The management of advanced gynecological malignancies generally consists of a combination of treatment modalities, specifically surgery, chemotherapy, and radiotherapy. A thorough assessment of the response to treatment should help to optimize disease management, and may result in reduced morbidity, increased survival, and improved quality of life.
The second look laparotomy in ovarian cancer patients is an example of a procedure aimed to improve assessment of the response to initial treatment. However, although many ovarian cancer patients underwent second look laparotomy following first-line chemotherapy during the 1980s and the beginning of the 1990s, the procedure was found to be unjustified. It carried important information about prognosis but it did not contribute to improved survival, and was, therefore, abandoned .
Blood serum tumor markers, ultrasound examinations, computed tomography (CT) scans, and MRI have been used to assess response to treatment, although most studies have failed to demonstrate survival benefits [2▪]. Most cross-sectional modalities (CT, MRI, etc) are able to detect morphologic changes, but may fail to discriminate between benign and malignant lesions. PET, using labeled glucose, fluorodeoxyglucose (FDG), exhibits high uptake of glucose in malignant cells, and may, therefore, be useful as a cancer monitoring test. The combination of PET and CT may provide an even better means of evaluating a structural and metabolic response to treatment . However, the effects of different treatments on glucose uptake by tumor cells should be considered in establishing the timing of examination and proper interpretation of imaging results.
This article will address the effect of radiation and chemotherapy on PET results, and will examine the value of PET and PET/CT as a cancer response imaging modality for various gynecologic malignancies.
PET/COMPUTED TOMOGRAPHY OF THE PELVIC AREA: PITFALLS, LIMITATIONS, AND POTENTIAL PROBLEMS IN ASSESSING RESPONSE TO TREATMENT
These may generally be divided into the normal physiology of FDG uptake and posttherapy features.
Normal variants commonly found in PET/computed tomography scans of the female reproductive system
In the pelvic area, physiologic FDG uptake is often observed in the alimentary or genitourinary tract and is easily identified due to its linearity and localization to the colon, ureter, or urethra. When the exact location of FDG activity is unclear, correlation with CT can help to further characterize the finding and to exclude pathology . Glucose uptake in the female reproductive tract is more complicated to define. As normal postmenopausal ovaries have no visible FDG uptake on PET/CT scans, any focal uptake in the region of the ovaries or adnexa in postmenopausal women usually indicates malignancy and should be considered pathologic until proven benign . In contrast, focal FDG uptake in premenopausal women is often identified in normal ovaries in correlation with the menstrual cycle. Such finding may be misinterpreted as pathologic, for example, as a metastatic lymph node [5,6]. When focal uptake is visualized in the adnexal region, information about the patient's menstrual status is crucial for interpretation. However, common irregularity in the menstrual cycle in cancer patients, especially during or shortly after chemotherapy or radiotherapy, makes physiologic ovarian glucose uptake unpredictable .
Physiologic FDG uptake may also be observed in the ovaries of women of reproductive age, even subsequent to hysterectomy . Further, benign ovarian tumors may demonstrate FDG uptake on PET/CT in both premenopausal and postmenopausal women. This may be related to the degree of the inflammatory process within the tumor . Endometrial uptake in premenopausal women is related to the menstrual cycle, with the highest level of uptake in the menstrual flow phase, followed by the ovulating phase [5,6]. Normal endometrial uptake is minimal in postmenopausal patients, any level of increased endometrial uptake is of clinical significance and should prompt further evaluation. Intense FDG uptake in the uterus usually represents a malignant process, but many benign diseases may also result in increased uptake, such as endometrial inflammation, leiomyomas, endometrial hyperplasia, endometrial polyp, and pyometra .
