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11C-Choline PET/CT as a guide to radiation treatment planning of lymph-node relapses in prostate cancer patients

Abstract

Purpose

To evaluate, in prostate cancer (PCa) patients the potential of 11C-choline PET/CT as a guide to helical tomotherapy (HTT) of lymph-node (LN) relapses with simultaneous integrated boost (SIB). The efficacy and feasibility of HTT in terms of acute toxicity were assessed.

Methods

We enrolled 83 PCa patients (mean age 68 years, range 51 – 82 years) with biochemical recurrence after radical primary treatment (mean serum PSA 7.61 ng/ml, range 0.37 – 187.00 ng/ml; PSA0) who showed pathological findings on 11C-choline PET/CT only at the LN site. 11C-Choline PET/CT was performed for restaging and then for radiation treatment planning (PET/CT0). Of the 83 patients, 8 experienced further LN relapse, of whom 5 were retreated once and 3 were retreated twice (total 94 radiotherapy treatments). All pelvic and/or abdominal LNs positive on PET/CT0 were treated with high doses using SIB. Doses were in the range 36 – 74 Gy administered in 28 fractions. After the end of HTT (mean 83 days, range 16 – 365 days), serum PSA was measured in all patients (PSA1) and compared with PSA0 to evaluate early biochemical response. In 47 patients PET/CT was repeated (PET/CT1) to assess metabolic responses at the treated areas. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) were used to assess acute toxicity.

Results

PET/CT0 revealed pathological LNs in the pelvis in 49 patients, pathological LNs in the abdomen in 15 patients pathological LNs in both the pelvis and abdomen in 18 patients, and pathological LNs in the pelvis or abdomen and other sites in 12 patients. All these sites were treated with HTT. With respect to PSA0, PSA1 (mean 6.28 ng/ml, range 0.00 – 220.46 ng/ml) showed a complete biochemical response after 66 of the 94 HTT treatments, a partial response after 12 treatments, stable disease after 1 treatment and progression of disease after 15 treatments. Of the 47 patients receiving PET/CT1, 20 showed a complete metabolic response at the treated area, 22 a partial metabolic response, 3 progression of disease and 2 stable disease. HTT with SIB was well tolerated in all patients. Grade 3 acute toxicity in the genitourinary tract was observed in two patients.

Conclusion

11C-Choline PET/CT is a valuable tool for planning and monitoring HTT in LN relapse after primary treatment. High-dose hypofractionated 11C-choline PET/CT-guided HTT with SIB is well tolerated and is associated with a high early biochemical response rate.

Introduction

Among patients with prostate cancer (PCa), tumour relapse occurs in 15 – 33 % after radical prostatectomy [1] and in 36 – 63 % after external beam radiotherapy [2]. Once recurrence is suspected on the basis of an increase in prostate-specific antigen (PSA), it is crucial to determine whether the recurrence has developed at local or distant sites in order to choose the most appropriate treatment strategy [3]. The presence of distant recurrence of PCa in both lymph nodes (LN) and bone after primary treatment is a major negative prognostic factor in these patients and systemic hormonal therapy is the best choice [4, 5].

Recently, alternative treatment strategies have been proposed for patients with recurrent LN disease for effective local control, that could also reduce the dose of concomitant systemic therapies and their associated side effects. However, the detection of LN metastases is one of the biggest challenges in urological imaging, and lymphadenectomy is still the most accurate modality for LN status evaluation [6]. Among various imaging modalities available for localizing the site of recurrence, PET/CT with the use of choline compounds (choline PET/CT) has proved to be a valuable tool for restaging patients with PCa with biochemical failure and particularly for detecting LN recurrences in providing better results than conventional imaging modalities, even in those with low serum PSA values [713].

Surgical dissection of pelvic and/or retroperitoneal LNs has been proposed specifically in patients with recurrences detected by conventional imaging or choline PET/CT [1417]. Alternatively, radiation therapy (RT), stereotactic RT and the high-conformal technique intensity-modulated RT (IMRT), such as helical tomotherapy (HTT), have also been evaluated in patients with LN recurrence [1821]. Choline PET/CT, as an image guide for RT planning in PCa recurrence, has provided promising results with regard to patient outcome and toxicity [2226].

PET has been proven to be helpful in the delineation of the gross tumour volume (GTVPET) for external RT in several tumour entities. A simultaneous integrated boost (SIB) can be also delivered to the GTVPET [27]. However, the final role of choline PET/CT as an image guide for IMRT planning in patients with LN recurrence has not yet been established yet in a large cohort of patients.

The aim of the present study was to evaluate in a large population of patients with recurrent PCa the potential role of 11C-choline PET/CT in guiding HTT with SIB in patients with LN recurrence. Biochemical and metabolic responses were used as reference. The feasibility of the treatment was assessed in terms of acute toxicity.

