Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients

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1 Tumori, 97: 49-55, 2011 Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients Franco Casamassima 1, Laura Masi 1, Claudia Menichelli 1, Ivano Bonucci 1, Emanuele Casamassima 2, Massimo Lazzeri 3, Massimo Gulisano 4, and Stefano Aterini 4,5 1 Clinical Radiobiological Institute, University of Firenze, Firenze; 2 Institute Ricerche Cliniche Fanfani, Firenze; 3 Department of Urology, Santa Chiara Hospital, Firenze; 4 Department of Anatomy, Histology and Forensic Medicine, University of Firenze, Firenze; 5 Misericordia e Dolce Hospital, Prato, Italy ABSTRACT Aims and background. In patients with recurrent prostate cancer, discriminating local or systemic recurrence is critical to decide second-line treatment. We investigated the capability of stereotactic body radiotherapy to treat limited nodal recurrences, detected using choline PET scan. Methods and study design. Seventy-one patients with biochemical failure were studied after prostate cancer treatment: prostatectomy (28), radiotherapy (15) or both (28). Following computed tomography and choline PET imaging, stereotactic body radiotherapy was delivered on pathological lymphatic areas by 6 MV Linac, using dynamic micromultileaf collimation and intensity-modulated arc therapy optimization. Sixty days post-treatment, choline PET/CT imaging was carried out. Results. Median follow-up was 29 months (range, ). Choline PET detected recurrences in 39 of 71 patients. Median PSA velocity was 0.40 ng/ml/year in PET-negative patients and 2.88 ng/ml/year in PET-positive subjects (P <0.05). Twenty-five patients with limited nodal recurrences, out of the 71 submitted to choline PET, received eradicative radiotherapy. Persistent regression was recorded in 13; early spread to bone was found in 2 cases; lymph node recurrences in 8, all in sites outside the irradiated areas; 2 patients were lost to follow-up. At the 3-year follow-up, overall survival, disease-free survival and local control rates were 92%, 17% and 90%, respectively. In patients with a complete regression, PSA fell from 5.65 to 1.40 ng/ml (median). PSA nadir value (median 1.06 ng/ml) was maintained for 5.6 months (median). Conclusions. Stereotactic body radiotherapy was effective in disease eradication of limited nodal recurrences from prostate cancer, saving patients from, or at least postponing, systemic treatments. Free full text available at Introduction Despite improved surgical and radiotherapeutic treatments, prostate cancer recurrence is not uncommon. Discriminating local, amenable to radiotherapy, or systemic recurrence, requiring androgen ablation therapy or systemic chemotherapy in case of hormone-refractory disease, is critical to decide what kind of second-line treatment should be given. Pelvic lymph nodes are a possible site of recurrence, not always associated with enlargement documented by imaging techniques 1-4. Choline positron emission tomography (PET) has the potential to help to differentiate the composition of these nodes as it relies on the metabolism of tumor cells. An increased choline peak and/or variable uptake may be caused by altered choline transport, increased choline kinase activity or increased catabolic activity 5, and it may be useful particularly for local staging and detection of the recurrence site 6-8. Key words: choline-pet, nodal relapses, prostate cancer, salvage stereotactic body radiotherapy. Correspondence to: Prof Franco Casamassima, UO di Radiobiologia Clinica, Piazza Indipendenza 14, Firenze, Italy. Tel ; fax ; f.casamassima@dfc.unifi.it Received March 31, 2010; accepted October 29, 2010.