The impact of therapy on fluorodeoxyglucose PET/computed tomography scan interpretation
Although the usefulness of FDG-PET imaging in the initial diagnosis and staging of many types of cancer is well documented, its role in monitoring the response to chemotherapy and radiotherapy is more complicated. The optimal time for performing posttreatment FDG-PET evaluation is always challenging, and precise time interval guidelines are currently unavailable. Early determination of nonresponse is crucial to optimizing treatment strategy so as to avoid chemotherapy or radiation therapy toxicity and to improve outcome. Further, PET imaging performed too close to the end of therapy may be nondiagnostic due to treatment-related metabolic changes . Radiation and chemotherapy may induce diffusely elevated FDG accumulation within normal tissues surrounding the target tumor because of inflammatory changes, and may, therefore, result in false-positive results . The lung is an example of an organ that is commonly affected by radiation therapy. Postradiation pneumonitis frequently appears in patients with lymphoma and with breast, lung, esophagus, and neck cancers . The inflammatory process related to pneumonitis leads to increased FDG accumulation, resulting in abnormal PET values [9,11]. Patients who received a high dose of radiation in the larynx were found to be particularly likely to have false-positive PET findings, possibly due to persistent radiotherapy induced inflammatory changes in the larynx. This limitation of posttreatment PET imaging can lead to frustration and reluctance to routinely undertake such evaluation . The ideal timing for the first FDG-PET study after radiotherapy has not been determined. A number of studies have shown high rates of false-positive and false-negative findings when PET studies were obtained too soon after radiotherapy completion [13,14]. For example, patients who received a high dose of radiation in the larynx were found to be particularly likely to have false-positive PET findings, possibly due to persistent radiotherapy induced inflammatory changes in the larynx . Inaccuracy in posttreatment PET imaging can lead to reluctance to routinely undertake such evaluation . On the contrary, some investigators have found little impact of postradiation changes on the assessment of the therapeutic response [15,16]. In a study of the role of presurgical PET imaging in advanced rectal cancer patients, the prevalence of PET abnormalities potentially attributable to posttreatment changes in normal tissues located in the radiation field was relatively rare . These data suggest that the confounding effect of altered FDG uptake in normal tissues does not significantly interfere with the use of postchemotherapy and radiotherapy PET in assessing treatment response preoperatively . In patients with head, neck, or esophageal cancers treated with radiation, it is recommended that 8–12 weeks elapse before an FDG-PET study to avoid false-positive interpretation of radiation-induced inflammatory changes [12,18]. In contrast, for locally advanced cervical cancer, the current literature supports the use of 18F-FDG PET for assessing treatment response 3 months after the completion of concurrent chemoradiation .
PET imaging performed within 4 weeks of operation was found to result in false-positive uptake in areas of active inflammation. Inflammatory reaction at the site of the surgical procedure is common. Evaluation of postsurgical patients at least 6 weeks after surgery may, thus, be appropriate . Nevertheless, FDG has been found to accumulate in irradiated tissues and to induce postsurgical inflammatory changes even up to 6 months after the end of treatment [20,21].
Endometrial cancer is the most common gynecological malignancy . Surgery is almost always the standard of care. Complementary treatment consists of chemotherapy and radiotherapy, according to the stage and grade diagnosed during surgery. The 5-year disease-free survival rate exceeds 90%, and therefore the value of tumor response evaluation is questionable .
Ten percent of patients with endometrial cancer present with high-grade tumor such as serous papillary or clear cell cancer. The prognosis of these patients is more similar to that of ovarian cancer, with recurrence and distant metastases relatively common . The role of PET/CT in these rare cases has not been studied in randomized trials.
Park et al. investigated the role of PET/CT for posttreatment surveillance in 88 patients with high-risk endometrial cancer. They reported treatment changes in 22% of the patients based on PET results, but did not demonstrate clinical benefit. On the basis of these data, the use of PET for monitoring response to treatment is unlikely to be cost-effective, as the probability of recurrence is low. Further studies in selected high-risk patient groups are needed to establish a role for the routine use of PET for the treatment of endometrial cancer.
Ovarian cancer is the leading cause of death among gynecological malignancies . Seventy-five percent of patients are diagnosed at an advanced stage and 75% of patients who reach remission following first-line chemotherapy suffer recurrence and eventually die from the disease [2▪].
Second look laparotomy, laparoscopy, ultrasound, CT, MRI, and serum tumor markers have all been investigated for cancer response evaluation, but none of these techniques were found to have an impact on overall survival or progression-free survival.
The use of PET/CT in ovarian cancer patients was not found to have a significant benefit as early detection of recurrence or lack of treatment response did not change significantly during the course of disease . Cho et al. found that PET may be useful in estimating the intermediate rate of tumor perfusion during regional hyperthermic intraperitoneal treatment. It was not clear, however, whether their findings can be translated to any clinical benefit.
The value of PET/CT imaging in the assessment of ovarian cancer patients is currently limited to the evaluation of recurrent disease when other conventional diagnostic modalities are negative or equivocal .
Cervical cancer is one of the leading causes of death among young women . Compared with endometrial and ovarian cancer, disease staging is not established by surgery, and therefore diagnostic modalities are of greater significance. PET/CT is widely used for treatment adjustment, radiotherapy planning, early detection of recurrence, and localization and definition of metastatic sites .
