA-125 tumor marker levels between those with positive scans (CA-125: 265 u/mL) and negative scans (CA-125: 17u/mL).79 Several studies reported that 18F-FDG PET/CT changed management in 30% to 58% of patients, either by guiding towards unplanned therapies or avoiding planned diagnostic procedures. This is concordant with findings from the US National Oncology PET Registry which showed 18F-FDG PET/CT changed management in 38% to 45% of cases on restaging scans.67 The NCCN guidelines recommend 18F-FDG PET/CT as clinically indicated for the surveillance and suspected recurrence of ovarian cancer, especially with rising tumor markers, an unreliable physical exam, and negative findings on other imaging modalities.71 These are also similar to the ESMO-ESGO and ESMO guidelines which recommend 18F-FDG PET/CT in patients with rising CA-125 levels and negative or equivocal cross-sectional imaging.80,81 While initial staging and management of ovarian cancer predominantly rely on modalities like CT, MRI, and serum CA-125 levels, 18F-FDG PET/CT plays a pivotal role in suspected recurrence.

Vulvar cancer comprises about 5% of all gynecologic malignancies.8 Squamous cell carcinoma is the predominant histological type, accounting for approximately 90% of all vulvar cancers, followed by melanoma, basal cell carcinoma, adenocarcinoma, and Paget disease.8,82 At the time of diagnosis, 60% of patients have localized disease, 28% have regional nodal spread, and 6% have distant metastases with 5-year survival rates based of 86%, 51%, and 21% respectively.8 Given that survival rates correlate with the extent of disease at diagnosis, this underscores the critical nature of early detection and intervention in vulvar cancer.

Imaging is not always mandated for the initial evaluation of vulvar cancer, particularly in cases of localized disease.83 While 18F-FDG PET/CT can provide metabolic information about the tumor and potential metastatic sites, its resolution might not be as detailed as anatomical imaging modalities like contrast-enhanced CT or MRI for local T staging. When there is low suspicion for metastatic disease, MRI is preferred for assessing the primary tumor's size, depth, extent, and invasion of adjacent organs.84 The accuracy rate of MRI for staging is approximately 85%.14,84 However, specific clinical parameters might necessitate further evaluation. 18F-FDG PET/CT is primarily reserved for scenarios where there is a strong clinical suspicion of lymph node involvement or distant metastases. Some studies have found that 18F-FDG PET/CT performs well in discriminating metastatic from nonmetastatic lymph nodes.85,86 A systematic review and meta-analysis evaluating 18F-FDG PET/CT's ability to detect lymph node involvement on a per-patient analysis demonstrated a pooled sensitivity, specificity, PPV and NPV of 70%, 90%, 86%, and 77%, respectively.87 This study also suggested that a negative preoperative scan may exclude nodal metastases in vulvar cancer patients and, as such, select those eligible for less invasive surgical treatment, at least in early-stage patients currently unfit for SLNM. A positive 18F-FDG PET/CT should be interpreted cautiously, as false positives can be seen with inflammatory lymph nodes.87 Although findings of distant metastases at diagnosis are relatively rare in vulvar cancer, identifying them accurately is crucial for prognosis and proper treatment planning. In essence, 18F-FDG PET/CT is primarily reserved for scenarios where there is a strong clinical suspicion of lymph node involvement or distant metastases. The NCCN Guidelines recommend its use for advanced local disease, T2 or larger tumors, or when there are clinical indications suggestive of metastatic involvement.88 It can also be considered in patients with positive sentinel nodes to evaluate for undissected nodal disease in the groin or pelvis that may require treatment.89

SLN biopsy remains the gold standard for assessing lymph node involvement in early-stage vulvar cancer.85,90 One of the most significant prognostic factors in vulvar cancer is the involvement of the inguinal lymph nodes. The NCCN guidelines recommend lymphoscintigraphy for early-stage tumors (T1b or T2) when there's no clinical suspicion of lymph node metastasis as well as no history of vulvar surgery.89 Ideal candidates for sentinel node mapping in vulvar cancer typically have a unifocal tumor, less than 4 cm in diameter, a depth of stromal invasion greater than 1 mm, and clinically negative nodes.8 While traditional methods like blue dyes and radiocolloid lymphoscintigraphy have served as the foundation for SLNM in vulvar cancer, the alternative use of ICG near-infrared imaging has gained traction.90 Typically, a peritumoral injection is performed at four sites in the 2, 5, 7, and 10 o'clock directions of the tumor.90 Regardless of the method used, SLNM performs well for detecting sentinel nodes in patients with vulvar cancer (Fig. 4). A retrospective study with 160 patients demonstrated an overall sentinel lymph node detection rate of 96.2%, irrespective of the modality. The inguinal lymph node detection rate using 99mTc radiocolloid combined with blue dye resulted in a detection rate of 91.8% while the combination of 99mTc radiocolloid and ICG resulted in a 100% detection rate.91 The additional use of preoperative SPECT/CT when using 99mTc radiocolloid results in precise anatomic localization of SLNs and reduces false-positive SLNs due to external contamination and presence of radioactivity in enlarged lymphatic vessels.92

