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Indian Journal of Cancer, Vol. 47, No. 4, October-December, 2010, pp. 355-359 Guest Editorial PET-CT scan in pediatric oncology: Where, when, how and at what price? B Arora1, PM Parikh2 1 Pediatric Oncology, Tata Memorial Hospital, Mumbai, India Correspondence Address: Code Number: cn10090 PMID: 21131746 DOI: 10.4103/0019-509X.73546 The advent of combined positron emission tomography-computed tomography (PET-CT) has been an important innovation in the diagnosis, staging, monitoring of response to therapy, and disease surveillance in adult oncology. [1],[2] Combined morphological and functional information along with rapid, non-invasive whole-body tumor staging has proven to be a boon for treating oncologists. However, the role of PET-CT in the pediatric cancers is less clearly defined at present. In the recent times, the use of PET-CT imaging in pediatric cancer patients is growing rapidly and it is likely to become an important part of therapeutic decision tree in the near future. [3] In this issue of "The Indian Journal of cancer", Samuel et al. have given a comprehensive overview of PET-CT protocols and its clinical applications in children with cancer. The increasing use of serial PET-CT scans in the management of children raises the serious consideration of radiation exposure. Hence, it is imperative to weigh the risk-benefit ratio of this potentially harmful modality in this young and vulnerable population from the perspective of a clinician and precisely define the current role of this modality in the current practice. Where and When PET-CT Should Be Used? PET-CT imaging is commonly performed after diagnosis for baseline staging, during or at therapy completion for monitoring disease response, and during follow-up for surveillance. For initial staging, imaging should always be performed before starting chemotherapy to minimize image misinterpretation caused by therapy related effects on tumors and other tissues. During therapy, for early response evaluation, imaging should be planned prior to initiation of the next course of therapy to avoid any "flare" response from chemotherapy. PET may be performed within 4 weeks after the completion of chemotherapy. In contrast, PET is generally not performed until 2-3 months after radiation or 1-2 months after surgery because acute inflammatory changes after radiation or surgery can result in false positive PET scans. [1] Currently, the most frequently requested indications for PET-CT imaging in pediatric oncology are lymphoma, sarcoma, neuroblastoma and brain tumors. Less frequent indications for PET imaging in pediatric oncology include evaluation of Langerhans cell histiocytosis (LCH), germ cell tumors, hepatoblastoma, Wilms′ tumor, malignancy of unknown primary, and neurofibromatosis type 1. [4] The current application of this imaging in common cancers is detailed below. Lymphomas In lymphomas, PET-CT is used for staging, evaluating response to therapy, restaging, assessment of residual masses after therapy and planning of radiation therapy. In the initial staging, PET-CT has been demonstrated to change staging and therapeutic management in 32-40% of pediatric patients. [5] It is significantly more accurate in distinguishing active disease from residual inactive masses, especially in nodular sclerosis subtype, after therapy. Also, PET-CT has a higher sensitivity, compared with CT alone, in evaluating patients for recurrent disease. A negative PET-CT scan at the end of therapy or during follow-up for lymphoma in children strongly suggests absence of disease but a positive PET-CT has low positive predictive value and should be interpreted with caution. [6],[7],[8] Pediatric Hodgkin′s lymphoma (HL) patients with a negative PET in early response assessment have an excellent prognosis while PET-positive patients have an increased risk for relapse. [9] PET-CT is being evaluated for monitoring of early response to therapy and improving the outcome of disease and decreasing the long-term toxicities of treatment by using a response-adapted "risk-stratified" approach to the use of radiation therapy, anthracyclines, and alkylating agents. Herein, patients with complete morphological response on CT and negative PET scan do not receive additional chemotherapy or radiotherapy in order to reduce the risk of secondary malignancies and organ toxicities. [10] Sarcomas The use of PET-CT in sarcoma (osteosarcoma, Ewing′s sarcoma and soft tissue sarcoma, in particular, rhabdomyosarcoma) is mainly for staging, assessing response to therapy, especially chemotherapy, and restaging/detection of relapse of those sarcomas that demonstrate metabolic activity. For baseline staging, PET has been found equal or superior to bone scintigraphy in the detection of bone metastases of sarcomas and also for detecting other non-pulmonary metastases. For the depiction of small lesions, mainly represented by pulmonary metastases, PET is less sensitive than helical CT. [11],[12] Many recent studies have shown that pretreatment tumor SUVmax and change in SUVmax after neoadjuvant chemotherapy predict chemoresponsiveness and independently identify patients at high risk of tumor recurrence in both bone and soft tissue sarcomas. [13],[14] It is also useful in monitoring response to radiation therapy, and radiofrequency ablation and aids the postoperative evaluation of tumor resection sites. Importantly, FDG-PET scan has been particularly helpful in sarcomas treated with radiation to differentiate scarring or fibrosis from persistent or recurrent disease. [11],[12],[13],[14],[15] FDG-PET has been found useful in differentiating between benign and malignant bone tumors. However, significant false positivity or negativity has been observed and caution must be used when basing an imaging diagnosis on SUVs. [16] It may also be valuable in the identification of unknown primary or recurrent rhabdomyosarcoma.