Materials and methods

Patient population

This study was conducted between January 2005 and May 2013 in patients with PCa relapse following primary radical treatment referred to our institution for 11C-choline PET/CT for restaging. Inclusion criteria were: (1) biochemical failure, defined as serum PSA >0.2 ng/ml after radical prostatectomy and as serum PSA ≥2 ng/ml above the nadir after RT (PSA0) [28]; (2) positive LN findings on PET/CT (PET/CT0); (3) referral for HTT with SIB of LNs positive on PET/CT0; (4) HTT to be performed within 4 months of PET/CT0; (5) availability of serum PSA measurements obtained at the time of PET/CT0 and after HTT to evaluate the biochemical response; (6) availability of biochemical and clinical follow-up; and (7) written informed consent for the performance of the PET/CT scan, HTT and anonymous publication of disease-related information. Patients with distant metastases detected either on PET/CT0 or by other imaging modalities, such as bone scintigraphy or CT, were excluded. Concomitant HTT of the prostatic fossa was not considered an exclusion criterion. These criteria were met by 83 patients who were included in the analysis, and a total of 94 HTT treatments with SIB of LNs positive on PET/CT0 were performed. These 94 treatments were considered in the data analysis. The serum PSA values obtained and the PET/CT scans performed at the time of each new relapse were considered as PSA0 and as PET/CT0, respectively. The clinical, biochemical and pathological features of the patients are summarized in Table 1.

Table 1 Characteristics of the 83 patients

In 66 of the 94 HTT treatments (70.2 %) the patient was receiving androgen deprivation therapy (ADT) at the time of HTT. The average clinical and instrumental follow-up after HTT was of 28 months with a median of 22 months in all patients (range 2 – 99 months). ADT administered during HTT was individualized according to the clinical features of the patient in terms of dose and timing. Thus standardization of ADT could not be achieved.

In 2009, after obtaining promising data from the first clinical pilot study, this study was submitted to and approved by the Ethics Committee of the San Raffaele Hospital.

Study design

PET/CT0 findings were used to guide HTT with SIB (see section HTT). The mean time between PET/CT0 and the beginning of HTT was of 47 days (range 7 – 103 days). To evaluate the early biochemical response, the serum PSA value after HTT (PSA1; mean 83 days, range 16 – 365 days) was recorded and compared to PSA0.

In a subgroup of patients PET/CT was performed after HTT (PET/CT1), and the findings were compared with those of PET/CT0 to assess metabolic response at the site of treatment and to detect potential new sites of recurrent disease. Acute toxicity was assessed to verify the feasibility of the treatment.

11C-Choline PET/CT protocol

Both the PET/CT0 and PET/CT1 studies were performed on three different integrated PET/CT systems, including a Discovery LS scanner, a Discovery ST scanner and a Discovery STE scanner (GE Medical Systems, Milwaukee, WI). Patients fasted and refrained from drinking for at least 6 h before the scan. Patients were positioned supine on the scanner bed with their arms above their head and placed in the RT position using immobilization systems to limit positioning errors between the PET/CT scan and the following sessions of HTT.

A CT scout scan was performed to define the axial extension of the body (from the pelvis to the base of the skull) to be imaged. After a low-dose CT scan, a 5-min frames centred on the pelvis were acquired immediately after intravenous injection of approximately 370 MBq of 11C-choline. At the end of the dynamic acquisition, a whole-body PET scan was performed. Acquisitions were performed in 2-D mode (4 min per bed position) with the Discovery LS and ST scanners, and in 3-D mode (2.5 min per bed position) with the Discovery STE scanner. PET images were corrected for random, scatter and attenuation, and reconstructed on a 128 × 128 image matrix using iterative algorithms as follows: 2-D ordered subsets expectation maximization (OSEM), 28 subsets and two iterations, with the Discovery LS scanner; 2-D OSEM, 30 subsets and two iterations, with the Discovery ST scanner; and 3-D OSEM, 28 subsets and two iterations, with the Discovery STE scanner. Attenuation correction was performed using CT images. Dead-time, random and scatter correction were also applied [2931].

PET/CT image analysis

PET/CT image analysis was performed on a Xeleris workstation (GE Medical Systems), which allows visualization of PET, CT and fused sections in transverse, coronal and sagittal planes. Two experienced nuclear medicine physicians independently and qualitatively evaluated the PET/CT images. Readers had knowledge of the clinical history of the patients and of the results of other diagnostic techniques. In the event of disagreement the images were re-examined and a consensus was reached. Each focal tracer accumulation deviating from the physiological distribution of the tracer was regarded as a site of recurrence. In particular, the diagnosis of LN involvement assessed on PET images was based on the evidence of a 11C-choline pathological uptake into LNs identified on CT images. Therefore, LNs with pathological tracer uptake were considered positive for cancer, even if their short axis was smaller than 10 mm. Diffuse, bilateral tracer uptake in inguinal LNs showing benign characteristics on CT images was considered as being inflammatory [32].

In addition to the qualitative image evaluation, the metabolic volume of PET/CT-positive LNs (GTVPET) was drawn by a nuclear medicine physician using visual evaluation with fixed windowing. This was the volume that received the HTT with SIB.

Treatment planning

After the PET/CT study, the CT images and GTVPET were sent to an Eclipse planning station and an experienced radiation oncologist contoured the clinical target volume (CTV). Depending on the presence of a previous RT, three different CTVs could be defined: (1) in previously irradiated patients with a favourable dose distribution in the organ at risk, the CTV was drawn on the entire LN chain including PET/CT-positive LNs (62 treatments); (2) in those patients previously irradiated and with an unfavourable dose distribution in the organ at risk, the CTV was drawn on PET/CT-positive LNs only, and thus corresponded to GTVPET (6 treatments); (3) in patients who had never undergone previous RT, the CTV was drawn on the entire LN chain including PET/CT-positive LNs plus the entire pelvis and prostatic bed (26 treatments; Fig. 1).

