PET/CT finds footing in breast, cervical, and ovarian carcinoma

PET/CT continues to find new applications in detection and monitoring of breast, cervical, and ovarian carcinoma. An estimated 211,000 new cases of invasive breast carcinoma, with almost 41,000 deaths, are expected to occur in the U.S. during 2007. Breast carcinoma is the most frequently diagnosed malignancy in women and ranks second in terms of cancer deaths after lung cancer.

• Initial diagnosis. Although promising results are emerging for FDG-PET to evaluate primary breast masses, the technique has not been used successfully for this application. Early studies by Wahl et al and other groups suggested that PET may have a high sensitivity for detecting primary breast lesions larger than 1 cm, but in the largest study to date, Avril and colleagues found that up to 40% of primary breast carcinomas smaller than 2 cm were not seen with PET imaging.1-4

The overall sensitivity and specificity for breast lesions, calculated by a Blue Cross/Blue Shield technology assessment examining 13 studies with 606 patients, were 89% and 80%, respectively.5 Based on the high incidence of breast cancer, PET's potential false-negative rate, and its cost compared with mammography, PET is not currently recommended to evaluate primary breast masses. It is not covered for reimbursement by Medicare.

Although PET is not sufficiently sensitive for detecting primary breast lesions, most studies have suggested that it does have a high positive predictive value, so that a positive lesion (even incidentally discovered) should be considered malignant until proven otherwise.

• Staging. The presence of tumor within axillary lymph nodes is an important prognostic indicator in patients with breast cancer. Anatomic imaging modalities are not useful because there is often microscopic involvement. Unfortunately, micrometastatic involvement is also a major limitation for current PET and PET/CT scanners.

Adler et al found a sensitivity and negative predictive value of 95% and an overall accuracy of 77% in a study of 50 patients.6 Avril and colleagues evaluating 51 patients found a sensitivity and specificity of 79% and 96%, respectively. When only patients with late-stage disease were considered (primary breast tumor > 2 cm, > pT1), however, the sensitivity and specificity of FDG-PET increased to 94% and 100%, respectively.7

The only PET/CT study evaluating axillary lymph node staging found in 15 patients a sensitivity, specificity, and accuracy of 80%, 90%, and 87%, respectively.8 Given the combined sensitivity limitations of both PET and CT for detecting micrometastases, it is unlikely that combining the two modalities will overcome these limitations or replace sentinel lymph node scintigraphy.9-13 Medicare does not cover PET staging of axillary nodes.

In contrast to the limited role PET plays in evaluating the axilla, it has been shown to be more useful for identifying unsuspected internal mammary lymph nodes and distant metastases (Figure 1). Although little evidence in the literature compares PET/CT with PET and CT performed separately, it is likely that PET/CT will improve precise localization of suspected metastatic lesions identified on PET.

• Restaging. Local or regional recurrence occurs in up to 30% of breast cancer patients after initial therapy, and imaging is crucial for surveillance and detection of early recurrence. It is clear from a number of studies that FDG-PET has a very high sensitivity (92% to 100%) for detecting recurrence, and it is reimbursed by Medicare.14-17 Depending on when PET or PET/CT is performed in the post-therapeutic period, however, the specificity tends to be lower (72% to 82%). Several studies have shown that PET is useful to detect unsuspected malignancy in bone and lymph nodes but somewhat less sensitive than CT in detecting local recurrence. False positives from physiologic uptake are a problem with PET, but these can be reduced significantly with combined PET/CT.

For the detection of osseous metastases, it is likely that PET and PET/CT will play a complementary role to traditional bone scintigraphy, rather than replace it. A preliminary report showed PET/CT detected lesions in 77% of patients suspected of recurrence based on clinical exam or tumor markers. Results led to a change in clinical management in 36%.18 Another group reported a patient-based sensitivity and specificity of 96% and 89%, respectively, which is in the range of most reported FDG-PET sensitivities but represents an improvement in specificity over PET alone.19 In general, PET is more sensitive for osteolytic lesions, and traditional bone scanning is more sensitive for osteoblastic lesions.

• Response to therapy. PET and PET/CT are indicated for evaluating response to therapy in patients with breast carcinoma. Several studies have demonstrated the ability of FDG-PET to differentiate potential responders from nonresponders.20-24 Often, with anatomic imaging studies, bulky areas of disease are difficult to evaluate early following therapy. PET/CT can accurately localize areas of persistent disease, as well as areas with persistent uptake for potential biopsy localization. This indication is covered by Medicare.

