What is the role of [11C]choline PET/CT in decision making strategy before post-operative salvage radiation therapy in prostate cancer patients?

To the Editor,

The use of [11C]choline positron emission tomography (PET) seems to be promising with a prostate-specific antigen (PSA) rise after primary treatment in prostate and appears superior to 18F-FDG PET and complementary to conventional imaging. Nevertheless, the capability to identify local regional disease, especially early in the course of recurrence with PSA lower than 1 ng/ml, when the cancer burden is lowest but most amenable to therapy, is drastically limited by the low sensitivity in this setting [1,2]. Thus, as stated by European Association of Urology (EAU) recommendation, it appears that there is an urgent need for well-conducted and histologically controlled trials to explore the potential role of [11C]choline PET/computed tomography (CT) [3].

The object of the present letter is to show and discuss the impact of the use of [11C]choline PET/CT in decision making strategy of a group of 32 patients, initially referred in our institute to salvage radiation therapy (RT) after biochemical failure. Surgery consisted of a radical prostatectomy with or without pelvic lymph node dissection. The median age at the moment of radiation oncologist evaluation was 71 years (range 58–84). The median GS was 7 (range 5–9). Treatments have been performed with VMAT (RapidArc©) technique as previously published in prostate [4]. The clinical target volume (CTV) 1 was the prostate bed only, including the bladder-urethral-anastomosis, the bladder neck, and the posterior bladder space. CTV2 was pelvic node, when involved in case of risk factors at surgery specimen or in case of pN1. CTV3 was a volume that encompasses PET positive lymph nodes in pelvis, where found at PET before RT. Planning target volume (PTV) 1 was defined as CTV plus 8 mm margin in all directions except cranial-caudal, where a 10 mm margin was used; in some cases, based on clinical judgement of patient anatomy, the posterior margin toward the rectum was decreased. PTV2 and PTV3 were, respectively, CTV2 and CTV3 plus 6 mm in all dimensions. Patient positioning was checked with daily Cone Beam CT (CBCT). The radiopharmaceutical [11C]choline was synthesized using a General Electric TracerLab FXc module, and administered in a total amount of 250–400 MBq in patients who had been fasting for at least 4 hours. The definition of pathologic findings was done by an experienced nuclear medicine physician and was principally based on visual analysis.

SPSS v 19.0 was used for statistical analysis. Distribution of quantitative data in various patient groups, were compared using the Mann-Whitney U-test. Fisher's exact test was used to compare frequency of categories. P-values less than 0.05 were considered statistically significant. Patients’ results were evaluated as following: after radical prostatectomy, the median time to relapse (defined as the second PSA rise above 0.20 ng/ml) was 36 months (range 10–192). Median PSA at choline PET/CT was 1.9 (range 0.27–64). PSA value was < 1 ng/ml in 14 patients (44%) and > 1 ng/ml in 18 (56%). The median PSA doubling time (PSADT) was 5.46 months (range 1.28–31.25 months) and median PSA velocity was 0.10 (range 0.02–20.35).

In all 32 patients [11C]choline PET/CT was performed before RT. A pathologic tracer accumulation defined as failure was found in 19 of 32 analyzed patients (59%). Pathologic uptake was observed in 14 of 18 patients (77%) with PSA > 1 ng/ml and in four of 14 patients (28%) with PSA < 1 ng/ml. For the definition of prostatic tumor localization, we considered as positive any focal uptake of [11C]choline superior to the background activity. For nodal involvement we considered as positive, regardless of size, any increased uptake in the iliac region (external iliac, internal iliac and common iliac), the obturatory fossa and the presacral nodes. In case of extra-pelvic findings, we reported as positive any increased uptake in lymph nodes greater than 10 mm in the longest diameter when located in the lumboaortic, retroperitoneal, retrocrural, mediastinal or supraclavicular regions. Inguinal nodes were usually considered as reactive, unless they showed as tracer-avid, round shaped and dense nodes, with a size > 10 mm.

Commonly we classified as malignant any increased uptake in the bone or bone marrow corresponding to clear sclerotic, osteolytic or mixed lesions on localization CT, unless they were attributable to degenerative changes, osseous dismetabolism and/or fractures. In the other cases, the uptake was considered as malignant when focal and visible in at least two consecutive slices. On an anatomical basis, pathological uptake was observed in the prostatectomy bed (13 of 18 patients, 72%), in lymph nodes (seven of 18 patients, 39%), and in bones (one of 18 patients, 5.5%). In one patient, PET/T showed an additional primitive tumor of esophagus.