Fig. 1
figure1

A 67-year-old man with PCa relapse (Gleason score 4 + 5, pathological stage at radical prostatectomy pT3bpN0, PSA0 at relapse 1.70 ng/ml). Coronal (a) and axial (b) choline PET/CT images show increased pathological uptake in the right common iliac LN. The dose distribution is shown in coronal (c) and axial (d) plain images. The CTV was the entire LN chain where PET/CT detected positive LNs, plus the pelvis and the prostatic bed. Two PTVs were defined (c and d): the smaller volume, PTV1 (red solid line), resulted from the addition of 5-mm isotropic margins to GTVPET (pathological uptake, dark blue solid line); the larger volume, PTV2 (orange solid line) resulted from the addition of 7-mm isotropic margins to the CTV (light blue solid line). The prescription dose was 51.8 Gy on PTV2 and the SIB technique was used to deliver concomitantly 65.5 Gy to PTV1

Two types of planning target volume (PTV) were defined: PTV1, that resulted from the addition of isotropic margins of 5 mm for set-up errors to the GTVPET; and PTV2, that resulted from the addition of isotropic margins of 5 – 7 mm to the CTV. After contouring, images and contours were sent to the HTT workstation for planning optimization: field width 2.5/5 cm, pitch 0.25 – 0.32 and modulation factors 2.5 – 3.5 were used in all patients. In the 94 treatments, the total doses ranged from 36 Gy to 74 Gy (mean 65 Gy) given in 28 fractions for PTV1 and from 42 Gy to 65 Gy (mean 52 Gy) given in 28 fractions for PTV2. The two PTVs were concomitantly treated. At least 95 % of PTVs received at least 95 % of the prescribed dose keeping the homogeneity of the dose distribution as high as possible. Planning optimization criteria were similar to those previously reported for prostate irradiation including pelvic nodes [3335].

In addition, if of PTV1 (to be treated at the higher dose) overlapped with bowel loops and/or duodenum, the dose was reduced in the overlap to 50 – 54 Gy. If abdominal LN were to be irradiated, kidneys were spared to reduce the dose as much as possible, with the objective of reducing the mean dose to at least below 10 Gy.

HTT

The HTT equipment consisted of a linear accelerator with a ring gantry and an integrated mega voltage image detector (Hi-Art II; TomoTherapy, Madison, WI). For treatment, the x-ray energy source of 6 MV rotates synchronously with the continuous longitudinal movement of the bed, creating an intensity-modulated beam with a spiral pattern that is collimated by an associated binary multileaf collimator composed of 32 pairs of leaves. The same x-ray source is used to acquire CT images (MVCT) before treatment using energy lower than or equal to 3.5 MV. Daily image guidance was performed in all patients: MVCT is matched with the planning CT by bone matching followed by manual adjustments to guarantee agreement between the planned and therapy patient position.

Evaluation of early treatment response

To evaluate the efficacy of PET/CT-guided HTT, the change in the serum PSA value after HTT was evaluated in all patients. The biochemical response was classified as: (1) complete response (reduction of more than 50 % of the initial PSA0 value); (2) partial response (reduction of between 10 % and 50 % of the initial PSA0 value; (3) stable disease (oscillation within 10 % of initial values); (4) progression of disease (increase in serum PSA value of more than 10 %) [19]. In addition the percentage variations between PSA1 and PSA0 were determined and the difference between these values was tested by the Mann-Whitney nonparametric rank test.

In the subgroup of 47 patients in whom a metabolic response was also evaluated by PET/CT1, two experienced nuclear medicine physicians independently qualitatively evaluated the local metabolic response at the treated LN sites as follows: (1) complete metabolic response, when LN uptake previously detected on PET/CT0 was not visualized on PET/CT1; (2) partial metabolic response, when LN uptake detected on PET/CT0 was reduced on PET/CT1, but had not completely disappeared; (3) stable metabolic disease, when no significant difference in LN uptake was detected on PET/CT1 compared with PET/CT0; (4) metabolic progression of disease, when LN uptake detected on PET/CT0 had increased on PET/CT1. In addition, the occurrence of distant metastatic disease either at a LN site or distant sites was indicated [19].

Toxicity of HTT

During HTT patients were periodically evaluated by a radiation oncologist. After the end of treatment, patients were followed-up every 3 months during the first year, every 4 months during the second year and every 6 months during the third year. For the current study, data on acute toxicity (during HTT and up to 3 months after HTT) were available; the Radiation Therapy Oncology Group (RTOG) morbidity grading scale was used [36].

Results

The LN sites positive on PET/CT0 referred for HTT with SIB are shown in the Table 2.

Table 2 PET/CT0 sites of disease referred for HTT with SIB

Biochemical response

Mean and median serum PSA values after HTT (PSA1) were 6.28 ng/ml and 0.44 ng/ml (range 0.00 – 220.46 ng/ml), respectively, with a significant reduction with respect to PSA0 (p < 0.0001). A reduction of 83 % in the median serum PSA value was observed (Fig. 2). An early biochemical response, either a complete or partial response, was detected following 78 of 94 treatments (82.9 %; Table 3).

