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cells and a higher SSTR expression is a rough predictor prognostication and risk stratification would theoretically
of response to PRRT. [55,60] Clinical studies demonstrated require multiple biopsies from different tumor sites and in
higher tumor remission rates after PRRT in patients with different moments over time through the evolution of the
a high baseline SUVmax on Ga-DOTA-peptide PET/CT disease, but obviously this is not always possible. [34,55]
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versus patients with a lower baseline SUVmax on Ga-
68
DOTA-peptide PET/CT. [59] Functional imaging can non-invasively and simultaneously
visualize in real-time all metabolically active tumor
Therefore, patients with positive 18 F-FDG PET/CT sites in the whole body. [39,55] While Ga-DOTA-peptides
68
but negative 68 Ga-DOTA-peptide PET/CT cannot be avidity is a feature of well-differentiated disease, F-FDG
18
effectively targeted with PRRT, as the negative Ga- avidity tends to be associated with more aggressive, de-
68
DOTA-peptide PET/CT indicates that the obligatory target differentiated disease. Variable tracer uptake at different
[66]
is not expressed. Such patients, who frequently harbor lesion sites within the same patient is a relatively common
high-grade NECs, may benefit instead from conventional finding, and reflects the wide spectrum of differentiation of
chemotherapy or, in selected cases, from biologic some NENs, where heterogeneity of cellular differentiation
[61]
agents such as everolimus or sunitinib. [62,63] Conversely, if may be present even within one single tumor lesion. [12,38]
patients have F-FDG-avid lesions which retain sufficient
18
SSTR expression as evidenced by concordant F-FDG This observation, while suggesting caution in the
18
and Ga-DOTA-peptides uptake, these sites of aggressive interpretation of Ki-67 indexes obtained from biopsy
68
disease can potentially be targeted with PRRT. Indeed, samples, on the other hand reflects the potential ability of
[64]
it has been reported that many such patients, including PET/CT to map cellular heterogeneity. Consistently, the
those who have failed conventional therapies, have prognostic value of F-FDG PET/CT positivity exceeded
[64]
18
remarkable responses to PRRT, although with shorter that of “conventional” parameters such as Ki-67 labeling
PFS compared to patients without a positive F-FDG index and presence of liver metastases in the study of
18
[55]
PET/CT scan. In a study conducted on patients with Binderup et al. Similarly, F-FDG PET/CT was found
18
[39]
metastatic, well differentiated (G1-G2) NETs, undergoing to be more sensitive than pathologic differentiation and
177Lu-DOTATATE PRRT, the disease control rate Ki-67 labeling index in the early prediction of rapidly
was significantly higher in patients who had a negative progressive disease in the report of Garin et al. A total
[2]
18 F-FDG PET/CT scan after 177 Lu-DOTATATE PRRT tumor population characterization using a combination
(100%) versus patients who had a positive PET scan after of F-FDG PET/CT and Ga-DOTA-peptides PET/CT
18
68
177Lu-DOTATATE PRRT (76%). Moreover, PFS was seems a clinically useful approach, being able to map the
[55]
[52]
significantly lower in patients who had a positive F-FDG entire degree of tumor differentiation in the same patient
18
PET/CT scan, of whom 48% had progressive disease (PD) at different time points throughout the natural course of
after a median follow-up of 20 months, versus patients disease. [22,38,52]
who had a negative F-FDG PET/CT scan, of whom 26%
18
had PD after the same follow-up time. In a study on ROLE OF MOLECULAR IMAGING IN
[55]
patients with metastatic well-differentiated NETs, of the THE EVALUATION OF RESPONSE AFTER
[65]
42 patients who had pretreatment F-FDG PET imaging, TREATMENT
18
31 patients had a positive F-FDG PET scan (SUVmax >
18
2.5) with an average survival time of 18.9 months (range Early prediction of therapy response in cancer patients is
1.4-45.8 months) and 11 patients had a negative F-FDG essential to guide therapy and avoid the side effects and
18
PET scan (SUVmax ≤ 2.5) with an average survival time of costs of ineffective therapies.
31.8 months (range 7.4-42.9 months). Survival in patients
with a negative F-FDG PET scan was significantly longer 68 Ga-DOTATOC PET/CT was found to be superior to
18
than in patients with a positive F-FDG PET scan (P = standard imaging with CT and/or MRI in the detection of
18
0.001 with 95% confidence interval). [65] primary tumor recurrence in pretreated patients in whom
tumor recurrence was suspected during the follow-up
It has been proposed that these patients could benefit from period (8/40 vs. 2/40, P < 0.001). [4]
the adjunct of radiosensitizing chemotherapy with 5-FU to
PRRT and trials are ongoing to assess this hypothesis. The role of 68 Ga-DOTATOC PET/CT in evaluating
[66]
treatment response after PRRT is debated. Some authors
Heterogeneity description reported that decreased Ga-DOTATATE uptake after
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The histopathological classification of NENs is limited by finishing the first cycle of PRRT significantly correlated
an intrinsic bias when applied to patients with metastatic with symptom improvement and a longer TTP in patients
disease. The tissue obtained from needle biopsy of a harboring well-differentiated NETs. [67,68] In other studies,
single lesion is not necessarily representative of the 68 Ga-DOTATOC PET was not found to be superior to CT
all the cells in that tumor, or all the tumor lesions in all in the assessment of response to SSTR-targeted PRRT.
[69]
tumor sites [38,39,55] given that NENs display a particularly For this reason, early variations in SUVmax of Ga-
68
high heterogeneity. Accurate tumor grading for DOTATOC PET actually cannot be used as a surrogate
[34]
Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 325