At univariate analysis, patients with positive [11C]choline PET/CT had significantly higher PSA (p < 0.02), significantly shorter PSADT (p < 0.03) and significantly higher PSA velocity (p < 0.002) than patients with negative PET/CT. Considering general management, in eight patients (26%) a changing of the intent was assessed: all started hormonal therapy, one of them patients also chemotherapy. Considering RT intent, six of 32 (18.7%) were not submitted to RT. In two patients (6.4%) a PTV expanding was performed adding pelvic lymph node irradiation. A RT dose prescription changing was performed in 14 (44%) patients: in seven of them (21.8%) a prostatic bed boost up to 74.2 Gy was added, in four (12.5%) patients the boost was to lymph nodal accumulation on PET, up to 65.5 Gy, while in three (9.3%) patients both boost were performed. In summary, in the group of 25 patients submitted to RT, an intent changing after PET was found in 14 (56%) patients.

The median time for evaluation of initial PSA response was 1.9 months (range 1–5). The median total follow-up time after RT was 12 months (range 4–20).

Excluding eight patients who started hormone therapy, 23 of 32 patients (72%) were evaluated for initial PSA response, estimated with PSA reduction. Twenty-one of 23 patients (91%) were initial responders and two of 23 (9%) were initial non- responders. Of the 15 patients with positive [11C]choline PET/CT scan treated with RT, 13 (87%) were initial responders and two (13%) were initial non-responders. In this group of patients, PET/CT at three months showed [11C]choline uptake in extrapelvic lymph nodes and bones. No grade 2 or higher toxicity was observed.

Discussion

PET with radiolabeled choline has been largely investigated in post-operative setting, after biochemical recurrence: the capability of PET to assess tumor localization and extension has been mainly utilized for salvage RT planning [5]. Overall detection rate is variable and it depends directly on PSA absolute value and PSA kinetics. It was confirmed also in the present study where patients with positive [11C]choline PET/CT had significantly higher PSA, significantly shorter PSADT and significantly higher PSA velocity than patients with negative PET/CT.

Souvatzoglou et al. [6] investigated [11C]choline PET/CT the impact on the extent of PTV delineation: in 13% of the patients with PET positive findings, the tracer accumulation was found outside of the prostatic bed, in pelvic nodes, implicating an extension of the PTV. In a prospective pilot study, 27 patients with biochemical relapse after radical prostatectomy were evaluated with [11C]choline PET/CT before salvage RT: in long-term follow-up, approximately 30% of treatment failures locoregional nodal or distant metastatic disease outside the radiation ports were found [5]. Würschmidt et al. [7] investigated the role of PET for irradiation of recurrent sites: PET choline in treatment planning was helpful to modify the PTVs and to perform a dose escalation strategy to the active sites of disease.

Thus, from these preliminary experiences, PET seems to be really useful in the pre-treatment phase to better establish the extension of target volume and/or to re-shape it for salvage RT. In the current study, the introduction of choline PET/CT before treatment changed the therapeutic management intent in 26% of the study population. In the group of patients submitted to RT, dose prescription and volumes changing after PET was found in 56% patients. In case of biochemical recurrence after radical prostatectomy, stereotactic radiation therapy (SRT) has shown to be more effective in patients with PSA values < 1 ng/ml, when sensitivity of PET could be poorer and it remains a huge limit of this routine application in the setting of recurrent patients suitable for SRT.

A criticism of the present study is, as well as most of previous discussed series, the absence of histological confirmation of PET finding. When biopsy is usually suggested, a longer waiting time period before the histological confirmation is common, due to the necessity to achieve a minimum value of PSA acceptable for the biopsy [9]. On the contrary, Stephenson et al. [8,10] affirmed that the most important finding from analysis of the literature is that early salvage RT could be the better approach when a PSA failure is initial, and thus when anastomotic biopsy and diagnostic tools are not suggested. Thus, the problem remains, as well as choline PET timing.

Other imaging modalities have been proposed, nevertheless, in a post-operative setting a lot of criticisms and uncertainties regarding the reliability and accuracy of magnetic resonance imaging (MRI) for prostatic be relapse definition remain. Hybrid PET/MRI machines could be useful to define a more detailed target volume, also in case of local relapse.

In conclusion, this experience showed that in our institute, the use of [11C]choline PET/CT really impacted on decision making strategy of a group of 32 patients, initially referred to salvage RT after biochemical failure. However, even if promising data are emerging prospective studies are needed to implement the benefit of RT with a salvage treatment based on PET imaging local relapsing prostate cancer. Based on this consideration, the integration of PET in prostate cancer treatment planning still remains an object of study.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.