2 50 F CASAMASSIMA, L MASI, C MENICHELLI ET AL Recurrent or persistent disease after treatment by prostatectomy or radiation therapy is often first detected as the reappearance of a measurable level of prostate-specific antigen (PSA) or as an elevated and rising PSA level 9,10. The issue of raised PSA and negative or indefinite imaging is a place where PET, among others, has a potential role In this regard, PSA kinetic measurements, assessed as PSA doubling time, have yielded divergent conclusions in previous studies. PSA velocity (PSAV) 14 was found to predict tumor stage, grade and time to disease recurrence, as defined by PSA level after radical prostatectomy 15. In the present study, we investigated the capability of radiotherapy to treat recurrent disease locally confined to lymph nodes and the reliability of choline PET to identify the site of recurrence in biologically relapsing prostate cancer patients. Moreover, a possible correlation, not yet clear, between PSA, PSAV and PET scan was assessed. Patients and methods Patient selection. Biochemical failure after prostate cancer treatment was defined following the American Society for Therapeutic Radiology and Oncology definition and the American Urological Association criteria 16,17 : 1) a rise by 2 ng/ml or more above the nadir PSA be considered the standard definition for biochemical failure after external beam radiotherapy with or without hormonal therapy; 2) the date of failure be determined "at call" (not backdated). According to such criteria, 71 patients were studied at the Clinical Radiobiological Institute, University of Florence, Italy: 28 relapsed after surgery, 15 after radical radiotherapy, and 28 after both treatments. PSAV. Using the PSA measurement closest in time before eradicative radiotherapy as second-line treatment (median, 0.5 months; range, ) and all prior PSA values that had been obtained within one year before eradicative radiotherapy, we calculated PSAV during the year before treatment. Choline PET scan modality. All PET scans were obtained with the Gemini GXL (Philips, Eindhoven, The Netherlands), a dedicated PET/CT (computed tomography) scanner comprising a 16-slice CT with a state-ofthe-art PET tomograph. The patients were fasted for at least 6 h before PET acquisition. At the beginning, 11 C- choline was used, but we switched to 18 F-choline, a more suitable commercial tracer, due to its more convenient half-life feature, which published reviews have shown to be valuable in prostate cancer imaging 18. Patients received an intravenous injection of 2.6 MBq/kg of 11 C/ 18 F choline and, starting 5 min after injection, total body emission and transmission images were both acquired for 5 min per bed position. The CT data were used for attenuation correction in all cases. All PET images were analyzed with dedicated software that allowed review of PET, CT, and fused-image data, in order to pinpoint anatomic spots of metabolic activity. Radiotherapy planning and treatment delivery. Radiotherapy was planned on pathologic lymphatic areas according to the disease extension as shown by PET scan. A clinical target volume for patients treated only at the site of recurrence and a boost volume for other patients was delineated on a CT scan acquired for planning (2.5- mm slice thickness). For all cases, PET images of the pathologic areas were used as a visual guide during clinical target volume delineation, and when possible (5 cases) planning CT and PET image fusion was performed. For all patients, a planning target volume was created by adding a 5-mm uniform margin which took into account only intra-fraction and residual errors after image-guided radiotherapy on-line corrections 19. Dose was prescribed to the isodose covering 95% of the planning target volume. A treatment plan was created (ER- GO ++, Elekta Crawley, UK) using multiple coplanar and non-coplanar arcs, and when required for the vicinity of organs at risk (great vessels, intestine loops), an intensity-modulated arc therapy plan was optimized. Treatment was delivered by a 6 MV Linac (Elekta Synergy, Elekta Crawley UK) and external dynamic micromultileaf collimator (5-mm leaf width). A cone beam CT (CBCT) volumetric image was acquired prior to each fraction for target positioning, which was performed in two steps using the XVI dedicated software of the Synergy system. First, the CBCT image was aligned with the planning CT image by means of a bone matching automatic algorithm. After registration on the bone structures, a physician, when necessary, corrected manually the position of the lymph node, when visible on CBCT, so that it appeared completely inside the planning target volume contour delineated on the planning CT scan. The positioning errors obtained by the XVI software were converted in table shifts, and on-line corrections were performed. Acute and late toxicity was prospectively assessed using the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (EORTC/RTOG) toxicity criteria 20. Follow-up. Sixty days after the end of the treatment (an appropriate interval according to the tumor biology to assess treatment efficacy), choline PET/CT imaging was carried out in all treated patients. At the same time and every 3 months successively, PSA values were checked. Median follow-up was 29 months (range, ). Statistical analysis. Values are expressed as the median and mean ± SD. The statistical significance for difference between means for two different groups was de-