Omitting inguinofemoral lymphadenectomy in early-stage vulvar cancer patients with a negative sentinel lymph node is safe, showing low groin recurrence, excellent survival, and minimal treatment-related morbidity. The multicenter prospective GROINSS-V study involving 403 women with early-stage vulvar cancer showed that in 259 patients with unifocal disease and a negative sentinel lymph node, the recurrence rate was low at 2.3%.93 Short-term and long-term morbidity was also significantly lower in patients with SLN dissection only compared to SLN removal and inguinofemoral lymphadenectomy. Moreover, on a follow-up study, this group with early-stage vulvar cancer, a unifocal primary tumor, and negative SLNB reported 3, 5, and 10-year disease specific survival rates of 97%, 93.5% and 90.8% respectively.94 In the GOG-173 prospective study involving 452 women with early-stage vulvar cancer undergoing SLNM, 418 women had at least one SLN identified with a sensitivity for SLN detection of 91.7% and false-NPV of 3.7%.95 Another review of 65 studies on the clinical use and technical procedures of SLN biopsy of vulvar cancer found that a negative SLN is associated with low inguinal recurrence and good 5-year disease-specific survival rate.85 While SLNM is standard in the initial presentation of vulvar cancer, evidence of the use of SLNM in recurrent disease is lacking. Overall, sentinel lymph node mapping in vulvar cancer offers a minimally invasive method to assess lymphatic spread, guiding treatment while potentially minimizing surgical morbidity, and is recommend for early-stage tumors (T1b or T2) when there's no clinical suspicion of lymph node metastasis.

In patients with locally advanced vulvar cancer, 18F-FDG PET/CT performed at baseline and 3 months after treatment is routine for assessment of treatment response (Fig. 5).8 A single-institution study of 21 women with vulvar cancer demonstrated that post-treatment response on 18F-FDG PET/CT was associated with improved locoregional control and OS. Patients with no evidence of disease on 18F-FDG PET/CT showed a significant higher 2-year locoregional control (89% vs 25%) and OS(100% vs 42%) compared to those with progressive disease. Additionally, the study reported that 18F-FDG PET/CT showed a 100% sensitivity and 71% specificity in detecting residual disease postneoadjuvant or definitive radiation therapy.96 Despite these promising findings, studies regarding metabolic activity and post-treatment changes in vulvar cancer are scant and further research is needed. The NCCN guidelines recommend considering 18F-FDG PET/CT to assess treatment response after definitive primary treatment.89

About 33% of patients with vulvar cancer experience disease recurrence within the first 1-2 years after initial treatment.8 Unfortunately, these patients tend to have poor prognostic outcomes, emphasizing the importance of routine follow-ups and monitoring. Consideration for MRI is also recommended to aid in further treatment planning. In a retrospective multicenter study evaluating the ability or 18F-FDG PET/CT to detect recurrent disease in patients with vulvar cancer, the sensitivity, specificity, PPV, NPV and accuracy were 100%, 92%, 98%, 100% and 98%, respectively. 18F-FDG PET/CT also impacted clinical management in 44% of the patients. Additionally, the study demonstrated an association with a positive 18F-FDG PET/CT and shorter PFS and OS compared to a negative scan.82 Given the poor prognosis of recurrent vulvar cancer, early detection of recurrence with 18F-FDG PET/CT can play a valuable role in a patient's work-up. The NCCN guidelines recommend considering 18F-FDG PET/CT for suspected or documented recurrence if not already previously performed during surveillance.89

As with any imaging modality, there are pitfalls of 18F-FDG PET/CT in diagnostic imaging. A thorough understanding of these limitations is important to aid in the accurate interpretation and management of patients with gynecologic malignancy. Sensitivity of tumor detection is dependent on tumor size, metabolic activity, serum glucose level, and surrounding background activity.1 Common false negatives include limited ability to identify small lesions <5 mm, low-level FDG accumulation in necrotic lymph nodes and low-grade tumors, and the masking of serosal and peritoneal implants by adjacent physiologic bowel or bladder activity.7,97 Possible false positives in 18F-FDG PET/CT scans can arise from physiologic FDG uptake in the endometrium and ovaries of premenopausal and perimenopausal women, natural FDG excretion in the ureters and bladder, and heightened FDG activity in benign conditions including uterine fibroids, pelvic inflammation, and benign endometriotic cysts.97,98 These pitfalls underscore the importance of further correlation with clinical history and MRI imaging, particularly in patients with mucinous or cystic lesions.