CERVICAL AND OVARIAN CANCER

Early experience with whole-body dedicated PET imaging in gynecologic malignancies has demonstrated a similar or, in some studies, slightly higher sensitivity, specificity, and accuracy compared with CT and MRI in staging these patients, as well as in the detection of recurrent disease.25-29 PET/CT has overcome many of the limitations of dedicated PET imaging, markedly improving anatomic localization and differentiation between pathologic and physiologic FDG activity.

Until recently, a major limitation to the use of combined PET/CT in gynecologic malignancies has been the lack of insurance reimbursement, with the exception of cervical carcinoma staging. Reimbursement for all indications of cervical and ovarian cancer is now available through the National Oncologic PET Registry.

• Initial diagnosis. FDG-PET and PET/CT are not routinely used for the initial evaluation of a cervical or ovarian mass. Almost all patients referred for PET or PET/CT have been previously diagnosed with cervical or ovarian carcinoma.

• Staging/treatment planning. At the University of Pittsburgh Medical Center, we have scanned approximately 400 patients with ovarian, cervical, or endometrial cancer, in different stages of their disease process. Although we have not performed a definitive analysis of these data, preliminary results are encouraging. Of the initial 56 patients with primary and recurrent gynecologic malignancies (35 ovarian, 21 cervical) who were evaluated for treatment planning, PET/CT identified additional lesions compared with their traditional pretreatment clinical CT in 10 of 21 (48%) cervical cancer patients and 28 of 35 (80%) ovarian cancer patients. Although seemingly impressive, the actual significance of these findings is in the effect they had in changing patient management in 35 of 56 (63%) patients.14-15

Another application particularly suited for PET/CT is radiation therapy planning. PET/CT offers the unique ability to more accurately define tumor extent and target volumes (Figure 2). Although not all patients with gynecologic malignancies are being sent for pretreatment PET/CT, they are increasingly being referred for this reason. Our experience is that PET/CT offers a much more accurate definition of the extent of disease and target volumes for radiation therapy planning in this patient population, although more studies are needed to confirm these findings.

• Restaging/recurrence. Several recent studies have shown marked improvements in the utility of PET/CT for restaging patients with gynecologic malignancies, particularly those with ovarian carcinoma.30-36 Figure 3 demonstrates a patient who was referred for suspected recurrence of ovarian cancer due to an increase in her CA-125 level. A CT scan performed at an outside institution just prior to her PET/CT study was interpreted as normal, even in retrospect. After an abnormality was identified along the gastrosplenic ligament on PET/CT, this patient was sent for a CT-guided biopsy of the lesion. The lesion could not be identified while the patient was on the biopsy table, however. Attempts were made to provide the fused PET/CT images to the interventional suite to help guide the biopsy, but the patient eventually refused the exam and was lost to follow-up. She returned over a year later for a repeat PET/CT study, which showed diffusely progressive metastatic disease, including abdominal lymphadenopathy and multiple masses within the mesentery. Now we routinely send fused images with the patient if she is going to have surgery or biopsies performed, particularly when we feel the fused image would be helpful in guiding the physician who is performing the procedure.

FUTURE APPLICATIONS

While more studies will help define the multiple potential roles of PET/CT in gynecologic malignancies, we are already seeing a significant increase in the number of affected patients as a result of the success we have demonstrated to date. Of course, challenges remain for PET/CT, as it retains some of the individual limitations of each separate modality.

Neither PET nor CT, for example, is yet capable of detecting microscopic disease-PET because of spatial resolution limitations, and CT because of the absence of an identifiable anatomic correlate. False-positive studies will continue to be a problem because of the identification of hypermetabolic nodes that are "reactive" but do not actually contain tumor. In our experience, however, these cases are the exception, and the value gained from the combined modalities far outweighs any potential limitations.

The future of PET imaging lies in the development of more specific imaging probes. As this development progresses, the need for combined anatomic and functional imaging modalities will become imperative because of the lack of uptake in background tissue and the increasing absence of anatomic detail. Regardless of the specificity of the probes developed, it is becoming evident that combined PET/CT imaging is having an increasingly significant impact on healthcare in oncology.

Dr. Blodgett is an oncologic imaging fellow, and Dr. Ryan is a research assistant, both in the radiology department at the University of Pittsburgh Medical Center.

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