3 SALVAGE RADIOTHERAPY IN PROSTATE CANCER RELAPSE 51 termined by the t-test: the difference between means for three groups was assessed by analysis of variance. P <0.05 was considered as significant. Results PET scan was negative in 32 patients (45%). Since all patients showed evidence of post-treatment biochemical failure, as previously defined, they were to be considered as false negative. Being not eligible for local treatment, they were referred for androgen deprivation therapy. PET scan was positive in 39 patients (55%). Bone metastases in 11 patients and recurrence at the prostate gland in 3 patients were detected: these patients received salvage brachytherapy at another center. The remaining 25 patients (64% of the PET-positive group) had positive PET locally confined to lymph nodes (22 pelvic and/or para-aortic, 3 mediastinal). Patient characteristics and tumor stage are reported in Table 1. CT scan showed pathologic lymph node enlargement only in a few cases (Figure 1), being often negative (Figure 2) or equivocal (Figure 3). Median PSA value was 1.04 ng/ml (range, ) in patients with a negative scan and 5.65 ng/ml (range, Table 1 - Characteristics of patients with positive choline PET for lymph nodes, according to initial treatment Surgery Radiotherapy Surgery P + RT No Age (yr) Mean ± SD 67.7 ± ± ± 7.6 NS Median NS Initial PSA (ng/ml) Mean ± SD 17.3 ± ± ± 1.2 a <0.05 Median <0.05 Gleason score Mean ± SD 8.25 ± ± ± 0.9 NS Median NS Time from initial treatment (mo) Mean ± SD 36.7 ± ± ± 7.3 <0.05 Median <0.05 Stage pt2b pn0 1 pt2c pn0 1 pt3b pn0 3 ct2b cnx 2 ct2c cnx 1 ct3b cnx 2 pt2c pn0 2 b pt3a pn0 4 b pt3b pn0 5 pt3b pn1 2 pt4a pn1 1 a Before radiotherapy treatment. b Patients with positive surgical margins and/or positive lymph nodes ) for subjects with a positive scan (P <0.05). In PET-negative patients, median PSAV was 0.40 ng/ml/year (mean, 1.36; range, ). In PET-positive subjects, it was 2.88 ng/ml/year (mean, 8.85; range, ) (P <0.05). Only 25 patients with limited lymph node uptake, out of the 71 submitted to choline PET, received eradicative radiotherapy to pathologic lymphatic areas. Fifteen were treated with stereotactic body radiotherapy (SBRT) to the recurrence site only, delivering 30 Gy in three consecutive fractions. Seven patients were treated on the whole pelvic area, delivering 50 Gy in 25 fractions plus 24 Gy as a boost on the positive lymph nodes in three consecutive fractions. The 3 patients with mediastinal uptake were treated by stereotactic hypofractionated radiotherapy, delivering a total dose of 30 Gy in three consecutive fractions. Sixty days after treatment, PET and CT imaging were repeated (Figure 1). Two patients were lost to follow-up. Tumor progression was recorded in 10 patients: 2 cases showed early (at 60 days) systemic spread to bone; 8 patients exhibited lymph node recurrence, all in sites outside the irradiated areas, either evident at 60 days (2 cases), or registered during long-term follow-up (6 subjects). In the latter group, recurrences occurred in 2 patients who received prophylactic irradiation of the whole pelvis and in 4 patients after irradiation limited to pathological lymph nodes. A complete regression in the irradiated lymph nodes was recorded in 13 patients. As regards post-treatment choline PET, among the 13 patients who maintained negative results at long-term follow-up, 11 had shown a complete regression of the pathologic uptake and 2 a great reduction in the standardized uptake value. Since they maintained their PSA nadir, they were regarded as cases with no evidence of disease. In contrast, the 6 relapsing cases registered during long-term follow-up (4 in non-irradiated areas and 2 in a prophylactically irradiated area of the pelvis) showed a new increase in their PSA values at different time intervals; simultaneous PET scans showed evidence of lymph node recurrences. When recurrence occurred in non-irradiated lymph nodes, patients underwent a new radiotherapy treatment plan. Otherwise, patients were switched to androgen deprivation therapy. There was no significant difference in terms of PSAV between the 13 patients exhibiting long-term complete remission and the 8 experiencing lymph node recurrence only after irradiation. Overall survival, disease-free survival and local control rates are reported in Table 2. In patients with a complete regression in the irradiated lymph nodes, PSA fell below the pre-recurrence values (median, 1.40 ng/ml; range, ), whereas it remained unchanged in one patient. PSA nadir value (median, 1.06 ng/ml) was maintained for 5.6 months (median; range, ), without any other specific therapy. As regards treatment-related acute or late toxicity, no more than RTOG grade 1 occurred throughout the study