Given the enhanced anatomic detail and utility of MRI in gynecologic malignancies, 18F-FDG PET/MRI has been emerging as an important clinical and investigative tool offering a range of potential benefits over traditional MRI or PET alone.99 The modality offers precise staging for cervical and endometrial cancers and excels in detecting peritoneal carcinomatosis.98

Combining the strengths of MRI's local disease extension assessment and 18F-FDG PET's capability to identify nodal or distant metastases, 18F-FDG PET/MRI offers comprehensive insights, especially in complex cases like cervical and endometrial cancer with concurrent conditions such as fibroids or adenomyosis. It aids in treatment planning for fertility preservation in endometrial and cervical cancers and possesses a high accuracy rate in distinguishing post-treatment changes from residual or recurrent disease (Fig. 6).99 For patients with allergies to contrast or with chronic kidney disease, or in pregnant patients, noncontrast 18F-FDG PET/MRI may serve as an effective alternative (Fig. 7). In ovarian cancer, it efficiently differentiates physiological activities from tumor deposits. In vulvar cancer, it is advantageous for detecting local recurrences amidst anatomical distortions and physiologic activity. While its clinical application has been limited due to factors such as availability, cost, and longer imaging time, its superior capability in detecting recurrent disease stands out.14 Offering a reduced radiation dose and superior anatomical details over CT, 18F-FDG PET/MRI positions itself as a pivotal tool in personalized gynecological cancer care.100 One meta-analysis comprising of 6 studies and 216 patients with gynecologic malignancies showed excellent diagnostic performance of 18F-FDG PET/MRI to assess primary tumor, nodal staging, and recurrent disease with a pooled sensitivity of 95% and pooled specificity of 95%.101 Another meta-analysis with seven studies and 257 patients also found that 18F-FDG PET/MRI had an excellent diagnostic performance in detection of recurrent disease with a pooled sensitivity of 96% and pooled specificity of 95%.102 Studies have also indicated its superiority over 18F-FDG PET/CT, especially for primary tumor delineation in cervical and endometrial cancer. However, when it comes to detecting nodal or distant metastases, its performance is similar to 18F-FDG PET/CT.103 Table 2 highlights the potential advantages of 18F-FDG PET/MRI imaging in common gynecologic malignancies when compared to contrast enhanced CT, MRI, or 18F-FDG PET/CT. Overall, in gynecological cancer care, 18F-FDG PET/MRI protocols are shaping up to be a comprehensive, single-stop solution for treatment planning.62

While 18F-FDG PET has an established role in gynecologic cancers, several novel PET radiopharmaceuticals show promise for enhancing patient diagnosis, staging, and treatment monitoring. Some of these novel agents and their applications in gynecologic cancers are subsequently described in this section.

Radiolabeled Fibroblast Activation Protein Inhibitor (FAPI) is an emerging class of radiopharmaceutical that not only offers imaging potential for staging, restaging, and follow-up, but may also serve as a theragnostic agent.104 Fibroblast activation protein (FAP) is a type II serine protease that is expressed by cancer-associated fibroblasts (CAFs) found in tumor stoma, thus promoting cancer growth and associated with a poor prognosis. Dendl et al.104 evaluated the impact of 68Ga-FAPI PET/CT in 31 patients with gynecological malignancies and 14 patients with breast cancer. They found that 18Ga-FAPI PET demonstrated high tracer uptake in primary and metastatic lesions with superior tumor-to-background ratios than 18F-FDG PET/CT.

Pentixafor is a peptide that targets chemokine receptor 4 (CXCR4), which is overexpressed in the tumor microenvironment and promotes tumor growth, angiogenesis, and metastasis. It is associated with more aggressive tumor behavior and a poorer prognosis. Studies have demonstrated the presence of high CXCR4 expression in several gynecological cancers including cervical, ovarian, and vulvar cancer. Often, the cancers with high CXCR4 expression were associated with more advanced disease and a poorer overall survival.105 CXCR4-targeted imaging could potentially serve as both a prognostic and predictive marker while selecting patients for targeted therapies such as CXCR4 antagonists and 177Lu-Pentixather.