For decades, clinicians have been searching for an accurate nonsurgical modality to determine response to treatment for cervical cancer. Using the SUVmax value to predict tumor response, Kidd et al. and Xue et al. concluded that FDG-PET in the pretreatment setting enables prediction of local tumor response to therapy and survival [29,30]. Lin et al. and Scharz et al. suggested that FDG-PET may also be an important tool for assessing treatment response during a radiotherapy course. They noticed that a rapid decrease in primary tumor SUVmax and physiologic volume measured by PET during radiotherapy may be correlated with response to treatment [31,32].
In one of the most important studies using FDG-PET for monitoring response to treatment in cervical cancer, Grigsby et al. found that PET in the posttreatment setting, can detect residual disease in asymptomatic women . Supporting this observation, Havrilesky et al. suggested that the detection by PET of local disease following radiotherapy may afford a survival benefit. In another study, Grigsby et al. retrospectively evaluated the response of 152 patients to therapy using posttherapy FDG-PET, and compared the response with patient outcomes. All patients underwent a pretreatment and posttreatment FDG-PET. Patients were treated with external irradiation and intracavitary brachytherapy, and most received concurrent weekly cisplatin. Posttherapy FDG-PET was performed 1 to 12 months (a mean of 3 months) after completion of treatment. A Cox proportional hazards model of survival outcome indicated that abnormal posttherapy FDG uptake (persistent or new) was more significant than all other pretreatment-related and treatment-related prognostic factors assessed for predicting developing metastatic disease and death from cervical cancer. Treatment-related prognostic factors evaluated in the study included pretreatment FDG-PET lymph node status, the International Federation of Gynecology and Obstetrics (FIGO) stage, total irradiation dose, overall treatment time, and the use of concurrent chemotherapy.
Figure 1 depicts an example of posttreatment PET/CT in a patient with cervical cancer. The patient was diagnosed with cervical adenocarcinoma stage IB2, and was treated by radiotherapy with concomitant chemotherapy. Three months following completion of treatment, PET/CT indicated FDG uptake in the cervix. Total abdominal hysterectomy revealed a small lesion of adenocarcinoma. She is 2 years following surgery with no evidence of disease.
As discussed above, the optimal time for performing functional imaging after treatment is controversial. Results of FDG-PET performed after radiotherapy or surgery may be ambivalent due to confounding factors associated with response to treatment and/or inflammation. Conventional noninvasive imaging modalities such as MRI may provide excellent morphologic information for residual lesions, especially in the pelvis; however, they do not always differentiate between residual tumors and posttreatment changes. A study that included 20 patients with malignant tumors at different sites showed dual-time FDG-PET imaging just after completion of radiotherapy to be potentially useful for predicting early regrowth of malignant tumors. However, only two patients included in that study were female patients with uterine–cervix cancer . It seems that the role of dual-time FDG-PET imaging, mostly when performed immediately after irradiation, should be further evaluated, especially in highly proliferative – and potentially curative – diseases such as uterine–cervix squamous cell cancer .
In a study aimed to investigate patterns of treatment failure in patients with cervical cancer undergoing chemoradiotherapy and evaluated by early posttherapy FDG-PET [38▪▪], the average time from completion of treatment to posttherapy FDG-PET study was 12 weeks. That study of 238 patients treated with curative intent demonstrated the importance of posttreatment FDG-PET in determining prognosis. One-third of the study population showed persistent abnormal FDG uptake after therapy, although they did not experience treatment failure. This suggests that persistent FDG uptake on posttherapy PET falsely indicated the presence of persistent tumors in these patients. No statistically significant differences were observed in the SUVmax of the residual focus of FDG uptake between patients with documented residual/recurrent malignancy and those who were free of disease [38▪▪].
We emphasize that patients who experience loco-regional failure can be treated with curative intent, hence the importance of posttreatment FDG-PET in early detection of potentially curative patients. Patients with early posttherapy distant disease most probably had occult micrometastatic disease at the time of diagnosis. Patients with persistent abnormal FDG uptake in the cervix on posttherapy PET are at increased risk of isolated local failure (Fig. 1).
The role of PET/CT in the assessment of response to therapy of gynecological malignancy has yet to be established. Growing evidence supports an important role for functional imaging FDG PET/CT as a monitoring tool in patients with uterine–cervix carcinoma. Further studies are needed to establish the clinical benefits of this modality in this population.
Conflicts of interest
No financial support of any kind was received due to the writing of this article.
The authors disclose no conflict of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 83).
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This is outstanding as it touches on the specific issue of response to treatment in patients of cervical cancer. It presents the advantages and drawbacks of performing PET/CT in different stages of the disease.