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The utilization of PET/CT to assess response to therapy is increasing in the US related, in part, to the creation and subsequent favorable results of the National Oncologic PET Registry (NOPR)

Changes in size as a result of therapy may take many months to develop and any opportunity to make early decisions about therapy success or failure is often unduly delayed or lost altogether

measures of changes in metabolic activity via FDG PET/CT can provide an alternate approach to assess response to therapy -- often very early in the course of treatment

Current recommendations are that tumor SUVs should be reported

The true tracer uptake in a patient is composed of two components: the first being the amount of tracer uptake (e.g. FDG) associated with the disease status (the signal of interest), which can be modified by the biophysiological status of the patient. One of the more important patient parameters is the blood glucose level, which has been shown to inversely-linearly affect SUVs

A prospective study by Crippa et al.30 in eight patients showed that as blood glucose levels were increased from 92.4 ±10.2 to 158 ± 13.8 mg/100 ml by glucose loading, the average SUV of 20 liver metastases decreased from 9.4 ± 5.7 to 4.3 ± 8.3

chemotherapy can result in impaired renal function, significantly reducing the clearance of plasma FDG through the kidney and thus increasing tumor SUV relative to an initial PET scan

The second component of the true tracer uptake is biological variability

The biological variability has been estimated in several test-retest studies7,32–35 at approximately 10% for scans repeated within a few days

The technique is valuable for predicting the prognosis of patients with recurrent breast cancer and for determining and predicting the outcomes of neoadjuvant chemotherapy

FDG-PET/CT is useful not only for evaluating metastasis but also for predicting the prognosis of recurrent breast cancer and measuring treatment effects

reports remain limited to small-scale clinical trials of about 100 patients.

MaxSUV, which is the most popular FDG-PET/CT value, can vary up to 30 % because of differences among PET/CT devices and among the operators who create the images

the degree of malignancy would increase with an increase in maxSUV when ER or HER-2 signaling is involved.

Factors that determine the rate of cancer progression include T-factor (tumor diameter) and N-factor (presence or absence/number of lymph node metastasis)

The prognostic factors applied in breast cancer can be broadly divided into those that determine staging and those that determine biological tumor characteristics

Prognosis was previously predicted based on T, N, and M staging, which indicates the degree of progression. However, prognosis is now predicted and treatment regimes are presently selected by also considering ER and HER-2 levels, which determine the nature of the tumor

maxSUV presently serves as an indicator of metabolic activity during cancer therapy. For instance, the maxSUV of primary lung and hematological cancer lesions correlates with metastasis and prognosis, whereas maxSUV also seems useful for predicting the prognosis of recurrent breast cancer and in determining and predicting the outcome of neoadjuvant chemotherapy

The maxSUV cut-off calculated from ROC curves for recurrence was 3.0

Factors that determine the nature of tumors also include ER, HER-2, Ki-67 labeling index, and nuclear grade

both ER status and maxSUV as independent prognostic factors

maxSUV has a closer correlation with prognosis

maxSUV, clinical T-factor and ER were significant prognostic factors

Our results showed that maxSUV has the potential to be a novel prognostic factor and that it can be used to determine future therapies

In terms of the histological proliferation biomarker Ki-67, we have shown a good correlation with FLT-PET pre-chemotherapy. The best predictive marker of response in terms of pCR was baseline Ki-67

Our study has shown that baseline Ki-67 and FLT SUVmax is well correlated in keeping with FLT-PETs status as a proliferation biomarker, although Ki-67 had a better predictive ability in terms of pathological outcome

The association between FDG uptake and tumor burden or stage has been well documented

advanced tumors tend to have higher FDG uptake (and thus higher SUV values)

the impact of the SUV on treatment outcome has been observed even within a given tumor stage

primary tumor SUVmax >10 predicted survival, independent of the tumor stage and diameter

FDG uptake not only reflects tumor burden/stage but also expresses, at least in part, some intrinsic biologic characteristic(s) of the tumor

SUVmax reflects the highest voxel value within the ROI or VOI. It is the most widely used parameter to measure metabolic tumor activity in oncologic FDG-PET/CT imaging

Several studies suggest that primary tumor baseline SUVmax also has predictive value in assessing the tumor burden, lymph node involvement and local extension