PARP inhibitors (PARPi) are approved for the maintenance therapy and treatment of recurrent ovarian cancer.106 Despite stringent selection criteria, response to these agents remain variable which highlights the need for better biomarkers that predict response to PARPi. A study by Makvandi et al.106 showed that the PET agent 18F- FluorThanatrace (18F-FTT), a measure of PARPi expression (the pharmacologic target of PARPi) and drug-target engagement, can serve as a potential biomarker to predict response to PARPi therapy.

Carbon-11 radiolabeled methionine (11C-MET) is considered potentially useful for imaging gynecologic cancers and is hypothesized to offer greater specificity.19 In one study of 14 patients with cervical or endometrial cancer, all patients demonstrated increased uptake of 11C-MET, demonstrating its potential utility in imaging of gynecologic cancers.107

The two major radiolabeled hypoxia imaging agents are nitroimidazole derivatives and diacetyl-bis (N4-methylthiosemicarbazone) (ATSM) analogues. The hypoxia tracer, 1-(2-hydroxy-3-18F-fluoropropyl)-2-nitroimidazole (18F-FMISO) and 64Cu-CuATSM are most extensively studied in clinical trials and are particularly relevant for cervical cancer, where tumor hypoxia is a significant concern. These imaging agents can identify pretherapy hypoxia which can serve as an important prognostic parameter as well as measure hypoxic tumor volumes, which often correlate with resistance to treatment. This can help guide the selection of appropriate systemic hypoxia-directed therapies or local therapies such as boost radiotherapy.108

18F-Fluorothymidine (18F-FLT) PET is a biomarker for tumor proliferation activity (Ki-67 index) and has been evaluated for its potential role in postradiation response in various cancers including gynecological malignancies after radiation therapy. Because only proliferating cells (ie malignant tissues) enable thymidine incorporation in DNA synthesis, 18F-FLT imaging is an attractive tool for differentiating between residual/recurrent malignancy and inflammation. A pilot study by Cho et al. in patients with cervical and vaginal cancer reported that 18F-FLT tracer uptake was markedly decreased in tumors after CCRT. The study also suggested that there may not be significant effect of inflammation on 18F-FLT uptake in gynecologic cancers, thus proposing a role of 18F-FLT PET in assessing treatment response following CCRT.109 Another study by Richard et al. in patients with ovarian cancer reported an increasing trend between 18F-FLT uptake and Ki67 mitotic index in malignant tumors, suggesting a potential role of 18F-FLT PET in the non-invasive evaluation of tumor proliferation.110

Another novel agent, 16α-18F-fluoro-17β-estradiol (18F-FES) PET is useful for the noninvasive evaluation of in vivo tumor estrogen receptor alpha (ERα) expression and heterogeneity of tumor phenotype. This helps provide prognostic information and predict the potential response to endocrine therapy. Studies have shown that the ERα expression highlighted by 18F-FES PET, glucose metabolism expressed by 18F-FDG PET, and 18F-FDG/ 18F-FES SUV ratio provide information on tumor aggressiveness and discriminate between high vs low-risk endometrial cancers and hyperplasia. High ER expression and low glucose metabolism were noted in low-risk tumors whereas low ER expression and high glucose metabolism and were noted in high-risk and malignant endometrial cancers. A study by Yamada et al. reported that low 18F-FES uptake in primary endometrial tumors is associated with adverse prognostic factors such as lymphovascular space invasion and lymph node metastasis. In addition, 18F-FES was an independent prognostic factor of PFS in patients with endometrial cancer.111 In a study by van Krutchen et al. involving 15 patients with epithelial ovarian cancer, 18F-FES PET/CT reliably assessed the ERα status in the primary tumor and metastases when compared to immunohistochemistry with a sensitivity of 79%, specificity of 100% and accuracy of 86%. The authors suggested that 18F-FES PET/CT may be a valuable predictive marker for selecting patients for endocrine therapy.112

Overall, the development and application of these novel radiopharmaceuticals could significantly advance the diagnosis and management of gynecological malignancies. Further research and clinical trials are needed to validate their efficacy.