[11] Finally, PET-CT has been found very useful in differentiating benign neurofibromas from malignant peripheral nerve sheath tumors in patients with neurofibromatosis, which are unreliably evaluated by conventional imaging modalities. [17] Overall, PET-CT with contrast-enhanced standard dose chest CT is preferred in sarcoma patients, and magnetic resonance imaging (MRI) is used for imaging of the primary tumor site. Neuroblastoma Limited information is currently available regarding the utility of PET-CT imaging in neuroblastoma and associated diseases. [15],[18],[19],[20] (18)F-FDG is avidly concentrated by primary and metastatic sites of disease at diagnosis, but this uptake varies after therapy. At diagnosis, (18)F-FDG is superior in depicting stage 1 and 2 neuroblastoma, although (123)I-metaiodobenzylguanidine (MIBG) is required sometimes to exclude higher-stage disease. (18)F-FDG PET is very useful for patients with tumors that weakly accumulate (123)I-MIBG and for decision making during therapy (i.e., before stem cell transplantation or surgery). (18)F-FDG can also better characterize disease extent in the chest, abdomen, and pelvis, whereas (123)I-MIBG is significantly better in the evaluation of stage 4 neuroblastoma, primarily because of the better detection of bone or marrow metastases. [15],[18],[19] The value of PET-CT to distinguish between neuroblastoma, ganglioneuroblastoma, and ganglioneuroma is unclear. After completion of therapy, PET-CT and bone marrow studies suffice for following high-risk neuroblastoma patients. However, MIBG scan is significantly more sensitive for individual lesion detection in relapsed neuroblastoma than FDG-PET, though FDG-PET may play a complementary role, particularly in soft tissue lesions. [19],[20] Finally, novel sympathetic nervous system specific PET tracers, such as C-11-hydroxyephedrine (HED), are being evaluated for detection of disease, staging, and monitoring therapy in neuroblastoma, which might be useful in future. [21] Wilms′ Tumor PET-CT may be considered for confirming metastatic disease, identifying biopsy sites, helping with surgical planning, and differentiating nephroblastomatosis from Wilms′ tumor. [22],[23] PET-CT imaging may help in distinguishing benign nephrogenic rests from nephroblastomatosis and to identify their potential evolution into Wilms′ tumor. [15],[22] A recent study has shown that FDG-PET does not provide any supplementary information to the standard imaging for staging, preoperative response assessment evaluation and for predicting clinical outcome. However, FDG-PET was advantageous in ruling out residual disease after completion of first line treatment and in pretreatment staging of relapse patients. Furthermore, there was good correlation between initial SUV and histological differentiation. [22],[23] Overall, the impact of this modality on staging, treatment response assessment, and ultimate patient outcome in Wilms′ tumor is yet to be fully determined and should await large studies. Langerhans Cell Histiocytosis Currently, identification of disease sites and evaluation of response to therapy, especially bone lesions with conventional imaging (radiography and bone scanning), is a major challenge in the management of LCH. PET-CT′s ability to exhibit lesional activity in addition to lesion localization is crucial for the diagnosis and follow-up of LCH. [15],[24],[25] A recent study has shown that PET-CT can detect disease activity and early response to therapy with greater precision than other conventional imaging modalities in patients with LCH lesions in the bones and soft tissues. [25] Brain Tumors PET-CT scan may be used in CNS tumours for grading, prognostic stratification, planning biopsy or surgery, assessing response to therapy, detection of recurrence and radiation therapy planning. [26],[27],[28],[29],[30] Novel PET tracers are commonly used in brain tumors, e.g., labeled amino acids. Many recent studies have shown that PET has a significant impact on the surgical decisions and procedures for managing pediatric brain tumors. MET-PET guidance could help to improve the number of total resections and the amount of tumor removed in infiltrative gliomas in children. [26],[27] PET guidance also improves the diagnostic yield of stereotactic biopsy sampling and allows the practitioner to reduce the number of sampling procedures, especially in patients with infiltrative brainstem lesions. [28] FDG-PET of the brain with MRI coregistration can be used to obtain a more specific diagnosis with respect to malignancy grading. Furthermore, MET-PET appears be a useful tool to differentiate tumorous from non-tumorous lesions in children, compared to routine structural imaging. [29] PET along with proliferation index has also been found to be a useful measure in the identification of high-risk, low-grade gliomas. Lastly, its ability to identify a subset of aggressive low-grade glioma early helps in planning further therapy including resurgery or aggressive adjuvant treatment. [30] Incorporation of PET-CT Information into Surgery or Radiation Therapy Planning PET-CT with diagnostic CT may be utilized for planning local therapy such as surgery or