ORIGINAL ARTICLE
Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure? Jeffrey Goldstein, MD,* Einat Even-Sapir, MD,w Simona Ben-Haim, MD,* Akram Saad, MD,* Benjamin Spieler, BA,z Tima Davidson, MD,* Raanan Berger, MD, PhD,* Ilana Weiss, MA,* Sarit Appel, MD,* Yaacov R. Lawrence, MD,* and Zvi Symon, MD* Purpose: The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. Methods: This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center’s Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric w2 test was used to compare the initial and final treatment recommendations following choline PET/CT. Results: Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n = 6), radiation therapy (RT) (n = 6), brachytherapy (n = 2), RP + salvage prostate fossa RT (n = 14), and RP + salvage prostate fossa/lymph node RT (n = 6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans. PET/CT altered treatment approach in 18 of 33 (55%) patients (P = 0.05). Sixteen of 27 patients (59%) treated previously with radiation were retreated with RT and delayed or eliminated androgen deprivation therapy: 1 received salvage brachytherapy, 10 received salvage pelvic lymph node or prostate fossa irradiation, 2 brachytherapy failures received salvage prostate and lymph nodes IMRT, and 3 with solitary bone metastasis were treated with radiosurgery. Eleven of 16 patients retreated responded to salvage therapy with a significant
From the *Departments of Radiation Oncology, Nuclear Medicine, Medical Oncology, Urology, Chaim Sheba Medical Center; wDepartment of Nuclear Medicine, Tel Aviv Sourasky Medical Center, both affiliated with the Sackler School of Medicine, Tel Aviv University, Israel; and zMt Sinai School of Medicine, New York, NY. Accepted for Presentation: American Society of Therapeutic Radiation and Oncology (ASTRO) September, 2014 San Francisco, CA. Supported by an unrestricted grant from the Leroy Schechter Foundation. The authors declare no conflicts of interest. Reprints: Zvi Symon, MD, Department of Radiation Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel. E-mail: [email protected]. gov.il. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000139
American Journal of Clinical Oncology
PSA response (< 0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500 ± 447 days. Two of 6 patients with no prior RT were referred for salvage prostatic fossa RT: 1 received dose escalation for disease identified in the prostate fossa and another had inclusion of “hot” pelvic lymph nodes in the treatment volume. Conclusions: These early results suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines may change management and improve care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning, and delaying or avoiding use of androgen deprivation therapy. Key Words: prostate cancer, radiation therapy, salvage, PET choline
(Am J Clin Oncol 2014;00:000–000)
O
ptimal management of prostate cancer patients with rising PSA following definitive treatment with surgery, external beam radiation, or brachytherapy is unknown.1 Imaging studies using computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or 18F FDG PET/CT often fail to identify the cause for biochemical failure. Uncertainty in location and extent of recurrent disease may adversely impact disease management and patients may undergo futile treatment. Improved imaging is warranted for determination of the cause for biochemical failure and tailoring the optimal treatment approach with consequent improved outcome. Recently, 11C choline PET/CT was approved by the US Food and drug Administration (FDA) as an imaging agent for detection of recurrent disease in patients with rising PSA following definitive treatment.2 Although labeled-choline PET/CT has limited utility in the initial staging of prostate cancer, it has been shown to locate sites of recurrence in patients with biochemical failure.3,4 Updated 2014 NCCN guidelines5 now suggest the use of labeled-choline PET/CT in patients with biochemical failure. The goal of optimal imaging in this clinical scenario is to assist in patient selection for observation or targeted radiotherapy avoiding or delaying androgen deprivation therapy (ADT).3,6 In addition, patients with metastatic disease will be diagnosed and offered ADT rather than salvage radiation.3,6 Few studies describe how labeled choline PET/CT imaging impacts decision making and treatment of patients with biochemical failure following definitive therapy.3,7–10 In this study we report the impact of labeled choline PET/CT scans on management decisions and subsequent treatment for 33 patients with rising PSA after failed primary or salvage therapy.
METHODS This retrospective review of a prospective database was approved by the Tel Aviv Sourasky Medical Center and Sheba
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Medical Center’s Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and precholine PET/CT treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with a labeled choline PET/CT scan or treatment based on NCCN guidelines. All radiation treatments were given under the direction of a single radiation oncologist (Z.S.) in the Department of Radiation Oncology at Chaim Sheba Medical Center, Ramat Gan, Israel. When patients were treated with radiation, the scan results were incorporated into the planning process. Prostate recurrences were offered brachytherapy and brachytherapy recurrences were offered prostate irradiation. Lymph node recurrences in patients with prior treatment to the prostate or prostate fossa were offered lymph node salvage therapy. Patients with oligometastatic disease were offered ADT or radiation therapy. Scan results and revised treatment recommendations were compared with prescan recommendations. Pathologic confirmation was obtained before prostate retreatment. Thirty 11C Choline PET/CT studies were performed at the Department of Nuclear Medicine, Sourasky Medical Center, Tel Aviv, and four 18F Choline PET/CT studies were performed at the Department of Nuclear Medicine, Chaim Sheba Medical Center, Tel Hashomer. Tracer was supplied from the cyclotron at Hadassah Medical Center in Jerusalem, Israel. Whole-body PET/CT scanning was performed with a 64-row helical detector Discovery PET/CT 690, GE Healthcare at Sourasky, and 16 row helical detector Gemini GXL Discovery PET/CT, Phillips Medical at Sheba. Both scanners allow acquisition of PET and CT without changing the patient’s positioning and provide head to thigh images with multiple bed positions. Acquisition started soon after IV injection of 370 Mbq of either 11C-Choline or 18F-Choline and was repeated at 60 minutes after the injection of 18FCholine. Fusion of PET and CT data is done using the GE Healthcare Xeleris workstation at Sourasky or the Phillips Portal computer workstation at Sheba. A nonparametric w2 test was used to compare the effect of PET choline CT on the change in treatment recommendations.