Theragnostic is defined as a combination of molecularly targeted imaging and therapy in which the imaging provides actionable information (ie the presence and distribution of the highly specific molecular targets enabling new and effective treatments). This definition is broader than the commonly used definition of theragnostics, wherein a highly specific molecularly targeted and optimized ligand is used for chelating a radionuclide with imaging properties that can be readily swapped for a radionuclide with therapeutic properties.113,114 The following section briefly outlines of some of the most interesting current and future theragnostic applications in gynecologic oncology.

18F -Fluoroestradiol PET (18F-FES-PET), as described under novel imaging agents, is an estrogen receptor targeting agent which serves as a diagnostic tool for evaluating estrogen receptor expression. As aforementioned, 18F-FES-PET uptake has been shown to correlate with histology and immunohistochemistry at the time of debulking surgery in patients with epithelial ovarian cancer. Therefore, it can provide a rationale for antihormonal therapies in these patients.112 A study by Yamada et al. also reported the utility of 18F FES-PET as a predictive marker for evaluating response to fertility-sparing hormonal treatment in patients with low-grade endometrial cancer.115

Also discussed under novel imaging agents, Fibroblast activation protein (FAP) is a pan-cancer target with an excellent tumor-to-background ratio, and as such, FAP is considered an attractive target for radionuclide therapy. FAPI variants labeled with therapeutic radionuclides (such as 131I, 90Y, 177Lu, and 225Ac) have been studied amongst various cancers in both preclinical and clinical studies. Baum et al.116 conducted the first in-human study of 177Lu-FAP-2286 administered to 11 patients with diverse adenocarcinomas, including ovarian cancer, and the drug was well tolerated with acceptable side effects.116

Several other molecular targets have been studied for ovarian cancer detection and therapy. CA-125, a mucin-type-O-linked glycoprotein, is expressed as a membrane-bound protein at the ovarian cancer cell surface. PET probes targeting CA-125 could be valuable tools in the management of ovarian cancer for whole-body visualization and quantification of CA-125. Sharma et al., demonstrated that a Zr-89 labeled anti-CA125 murine antibody B43.13 could delineate CA-125 positive human tumor xenografts from negative tumors in mouse models. The data from this study showed the potential for developing a theragnostic variant for detecting and targeting CA-125-positive ovarian cancer.117 The production of CEA by epithelial ovarian cancer also provides another attractive theragnostic target, which several groups have investigated. In a phase 1 trial involving 14 patients with refractory epithelial ovarian cancer, Juweid et al.118 administered escalated doses of I-131-labeled anti-CEA monoclonal antibodies in a theragnostic approach, where CEA expression was established with a preceding diagnostic scan. No dose-limiting toxicity was observed.

The overexpression of Folate Receptor α (FRα) in cancer has also led to the development of various FR-targeted therapeutics, including antibody-drug conjugates. One such agent is mirvetuximab soravtansine (IMGN853), an FRα-targeting humanized monoclonal antibody-drug conjugate that is being tested in several clinical trials in cancer patients, including platinum-resistant ovarian cancers (nearly 90% of high-grade serous ovarian cancers overexpress FRα). To improve patient selection and therapeutic interventions, the 89Zr-radiolabeled version of M9346A (parent antibody of IMGN853) is developed as a radiotracer for FRα detection and serving a theragnostic tool to prescreen cancer patients, including ovarian cancer patients, for IMGN853 therapy.119

Another promising theragnostic target is HER2 (or Erbb2), which is a 185 KDa transmembrane glycoprotein known to be overexpressed in a variety of cancers including breast, ovarian, cervical, colon, endometrial, esophageal, lung, and pancreatic cancers. HER2 overexpression contributes to poor survival, and patients with HER2-positive tumors are treated with a monoclonal antibody targeting HER2, including trastuzumab and pertuzumab. Several imaging agents including 89Zr-trastuzumab and 89Zr-pertuzumab have been used to quantify HER2 expression noninvasively and to assess HER2-positive tumor response to therapy. The overexpression of HER2 and high trastuzumab selectivity in various of cancers has also been exploited to develop radioimmunotherapy. Trastuzumab radiolabeled with α- and β-emitting radionuclides has been investigated for the treatment of disseminated peritoneal disease and tumors with HER2 expression.120 Intraperitoneal radioimmunotherapy using an α-emitter (212Pb), conjugated to trastuzumab, in a first-in-human study in patients with ovarian cancer was found to be safe with patients showing a trend of decreasing tumor growth and blood-based biomarkers with increasing administered radioactivity.121131I-trastuzumab also provides an attractive theragnostic possibility for ovarian cancer with over-expression of HER-2.122

While these theragnostic applications hold substantial promise, their translation to clinical practice mandates meticulous res