According to EORTC, a drop (delta between baseline and post-therapy) of 15–25% in SUVmax may represent a good treatment response

PERCIST criteria was proposed by the investigators at the Johns Hopkins Medical Institutions and suggested that a decrease in SUV normalized to lean body mass of at least 30% should be achieved before considering partial tumor response

Far more important than the SUVmax is the pattern rather than intensity of metabolic abnormality and the correlative CT findings

Descriptively, we define SUV < 5 as “low intensity”, 5–10 as “moderate”, 10–15 as “intense” and >15 as “very intense”

Evolving literature suggests that intensity of uptake is an independent prognostic factor and in some tumour subtypes superior to histopathologic characterisation.

aerobic glycolysis

Our practice of thresholding the grey and colour scale to liver as detailed above results in similar image intensity to a fixed upper SUV threshold of 8 to 10

The advantage of using the liver as a reference tissue is also aided by this organ having rather low variability in metabolic activity

When the liver is abnormal and cannot be used as a reference organ, we use the default SUV setting of an upper SUV threshold of 8

One of the most challenging aspects of oncologic FDG PET/CT review, however, is to recognise all the patterns of metabolic activity that are not malignant and which consequently confound interpretation

Many benign and inflammatory processes are also associated with high glycolytic activity

Future articles in the “How I Read” series will address the specific details of reading PET/CT in various cancers

The intensity of uptake in metastases usually parallels that in the primary site of disease

For example, discordant low-grade activity in an enlarged lymph node in the setting of intense uptake in the primary tumour suggests it is unlikely malignant and more likely inflammatory or reactive

By CT criteria the enlarged node is ‘pathologic’ but the discordantly low metabolic signature further characterises this is as non-malignant since such a node is not subject to partial volume effects and therefore the intensity of uptake should be similar to the primary site

The exception is when the lymph node is centrally necrotic as a small rim of viable tumour is subject to partial volume effects with expectant lower intensity of uptake; integrating the CT morphology is therefore critical to reaching an accurate interpretation

Small nodes that are visualised on PET are conversely much more likely to be metastatic as such nodes are subject to partial volume effects.

The exception to this rule is tumours with a propensity for tumour heterogeneity at different sites

The combination of FDG and a more specific tracer, which visualises the well-differentiated disease can be very useful to characterise this phenomenon

“metabolic signature”

For the majority of malignant processes, the intensity of metabolic abnormality correlates with degree of aggressiveness or proliferative rate.

a negative PET/CT study in a patient with biopsy proven malignancy would be considered false-negative

Warburg effect

There, however, are a significant minority of tumours that utilise substrates other glucose such as glutamine or fatty acids as a source of the carbon atoms required for growth and proliferation

This includes a subset of diffuse gastric adenocarcinomas, signet cell colonic adenocarcinomas and some sarcomas, particularly liposarcoma

There may be a role for other radiotracers such as fluorothymidine (FLT) or amino acid substrates in this setting.

Some tumours harbour mutations that result in defective aerobic mitochondrial energy metabolism, effectively simulating the Warburg effect

patients with hereditary paraganglioma and pheochromocytoma highlight this phenomenon

These have intense uptake on FDG PET/CT despite often having low proliferative rate.

Uterine fibroids, hepatic adenomas, fibroadenomas of the breast and desmoid tumours are benign or relatively benign lesions that can have quite high FDG-avidity.

Metabolic activity switches off rapidly following initiation of therapy

Common examples where patients have commenced active therapy but the referrer is requesting “staging” includes hormonal therapy (eg. tamoxifen) in breast cancer, oral capecitabine in colorectal cancer or high dose steroids in Hodgkin’s lymphoma

It is therefore critical to perform PET staging before commencement of anti-tumour therapy

The potential advantage of routine diagnostic CT is improved anatomic localisation and definition

Without intravenous contrast, additional identification of typical oncologic complications such as pulmonary embolism or venous thrombosis cannot be identified

If the study is performed as an “interim” restaging study after commencement of therapy but before completion, in order to reach a valid or clinically useful conclusion findings must be interpreted in the context of known changes that occur at a specific timing and type of therapy

The most well studied use of interim PET is in Hodgkin’s lymphoma where repeat PET after two cycles of ABVD-chemotherapy provides powerful prognostic information and may improve outcomes by enabling early change of management