4 52 F CASAMASSIMA, L MASI, C MENICHELLI ET AL A B C D Figure 1 - Patient relapsed after radical radiotherapy. A) CT-PET showing nodal relapse in iliac chain (standardized uptake value, SUV, 9.60). B) Planning CT at isocenter level showing the high conformity of isodose distribution. C) CBCT aligned with planning CT using the XVI software and on-line correction. D) CT-PET recorded 60 days after treatment (SUV 1.30); at the same time PSA decreased from 5.65 to 1.47 ng/ml. period. Transient nausea occurred in SBRT patients treated at the lumbo-aortic area. Sporadic transitory cases of diarrhea occurred in patients treated on the whole pelvic area. Patients treated at the mediastinal area exhibited no acute or late toxicity. Discussion In the present study, high doses of radiotherapy, delivered with a high conformal technique (SBRT), yielded a high rate of local control in prostate cancer recurrence confined to lymph nodes. In the long-term follow-up, local control was maintained, leaving androgen deprivation therapy for potential future prostate cancer recurrences. Prophylactic treatment of the whole pelvis seems to add efficacy in disease control, since there were only 2 recurrences in the 7 prophylactically treated patients, even though the number of treated patients was small. Moreover, hypofractionation to the single local recurrence site (SBRT), rather than to the whole pelvic area, was associated with greater patient comfort, delivering treatment in three sessions only, with lower gastrointestinal toxicity. Treatment with a Linac through multiple arcs using dynamic micromultileaf, intensitymodulated arc therapy optimization and target position control by CBCT allowed delivery of high-dose hy-

5 SALVAGE RADIOTHERAPY IN PROSTATE CANCER RELAPSE 53 Figure 2 - Patient imaging showing a positive choline PET scan with the corresponding negative CT. Figure 3 - Patient imaging representing a positive choline PET scan with an equivocal CT. Table 2 - Follow-up of patients with limited nodal metastases from prostate cancer treated with high doses of radiotherapy, delivered with a high conformal technique (SBRT) 1 year 2 years 3 years Overall survival (%) Disease-free survival (%) Local control (%) pofractionated treatments (SBRT), in full respect of organs at risks constraints, particularly gastrointestinal, and limiting toxicity to grade 1 RTOG. The present study supports the recently reported 21 efficacy of radiotherapy in biochemical recurrence-free survival and cancerspecific survival of node-positive patients. The potential of PET scan for the detection of prostate cancer recurrence sites may be of interest in patients with elevated or rising PSA level, although within normal values, and even earlier when there is a dubious increase in PSA. The detection of the reccurence site after external beam radiotherapy and after radical prostatectomy using choline PET has been reported 13, The identification of patients with limited metastatic lymph node disease makes them suitable for aggressive local radiotherapy The findings reported in the present study are consistent with previous investigations in which PET showed evidence of a solitary lesion in 53% of patients with an increasing PSA level after radical treatment for prostate cancer 28 and PET focal increases in 47% of 100 consecutive patients referred for clinical prostate re-staging 29. Late lymph node recurrences in non-irradiated sites might support PET limitation, representing undetected disease still existing at the moment of the first PET investigation. However, in our experience, 32 choline PET scans were to be regarded as false negative. The finding

6 54 F CASAMASSIMA, L MASI, C MENICHELLI ET AL implies that more reliable tracers would be necessary in the assessment of early biochemical recurrence. In patients with evidence of biochemical failure after prostate cancer treatment, the discrepancy between PSA serum concentrations and PET scan results (i.e., negative PET scan with a PSA value of 77 ng/ml or positive PET scan with a PSA value of 0.37 ng/ml) might suggest that PSA values could be referred to the tumor burden, whereas a positive PET scan might be related to the increased choline kinase and metabolic choline activity and not necessarily linked to the tumor burden. The better relation between PSAV and positive PET scan might support this hypothesis, since PSAV is an index of cancer metabolic activity. No PSA threshold value to predict a positive scan could be established in our study, in agreement with previous reports 13, The pretreatment PSAV was significantly associated with high-grade (Gleason score 4+3 or more) prostate cancer at diagnosis, and it could identify men at high risk of harboring occult high-grade prostate cancer, allowing improved selection of radiotherapy fields 30. A limitation of the present study could be the small and heterogeneous group of the observed patients. However, we believe that they represent a subgroup of patients who are encountered in everyday clinical practice but who have not been thoroughly investigated. In these patients, it may be worthwhile considering aggressive local treatment of lymph node metastatic lesions, because a reasonable chance for cure could be possible using radiosurgical treatments. 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