Fig. 2
figure2

Median serum PSA values (ng/ml) and their 95 % confidence intervals comparing PSA0 and PSA1. The difference between these values is highly significant (p < 0.0001, Mann-Whitney nonparametric rank test)

Table 3 Biochemical response results (PSA1 vs. PSA0)

Metabolic response

In 47 of 83 patients (56.6 %) PET/CT was repeated because of new biochemical failure (PET/CT1). In 8 of these 47 patients PET/CT1 detected additional sites of LN relapse, and these sites were thus newly treated with HTT. Of these 8 patients, 5 were retreated once and 3 were retreated twice. In 42 (89.4 %) of these 47 patients in whom PET/CT1 was performed, a metabolic response at the treated LN areas was documented (complete metabolic response in 20, partial metabolic response in 22; Fig. 3). Of the remaining 5 patients (10.6 %), 2 showed metabolic stable disease and 3 showed metabolic progression of disease (Table 4). In addition, in 27 of the 47 patients (57.4 %) PET/CT1 detected new disease at distant sites.

Fig. 3
figure3

A 51-year-old man with PCa relapse (Gleason score 4 + 3, pathological stage at radical prostatectomy pT3bpN1, PSA0 at relapse 1.29 ng/ml). Coronal (a, f) and axial (c, h) choline PET/CT images show increased pathological uptake in the left common iliac and left external iliac LNs, respectively. The dose distribution is shown in coronal (b) and axial (d) plain images for the GTVPET of the left common iliac LN. The dose distribution is shown in coronal (g) and axial (i) plain images for GTVPET of the left external iliac LN. The CTV included the whole LN chain which received a dose of 51.8 Gy. SIB was delivered to both PET/CT-positive sites, that received 65.5 Gy. After the end of treatment the patient had stable disease (PSA1 1.26 ng/ml) and a complete metabolic response (e, j)

Table 4 Metabolic response results at treated areas (PET/CT1 vs. PET/CT0)

The correlation between biochemical response and PET/CT1 findings is reported in Table 5.

Table 5 Correlation between biochemical response and PET/CT1 findings in 47 patients

Acute toxicity

Acute genitourinary, upper gastrointestinal and rectal toxicity rates are shown in Table 6. Nine patients also showed other acute grade 1 toxicity for the presence of erythema (five patients), haematotoxicity (two patients) and asthenia (one patient). One patient had grade 2 erythema of the external genitals.

Table 6 Acute toxicities

Discussion

In the present study the value of 11C-choline PET/CT as a guide for IMRT with escalated boost doses to LN metastases was assessed in 83 patients with mainly an intermediate to high risk of recurrent PCa. This treatment strategy, performed irrespective of the serum PSA value and LN location, was aimed at providing effective local control, also possibly reducing the dose of concomitant systemic therapies and their correlated side effects. The current approach, that is also the policy in our institution, is to treat PCa patients showing relapse after surgery with salvage RT to the prostate bed and/or LN areas at the lowest serum PSA value above 0.2 ng/ml. In the present study choline PET/CT was performed to identify LN locations with the highest disease burden to be treated with SIB dose escalation, while performing the standard treatment. The rationale for this therapeutic approach is to enhance local control and progression-free survival, as previously demonstrated [1417].

In patients with recurrence after radical RT or surgery followed by adjuvant or salvage RT, ADT is the treatment of choice and is used in patients without contraindications or not already castration resistant. ADT is a palliative treatment that is effective for 24 – 30 months before the development of resistance [37]. Commonly, serum PSA increases rapidly after resistance, even in patients without bone or other extranodal metastasis. Patients with recurrence after previous RT without extranodal disease, independently of serum PSA value, were also included in this study with the same rationale and together with the systemic therapy.

Metastatic disease is currently considered a definitive indication for initiating ADT [4, 5, 38, 39]. Different clinical features, such as Gleason score, time to biochemical relapse, serum PSA doubling time and LN metastatic involvement are recognized as predictors of PCa-specific survival. The risk of disease progression is highest in high-risk PCa patients, in particular those with Gleason scores of 8 – 10, who show a 5-year metastasis-free survival of 22.8 % [39]. Thus, in this category of patients more aggressive treatment is advisable, such as the combination of RT to the relapse sites and ADT.

In our series, an early biochemical response, either a complete or partial response, was obtained following 82.9 % of treatments. In addition, in 89.4 % of patients in whom PET/CT1 was performed, a metabolic response at the site of treatment was detected. The use of metabolic data allowed the volume (GTVPET) of sites of recurrence to be delineated and where the absorbed dose should be increased to be defined.

Choline PET/CT has proved to be a powerful tool for restaging patients with PCa with biochemical failure in providing better results than conventional imaging modalities, even in patients with low serum PSA values [713]. However, in histologically proven studies, its diagnostic performance in patient-based and lesion-based analyses has been found to be variable. Some studies validated by open pelvic/retroperitoneal lymphadenectomy have shown good specificity and positive predictive value (PPV) of choline PET/CT in restaging LN metastases [4042]. Scattoni et al. found in a lesion-based analysis that the sensitivity, specificity, PPV, negative predictive value (NPV) and accuracy of choline PET/CT were 64 %, 90 %, 86 %, 72 % and 77 %, respectively. Of 21 choline PET/CT-positive patients, 19 (90 %) were true-positive [41]. Schilling et al. evaluated the accuracy of choline PET/CT in the diagnosis of LN recurrence after radical prostatectomy or primary RT, with a median of 5.5 (range 1 – 22) nodes removed. Patient-based PPV was 70 % [17]. Similarly, Tilki et al. in a lesion-based analysis found a sensitivity, specificity, PPV and NPV of 40 %, 96 %, 76 % and 83 %, respectively. However, in LN-based analysis the PPV has been reported to be rather low [10, 13]. Therefore, when a choline PET/CT-based target therapy is considered, either surgery or RT, extensive treatment to the whole LN chain including choline PET/CT-positive LNs should be planned. This was in fact the standard approach in the majority of patients in our series. An exception was in six patients who had already been referred for previous irradiation to the same LN chain and showing an unfavourable dose distribution in the organ at risk. We decided not to exclude these patients from the study with the aim of enhancing local control and progression-free survival. Long-term treatment outcome results are needed to draw conclusions as to the eligibility of this subgroup of patients for such a selective treatment.