radiotherapy. Radiation planning incorporating PET-CT information can be particularly beneficial in minimizing treatment toxicities through reduction of radiation therapy dose or volume. This treatment targeting is based on an established (18)F-FDG threshold of activity in addition to size and contrast uptake, as shown by CT or MRI. [31] PET imaging is able to demarcate areas not previously identified or of unknown value when evaluated by anatomical imaging. [32] For brain tumors, initial PET-CT with radiolabeled amino acids may be easily integrated into the simulation and planning of radiotherapy (commonly with MRI coregistration). [31] In patients requiring definitive radiation after induction chemotherapy, such as those with Hodgkin′s disease, Ewing tumors, soft tissue sarcomas or neuroblastomas, a response-adapted PET-CT approach to plan the irradiation dose and volume may be used. In these patients, use of PET-CT after chemotherapy completion also helps save one additional radiotherapy planning CT. [10],[15] What are the Long-Term Costs of PET-CT? Rapidly rising use of PET-CT along with serial CT and plain-film radiography in the management of children with cancer for prolonged periods ranging from 3 to 5 years raises the important issue of radiation exposure. Children have an increased risk of developing secondary malignancies from radiation exposure compared with adults as confirmed by extrapolating data from atomic bomb survivors, in which increased risk is by an order of magnitude much greater than that of adults. This risk may be explained by greater life span and a greater proportion of actively dividing cells in children, making them more susceptible to radiation-related damage. Also, organ doses for children from radiation exposure due to CT scan are clearly higher than those for adults. [33],[34] The greatest contributor to overall radiation exposure in PET-CT is the whole-body diagnostic CT. The average total radiation dose of 25 mSv from one adult whole-body PET-CT is roughly equivalent to an exposure of 7 years of background radiation in an adult. [35],[36] In pediatrics, the radiation exposure from a standard PET-CT with diagnostic contrast-enhanced CT ranges from 15 to 20 mSv depending upon the age and weight. Using combined FDG-PET/low-dose CT, the radiation exposure is roughly reduced by 50%. [37] Overall, imaging related radiation exposure assumes greater relevance in children because most children achieve long-term cure of disease. How Should PET-CT Be Used in Pediatric Oncology It is imperative to strictly follow ALARA (as low as is reasonably achievable) principle in the radiation exposure of PET-CT, without losing the diagnostic information.[38] The major contributor to overall radiation exposure in PET-CT is the whole-body diagnostic CT and this can be reduced significantly by decreasing the tube current (mA) value and by following the pediatric protocols. Combined PET-CT with diagnostic CT should be avoided if the desired information can be gained by other safer imaging techniques without radiation exposure (e.g., ultrasound or MRI). MRI is the modality of choice for morphological tumor imaging in most regions of the pediatric patient′s body, except thorax. Hence, except for pulmonary lesions, PET should be performed using PET-CT with low-dose CT. [3],[12],[15] PET-CT may be necessary initially for planning surgery and biopsy of FDG-avid lesions, since morphological imaging (CT scan) is essential. However, for monitoring early response and follow-up, PET alone may be sufficient, especially if no abnormal FDG uptake is observed. Furthermore, instead of using whole-body PET-CT at each point in management, CT or PET-CT limited to the area of interest or area of PET avidity may be considered, whenever appropriate. Each institution should have clear guidelines for the optimal interval, number, and frequency of PET-CT scans for each pediatric malignancy, to minimize its misuse. [3],[4],[15] In conclusion, PET-CT with a so-called diagnostic whole-body, contrast-enhanced CT scan should not be routinely performed in pediatric oncology. Instead, FDG-PET alone or PET-CT with ultralow-dose plain CT scan should be combined with diagnostic breath-hold CT of the thorax, if necessary. What is the Way Forward from PET-CT to Perfect-CT It is likely that PET-CT would play a crucial part in correct diagnosis, staging, therapy monitoring and risk-adapted, individualized treatment in the near future. There is a serious need for evidence-based guidelines on frequency, interval and number of PET-CT scans in the management of pediatric malignancies. This can be fulfilled by conducting prospective scientific studies to confirm the overall benefit of PET-CT in improving patient care and to explore whether PET-CT can be used as "one stop shop" for staging and follow-up in cancer patients instead of employing multiple imaging tools. Also, combined PET/MRI may be a superior option to reduce radiation exposure in the future, except for evaluation of lung metastases. However, this may be challenging because children would require sedation for the long duration of an MRI. The scope and utility of PET-CT in pediatric oncology is likely to expand further through use of novel PET tracers targeting biological functions such as apoptosis, hypoxia or angiogenesis. Till such time, PET-CT in children should be used very judiciously on a case-by-case basis with particular thrust on the assessment of risk-benefit and cumulative radiation dose to children. References
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