The antiproliferative effect of the peptide hormone somatostatin is mediated by binding to somatostatin receptors (SSTRs) in neuroendocrine tissues. Melanoma cells are derived from the neural crest and therefore express SSTRs. Five subtypes of SSTR (SSTR1–SSTR5) have been described to date 1.
An in-vitro study of 23 melanomas found expression of SSTR1 in 93%, SSTR2 in 83%, SSTR3 in 61%, SSTR4 in 57% and SSTR5 in 9%. Two-thirds of these melanomas showed uptake of In-111 octreotide in vivo 2.
On the basis of these results, our study aimed to investigate whether at least some melanomas show an SSTR expression that may be of therapeutic relevance quantitatively, as adjuvant treatment options for metastasized melanoma are limited. We used the somatostatin agonist DOTATOC, which has been shown to have a higher binding affinity to SSTR2 and SSTR5 compared with octreotide. Further, a previous study has demonstrated a higher sensitivity of Ga-68 DOTATOC compared with In-111 DTPAOC SPECT for pretherapy staging of neuroendocrine tumours 3. The radiation exposure is markedly lower than for In-111 octreotide – 2.5 mSv/110 MBq (0.25 rem/3 mCi) vs. 12 mSv/222 MBq (1.2 rem/6 mCi) 4.
Materials and methods
Between February 2007 and December 2008 we investigated 18 patients (nine men and nine women; mean age 61 years) with metastasized melanoma using PET/CT (Biograph 16; Siemens CTI, Knoxville, Tennessee, USA), first with F-18 fluorodeoxyglucose (18F-FDG) and then with Ga-68 DOTATOC an average of 11 days later (median 7, range 1–86 days). Computed tomography (CT) was performed as a low-dose scan for attenuation correction and anatomical correlation. Informed consent was signed by every patient before the investigation.
The 18F-FDG scan was performed 80±16 min after injection of 345±40 MBq 18F-FDG. We acquired 7–15 bed positions of 3 min each. The DOTATOC scan started 48±18 min after injection of 141±36 MBq Ga-68 DOTATOC. The scan range was limited to those areas with 18F-FDG-positive lesions. Therefore, 2–12 bed positions of 3 min each were acquired.
Scans were analysed visually by two experienced nuclear medicine physicians using transverse, coronal and sagittal slices. The number of 18F-FDG-positive or DOTATOC-positive lesions was determined for each patient. The maximum standardized uptake value (SUVmax) was measured for an index lesion with the greatest uptake using a volumetric region of interest drawn semiautomatically using an SUV cutoff of 2.5.
DOTATOC-positive metastases were found in 11 of 18 patients (61%). In total, we detected 263 lesions using 18F-FDG, of which 59 (22%) were DOTATOC positive as well. We found no 18F-FDG-negative, DOTATOC-positive lesions, although the field of view of the DOTATOC scan was limited to areas with positive 18F-FDG uptake. The mean SUVmax was 28.2 (range 2.3–115) for 18F-FDG and 3.1 (1.2–4.2) for Ga-68 DOTATOC (Table 1 and Fig. 1).
None of the patients showed a degree of DOTATOC uptake that was considered to be of therapeutic relevance. As the tumour-to-background ratio is much higher with DOTATOC than with 18F-FDG, we were looking for a minimum SUVmax of 15 and uptake in (nearly) all known lesions when assessing the potential for therapy.
The antiproliferative effect of somatostatin analogues is mediated by binding to SSTR. An overexpression of SSTR such as seen in neuroendocrine tumours is the pathophysiological basis of using these agents, either unlabelled or labelled with a β-emitting radioisotope, for treatment.
Lum et al. 2 investigated SSTR expression in 23 surgically removed cases of melanoma metastases and found expression of SSTR1 in 96%, SSTR2 in 83%, SSTR3 in 61%, SSTR4 in 57% and SSTR5 in 9%. A presurgical In-111 octreotide scan demonstrated 63% of those lesions. There was no relationship between the pattern of SSTR expression and octreotide uptake.
Valencak et al. 5 found uptake of In-111 octreotide in 43% and of In-111 DOTALAN in 62% of known metastases in 23 melanoma patients. In each of those patients, more lesions were detected using 18F-FDG.
In a 3-year follow-up study on 35 melanoma patients, Zissimopoulos et al. 6 reported a sensitivity of 87% and a specificity of 94% for In-111 octreotide scans in detecting recurrence or metastases of melanoma. In this setting, SSTR scintigraphy was seen to be superior to CT by detecting 56 lesion sites, whereas CT could detect only 31.
In contrast to this, in our study, Ga-68 DOTATOC was positive in 61% of the investigated patients. However, on a lesion-by-lesion basis it could detect only 22% of 18F-FDG-positive metastases. The short uptake period between injection of Ga-68 DOTATOC and the scan may seem a possible explanation. In contrast, a small study by Kowalski et al. 7 found a high SUV 45–60 min after injection, with a peak at 60 min, which made an injection-to-scan interval of 1 h seem advantageous.
Compared with octreotide, Ga-68 DOTATOC will also allow a more reliable estimation of uptake under (potential) therapeutic conditions, as the tracer can also be labelled with Y-90 or Lu-177 for therapy. Van Essen et al. 8 had two melanoma patients in their study on Lu-177 DOTATATE usage in patients with non-neuroendocrine tumours and they did not observe a therapeutic effect, although In-111 octreotide uptake was only moderate.
Although the different biodistributions of 18F-FDG (less liver, spleen and renal parenchymal uptake) and DOTATOC (no brain, heart uptake) may be seen as a theoretical advantage of dual-tracer imaging, our results show that metastasized melanoma does not exhibit a therapeutically relevant degree of DOTATOC uptake. This may reflect a comparatively low degree of tumour differentiation and is in keeping with the in-vitro study by Martinez-Alonso et al. 1 who demonstrated a moderate antiproliferative effect of somatostatin analogues on melanoma cell lines at high concentrations only.
The limitations of our study include the reliance on a previously determined optimum uptake time period 7 and the limitation of the field of view of the DOTATOC scan to areas with positive 18F-FDG uptake, which may have overlooked 18F-FDG-negative, DOTATOC-positive lesions.
In two-thirds of the metastasized melanoma patients investigated, the DOTATOC scan was positive. However, on a lesion-by-lesion basis only moderate DOTATOC uptake was found in 22% of known metastases in 18 melanoma patients. Radiolabelled DOTATOC does not seem to be a promising agent for treatment of metastasized melanoma.
Conflicts of interest
There are no conflicts of interest.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
DOTATOC; 18F-FDG; melanoma; PET; somatostatin analogues