Different studies have investigated the potential value of 11C-choline PET/CT-guided RT in patients with PCa recurrence, especially pertaining to local and LN recurrence [21, 2426, 43, 44]. The present study confirmed the feasibility of HTT of LN metastases, in accordance with our preliminary data [21, 43, 44].

Souvatzoglou et al. demonstrated that the use of 11C-choline PET/CT in treatment planning in PCa patients referred for prostatic fossa salvage RT led to an extension of the PTV in 13 % of patients. In addition, 75 % of these patients were relapse-free during the follow-up period (median 3.8 years after salvage RT) [24]. In a population of 19 patients studied using 18F-fluoroethylcholine PET/CT, Würschmidt et al. found a biochemical relapse-free survival rate of 49 % during a median follow-up of 28 months. In the majority of patients (84 %), no or mild late side effects were observed. In addition, the authors concluded that choline PET/CT planning could be helpful in dose escalation allowing boost doses higher than 60 Gy to metastatic LN regions [25]. Casamassima et al. investigated the use of stereotactic body RT to treat limited nodal recurrences, as detected by choline PET in 25 patients. At the 3-year follow-up, overall survival, disease-free survival and local control rates were 92 %, 17 % and 90 %, respectively [26].

Since serum PSA alone is not a reliable marker for quantifying response to therapy, 11C-choline PET/CT could be also proposed as an imaging tool for the assessment of treatment response. While European Organization for Research and Treatment of Cancer Criteria based on tumour glucose metabolism variations using FDG PET/CT are well standardized, the role of alternative PET compounds, such as choline, in the assessment and prediction of responses to cancer treatment has not yet been thoroughly investigated in large series [45]. This study was not specifically designed for the evaluation of the accuracy of treatment assessment. However, in almost 90 % of patients in whom PET/CT1 was performed, a metabolic response at treated LN areas was documented. In addition, of particular clinical relevance is the fact that PET/CT1 was able to detect the presence of distant progressive disease in more than 50 % of patients. Being a whole-body modality, PET/CT may thus represent a valuable tool not only in guiding tailored treatment and in assessing local response to treatment, but also in patient monitoring and follow-up. Considering the fact that serum PSA takes up to 18 – 24 months to decrease after primary RT of PCa [46], choline PET/CT could be useful in evaluating RT response at an earlier time point if a reduction in serum PSA does not occur and in guiding further therapy. However, further studies are needed to support this hypothesis.

In the population evaluated in the present study, HTT was well tolerated. In particular, acute genitourinary and gastrointestinal toxicity of grade 1 was seen in 5.3 % and 28.7 % of treatments, respectively. The rate of grade 2 gastrointestinal toxicity was very low with no grade 3 reported. This excellent result is in line with those of previously reported studies on pelvic node irradiation using HTT in PCa patients [34, 35, 47]. Importantly, the acute gastrointestinal profile was also more than acceptable when extrapelvic nodes were included in the treated volumes, which is a highly valuable result. Similar to the finding of other studies, choline PET/CT has been shown to be able to guide RT allowing a dose escalation to macroscopic intraprostatic and LN lesions without significantly increasing toxicity [18, 19, 23, 48].

In the present study we included patients who were studied with three different types of PET/CT scanner, although produced by the same manufacturer: a Discovery LS, a Discovery ST and a Discovery STE scanner. The main difference among them was that the Discovery LS and ST scanners were used in 2-D mode, while Discovery STE was used in 3-D mode and images were reconstructed using a fully 3-D algorithm. Phantom studies have shown greater or equal lesion detectability of 3-D compared to 2-D systems [30]. The Discovery STE scanner also differs from the Discovery ST and LS with regard to spatial resolution, coincidence window and energy threshold for detection of true events. However, Giovacchini et al. studied a series of 358 patients, and found no significant differences in the results using these scanners [32].

The main limitation of this study was the lack of standardization of ADT administered during HTT. In fact, some patients had already started systemic treatment before PET/CT0, while other patients started ADT only after PET/CT0. Consequently, the assessed responses to treatment included the combination of both therapy modalities, and long-term results should be awaited to allow better assessment of the value of the current approach. The combination of ADT and RT has been demonstrated to perform better in disease control [37, 49]. However, as is well known, ADT is associated with multiple side effects. Probably, an effective local therapy, such as HTT, might reduce the burden of systemic therapies administered to patients with metastatic PCa [6, 28]. To define the best combination of ADT and HTT, further investigations with standardized systemic therapies are necessary.

Conclusion

High-dose hypofractionated 11C-choline PET/CT-guided HTT is well tolerated and achieves a high rate of early biochemical response. Although affected by some limitations in diagnostic accuracy, choline PET/CT was demonstrated to have a great potential for guiding targeted HTT of LN recurrence in PCa patients, and also to be a useful tool for assessing treatment efficacy. Further analyses are needed stratifying patients according to their clinical and imaging features to identify those who are most likely to respond and benefit from such treatment. Long-term results should be awaited to allow a full assessment of the clinical value of this promising approach to the treatment of advanced PCa.

References

  1. 1.

    Ward JF, Blute ML, Slezak J, Bergstralh EJ, Zincke H. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol. 2003;170:1872–6. doi:10.1097/01.ju.0000091876.13656.2e.

    PubMed  Article  Google Scholar 

  2. 2.

    Khuntia D, Reddy CA, Mahadevan A, Klein EA, Kupelian PA. Recurrence-free survival rates after external-beam radiotherapy for patients with clinical T1-T3 prostate carcinoma in the prostate-specific antigen era: what should we expect? Cancer. 2004;100:1283–92. doi:10.1002/cncr.20093.

    PubMed  Article  Google Scholar 

  3. 3.

    Bott SR. Management of recurrent disease after radical prostatectomy. Prostate Cancer Prostatic Dis. 2004;7:211–6. doi:10.1038/sj.pcan.4500732.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Gronau E, Goppelt M, Harzmann R, Weckermann D. Prostate cancer relapse after therapy with curative intention: a diagnostic and therapeutic dilemma. Onkologie. 2005;28:361–6. doi:10.1159/000085661.

    PubMed  Article  Google Scholar 

  5. 5.

    Iversen P, Roder MA. The Early Prostate Cancer program: bicalutamide in nonmetastatic prostate cancer. Expert Rev Anticancer Ther. 2008;8:361–9. doi:10.1586/14737140.8.3.361.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Heidenreich A, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. Eur Urol. 2011;59:61–71.

    PubMed  Article  Google Scholar 

  7. 7.

    Giovacchini G, Picchio M, Garcia-Parra R, Mapelli P, Briganti A, Montorsi F, et al. [11C]choline positron emission tomography/computerized tomography for early detection of prostate cancer recurrence in patients with low increasing prostate specific antigen. J Urol. 2013;189:105–10. doi:10.1016/j.juro.2012.09.001.

    PubMed  Article  Google Scholar 

  8. 8.

    Rigatti P, Suardi N, Briganti A, Da Pozzo LF, Tutolo M, Villa L, et al. Pelvic/retroperitoneal salvage lymph node dissection for patients treated with radical prostatectomy with biochemical recurrence and nodal recurrence detected by [11C]choline positron emission tomography/computed tomography. Eur Urol. 2011;60:935–43. doi:10.1016/j.eururo.2011.07.060.

    PubMed  Article  Google Scholar 

  9. 9.

    Hovels AM, Heesakkers RA, Adang EM, Jager GJ, Strum S, Hoogeveen YL, et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clin Radiol. 2008;63:387–95. doi:10.1016/j.crad.2007.05.022.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Passoni NM, Suardi N, Abdollah F, Picchio M, Giovacchini G, Messa C, et al. Utility of [11C]choline PET/CT in guiding lesion-targeted salvage therapies in patients with prostate cancer recurrence localized to a single lymph node at imaging: results from a pathologically validated series. Urol Oncol. 2014;32:38.e9–16. doi:10.1016/j.urolonc.2013.03.006.

    Article  Google Scholar 

  11. 11.

    Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol. 2013;64:106–17. doi:10.1016/j.eururo.2013.04.019.

    PubMed  Article  Google Scholar 

  12. 12.

    Picchio M, Briganti A, Fanti S, Heidenreich A, Krause BJ, Messa C, et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol. 2011;59:51–60. doi:10.1016/j.eururo.2010.09.004.

    PubMed  Article  Google Scholar 

  13. 13.

    Tilki D, Reich O, Graser A, Hacker M, Silchinger J, Becker AJ, et al. 18F-Fluoroethylcholine PET/CT identifies lymph node metastasis in patients with prostate-specific antigen failure after radical prostatectomy but underestimates its extent. Eur Urol. 2013;63:792–6. doi:10.1016/j.eururo.2012.08.003.

    PubMed  Article  Google Scholar 

  14. 14.

    Suardi N, Briganti A, Salonia A, Rigatti P. Salvage lymphadenectomy in postprostatectomy patients with prostate-specific antigen recurrence. Curr Opin Urol. 2011;21:237–40. doi:10.1097/MOU.0b013e328344e4c4.

    PubMed  Article  Google Scholar 

  15. 15.

    Winter A, Uphoff J, Henke RP, Wawroschek F. First results of [11C]choline PET/CT-guided secondary lymph node surgery in patients with PSA failure and single lymph node recurrence after radical retropubic prostatectomy. Urol Int. 2010;84:418–23. doi:10.1159/000296298.

    PubMed  Article  Google Scholar 

  16. 16.

    Martorana G, Schiavina R, Franceschelli A. Should we perform imaging-guided lymph node dissection in patients with lymphatic recurrence of prostate cancer after radical prostatectomy? Eur Urol. 2009;55:1302–4. doi:10.1016/j.eururo.2008.08.011.

    PubMed  Article  Google Scholar 

  17. 17.

    Schilling D, Schlemmer HP, Wagner PH, Bottcher P, Merseburger AS, Aschoff P, et al. Histological verification of 11C-choline-positron emission/computed tomography-positive lymph nodes in patients with biochemical failure after treatment for localized prostate cancer. BJU Int. 2008;102:446–51. doi:10.1111/j.1464-410X.2008.07592.x.

    PubMed  Article  Google Scholar 

  18. 18.

    Jereczek-Fossa BA, Fariselli L, Beltramo G, Catalano G, Serafini F, Garibaldi C, et al. Linac-based or robotic image-guided stereotactic radiotherapy for isolated lymph node recurrent prostate cancer. Radiother Oncol. 2009;93:14–7. doi:10.1016/j.radonc.2009.04.001.

    PubMed  Article  Google Scholar 

  19. 19.

    Jereczek-Fossa BA, Beltramo G, Fariselli L, Fodor C, Santoro L, Vavassori A, et al. Robotic image-guided stereotactic radiotherapy, for isolated recurrent primary, lymph node or metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:889–97. doi:10.1016/j.ijrobp.2010.11.031.

    PubMed  Article  Google Scholar 

  20. 20.

    Jereczek-Fossa BA, Kowalczyk A, D’Onofrio A, Catalano G, Garibaldi C, Boboc G, et al. Three-dimensional conformal or stereotactic reirradiation of recurrent, metastatic or new primary tumors. Analysis of 108 patients. Strahlenther Onkol. 2008;184:36–40.

    PubMed  Article  Google Scholar 

  21. 21.

    Alongi F, Schipani S, Gajate AM, Rosso A, Cozzarini C, Fiorino C, et al. [11C]choline-PET-guided helical tomotherapy and estramustine in a patient with pelvic-recurrent prostate cancer: local control and toxicity profile after 24 months. Tumori. 2010;96:613–7.

    PubMed  Google Scholar 

  22. 22.

    Picchio M, Giovannini E, Crivellaro C, Gianolli L, di Muzio N, Messa C. Clinical evidence on PET/CT for radiation therapy planning in prostate cancer. Radiother Oncol. 2010;96:347–50. doi:10.1016/j.radonc.2010.07.016.

    PubMed  Article  Google Scholar 

  23. 23.

    Pinkawa M, Piroth MD, Holy R, Klotz J, Djukic V, Corral NE, et al. Dose-escalation using intensity-modulated radiotherapy for prostate cancer – evaluation of quality of life with and without (18)F-choline PET-CT detected simultaneous integrated boost. Radiat Oncol. 2012;7:14. doi:10.1186/1748-717X-7-14.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  24. 24.

    Souvatzoglou M, Krause BJ, Purschel A, Thamm R, Schuster T, Buck AK, et al. Influence of (11)C-choline PET/CT on the treatment planning for salvage radiation therapy in patients with biochemical recurrence of prostate cancer. Radiother Oncol. 2011;99:193–200. doi:10.1016/j.radonc.2011.05.005.

    PubMed  Article  Google Scholar 

  25. 25.

    Würschmidt F, Petersen C, Wahl A, Dahle J, Kretschmer M. [18F]fluoroethylcholine-PET/CT imaging for radiation treatment planning of recurrent and primary prostate cancer with dose escalation to PET/CT-positive lymph nodes. Radiat Oncol. 2011;6:44. doi:10.1186/1748-717X-6-44.

    PubMed Central  PubMed  Article  Google Scholar 

  26. 26.

    Casamassima F, Masi L, Menichelli C, Bonucci I, Casamassima E, Lazzeri M, et al. Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients. Tumori. 2011;97:49–55.

    CAS  PubMed  Google Scholar 

  27. 27.

    Pinkawa M, Piroth MD, Holy R, Djukic V, Klotz J, Krenkel B, et al. Combination of dose escalation with technological advances (intensity-modulated and image-guided radiotherapy) is not associated with increased morbidity for patients with prostate cancer. Strahlenther Onkol. 2011;187:479–84. doi:10.1007/s00066-011-2249-z.

    PubMed  Article  Google Scholar 

  28. 28.

    Mottet N, Bellmunt J, Bolla M, Joniau S, Mason M, Matveev V, et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2011;59:572–83.

    PubMed  Article  Google Scholar 

  29. 29.

    Bettinardi V, Danna M, Savi A, Lecchi M, Castiglioni I, Gilardi MC, et al. Performance evaluation of the new whole-body PET/CT scanner: Discovery ST. Eur J Nucl Med Mol Imaging. 2004;31:867–81. doi:10.1007/s00259-003-1444-2.

    PubMed  Article  Google Scholar 

  30. 30.

    Bettinardi V, Mancosu P, Danna M, Giovacchini G, Landoni C, Picchio M, et al. Two-dimensional vs three-dimensional imaging in whole body oncologic PET/CT: a Discovery-STE phantom and patient study. Q J Nucl Med Mol Imaging. 2007;51:214–23.

    CAS  PubMed  Google Scholar 

  31. 31.

    Messa C, Bettinardi V, Picchio M, Pelosi E, Landoni C, Gianolli L, et al. PET/CT in diagnostic oncology. Q J Nucl Med Mol Imaging. 2004;48:66–75.

    CAS  PubMed  Google Scholar 

  32. 32.

    Giovacchini G, Picchio M, Coradeschi E, Bettinardi V, Gianolli L, Scattoni V, et al. Predictive factors of [(11)C]choline PET/CT in patients with biochemical failure after radical prostatectomy. Eur J Nucl Med Mol Imaging. 2009;37:301–9.

    PubMed  Article  Google Scholar 

  33. 33.

    Fiorino C, Alongi F, Broggi S, Cattaneo GM, Cozzarini C, Di Muzio N, et al. Physics aspects of prostate tomotherapy: planning optimization and image-guidance issues. Acta Oncol. 2008;47:1309–16. doi:10.1080/02841860802266755.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Di Muzio N, Fiorino C, Cozzarini C, Alongi F, Broggi S, Mangili P, et al. Phase I-II study of hypofractionated simultaneous integrated boost with tomotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2009;74:392–8. doi:10.1016/j.ijrobp.2008.08.038.

    PubMed  Article  Google Scholar 

  35. 35.

    Cozzarini C, Fiorino C, Di Muzio N, Alongi F, Broggi S, Cattaneo M, et al. Significant reduction of acute toxicity following pelvic irradiation with helical tomotherapy in patients with localized prostate cancer. Radiother Oncol. 2007;84:164–70. doi:10.1016/j.radonc.2007.07.013.

    PubMed  Article  Google Scholar 

  36. 36.

    Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341–6. doi:10.1016/0360-3016(95)00060-C.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    McGuire SE, Lee AK, Cerne JZ, Munsell MF, Levy LB, Kudchadker RJ, et al. PSA response to neoadjuvant androgen deprivation therapy is a strong independent predictor of survival in high-risk prostate cancer in the dose-escalated radiation therapy era. Int J Radiat Oncol Biol Phys. 2013;85:e39–46. doi:10.1016/j.ijrobp.2012.08.036.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Yossepowitch O, Bianco Jr FJ, Eggener SE, Eastham JA, Scher HI, Scardino PT. The natural history of noncastrate metastatic prostate cancer after radical prostatectomy. Eur Urol. 2007;51:940–7; discussion 947–8. doi:10.1016/j.eururo.2006.10.045.

    PubMed Central  PubMed  Article  Google Scholar 

  39. 39.

    Antonarakis ES, Feng Z, Trock BJ, Humphreys EB, Carducci MA, Partin AW, et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int. 2012;109:32–9. doi:10.1111/j.1464-410X.2011.10422.x.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. 40.

    Sironi S, Buda A, Picchio M, Perego P, Moreni R, Pellegrino A, et al. Lymph node metastasis in patients with clinical early-stage cervical cancer: detection with integrated FDG PET/CT. Radiology. 2006;238:272–9. doi:10.1148/radiol.2381041799.

    PubMed  Article  Google Scholar 

  41. 41.

    Scattoni V, Picchio M, Suardi N, Messa C, Freschi M, Roscigno M, et al. Detection of lymph-node metastases with integrated [11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: results confirmed by open pelvic-retroperitoneal lymphadenectomy. Eur Urol. 2007;52:423–9. doi:10.1016/j.eururo.2007.03.032.

    PubMed  Article  Google Scholar 

  42. 42.

    Suardi NG, Briganti A, Picchio M, Gallina A, Messa C, Gianolli L, et al. Detection of lymph-node metastases with integrated [11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: validation by open pelvic-retroperitoneal lymphadenectomy. J Urol. 2009;181:829.

    Article  Google Scholar 

  43. 43.

    Picchio M, Alongi F, Giovacchini G, Berardi G, Busnardo E, Crivellaro C, et al. 11C-Choline PET/CT image-guided tomotherapy treatment of lymph nodal relapse in prostate cancer patients. J Nucl Med. 2010;51:1274.

    Google Scholar 

  44. 44.

    Picchio M, Alongi F, Giovacchini G, Di Rosa E, Cozzarini C, Landoni C, et al. 11C-Choline PET/CT image-guided radiotherapeutic treatment of lymph nodal recurrence in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2008;35:388.

    Google Scholar 

  45. 45.

    Pantaleo MA, Nannini M, Lopci E, Castellucci P, Maleddu A, Lodi F, et al. Molecular imaging and targeted therapies in oncology: new concepts in treatment response assessment. a collection of cases. Int J Oncol. 2008;33:443–52.

    CAS  PubMed  Google Scholar 

  46. 46.

    Roach 3rd M, Hanks G, Thames Jr H, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65:965–74. doi:10.1016/j.ijrobp.2006.04.029.

    PubMed  Article  Google Scholar 

  47. 47.

    Fiorino C, Alongi F, Perna L, Broggi S, Cattaneo GM, Cozzarini C, et al. Dose-volume relationships for acute bowel toxicity in patients treated with pelvic nodal irradiation for prostate cancer. Int J Radiat Oncol Biol Phys. 2009;75:29–35. doi:10.1016/j.ijrobp.2008.10.086.

    PubMed  Article  Google Scholar 

  48. 48.

    Van Poppel H. Is radiotherapy useful in node-positive prostate cancer patients after radical prostatectomy? Eur Urol. 2009;55:1012–3.

    PubMed  Article  Google Scholar 

  49. 49.

    Warde P, Mason M, Ding K, Kirkbride P, Brundage M, Cowan R, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011;378:2104–11. doi:10.1016/S0140-6736(11)61095-7.

    PubMed Central  PubMed  Article  Google Scholar 

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Picchio, M., Berardi, G., Fodor, A. et al. 11C-Choline PET/CT as a guide to radiation treatment planning of lymph-node relapses in prostate cancer patients. Eur J Nucl Med Mol Imaging 41, 1270–1279 (2014). https://doi.org/10.1007/s00259-014-2734-6

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Keywords

  • Choline
  • PET/CT
  • Prostate cancer
  • Lymph-node relapse
  • HTT
  • RT
  • SIB