RESULTS Between June 2010 and January 2014, 34 labeled choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy, prostate radiation therapy, brachytherapy, and radical prostatectomy followed by salvage prostate fossa radiation therapy or salvage prostate fossa/lymph node radiation therapy. One patient had undergone 2 scans. Patients were asymptomatic at time of referral and suffered only from biochemical failure. Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Patient characteristics and results of the labeled choline PET/ CT studies are shown in Table 1. Local recurrence in the prostate, prostate fossa, or pelvic lymph nodes was seen in 17 patients, metastatic disease was seen in 9 patients, and failed to identify the cause for biochemical failure in 7 patients. Table 2 summarizes the initial management options offered to patients and the revised options when the results of the PET/CT were considered. Choline PET/CT altered treatment recommendation in 18 of 33 patients. A w2 test comparing the initial and final treatment recommendations for all 33 patients showed that use of choline PET/CT imaging significantly altered patient management (P = 0.05).
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TABLE 1. Characteristics of Patients Referred for Choline PET-CT
Parameters
Values
No. patients N = 33 Median age in years (range) 72 (57-81) Clinical T stage (%) T1 2 (7) T2 15 (52) T3 11 (38) T4 1 (3.5) Tx 4 patients Gleason score (%) 6 7 (22.5) 7 13 (42) 8 9 (29) 9 2 (6.5) Unknown 2 patients Median PSA ng/mL (range) at referral for scan 2 ng/mL (0.16-79) Androgen deprivation therapy (ADT) No 29 Yes 4 Prior therapy* Radical prostatectomy 6 Radical prostatectomy + prostate fossa radiation 14 Radical prostatectomy + pelvic radiation 6 Prostate external beam radiation 6 Brachytherapy 1 Brachytherapy + pelvic radiation 1 *n = 34, 1 patient had 2 prior therapies and was scanned twice.
Sixteen of 27 patients treated previously with radiation benefited by receiving RT and delaying or eliminating ADT: 1 received salvage brachytherapy after confirmation by biopsy, 10 received salvage pelvic lymph node or prostate fossa margin irradiation, 2 brachytherapy failures received salvage IMRT to the prostate (confirmed by positive biopsy) and pelvic nodes, and 3 patients with solitary bone metastasis (confirmed by MRI) were treated with radiosurgery. For these patients, 11 of 16 responded to salvage therapy with a significant PSA response (< 0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500 ± 447 days. Two of 6 patients with no prior radiation treatment who were offered salvage prostatic fossa RT benefited from choline PET/CT: 1 received dose escalation for disease identified in the prostate fossa and 1 had the treatment volume increased to include involved pelvic lymph nodes along with the prostate fossa. Three patients with elevated PSA’s and nondiagnostic scans selected observation rather than ADT or other salvage therapy. One of these patients had initial prostate radiation followed by a PSA elevation 3 years after treatment. As evaluation with choline PET/CT was nondiagnostic, the patient declined ADT. This patient’s PSA subsequently declined and he continues to do well without intervention three years later.
DISCUSSION The patients in our series were strongly motivated to avoid ADT as their initial salvage treatment and were willing to shoulder the cost of the study. The use of choline PET/CT scans had a significant impact on disease management (Table 2): when scans showed metastatic disease, patients received either targeted radiosurgery or ADT and avoided salvage prostatic fossa radiation; when scans showed local or regional disease, patients received salvage radiation and delayed or avoided ADT. Several patients with nondiagnostic scans selected observation and r
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Choline PET CT in Management of Prostate Cancer
TABLE 2. Treatment Offered Before and After Choline PET-CT Imaging
Prior Therapy
Changew in Plan (n)
Treatment Delivered Following Choline PET-CT Imaging
Prostate fossa radiation
2
14
ADT or observation
7
6
ADT or observation
2
6
ADT or local salvage or observation ADT or observation
4
Dose escalation n = 1 Inclusion of pelvic lymph nodes n = 1 Salvage lymph node RT n = 6 RT to bone metastasis n = 1 SRT to marginal recurrence n = 1 RT to bone metastasis n = 1 Salvage brachytherapy n = 1 Salvage lymph node RT n = 3 Salvage prostate and lymph node RT n = 2 RT to bone metastasis n = 1z
Scans
Radical prostatectomy Radical prostatectomy + prostate fossa RT Radical prostatectomy + prostate fossa and lymph node RT Prostate RT
6
Brachytherapy
2
Proposed Treatment Before Choline PET-CT
3
*P = 0.05. wObserved versus expected change in treatment plan Chi test. zOne patient had a second course of RT. ADT indicates androgen deprivation therapy; PF, prostatic fossa; RP, radical prostatectomy; RT, radiation therapy; SRT, SRT stereotactic radiation therapy.
delayed all treatment. In one of these patients the PSA declined and the patient remains free of recurrence. In addition to assisting with treatment selection, choline PET/CT scans also improved radiation therapy planning and delivery. As the scans identified sites of suspected recurrence, radiation planning was able to target sites of macroscopic disease for dose escalation. Several authors have described the benefits of using imaging studies including choline PET/CTs for initial radiation therapy planning11 and for salvage treatments.3,4,12 In postprostatectomy patients with biochemical recurrence, radiation treatment of the prostatic fossa has been shown to improve biochemical survival.13 Imaging studies, which have the potential to detect the location of recurrent disease in the prostate fossa, should allow for improved results through targeted dose escalation13,14 and better delineation of the treatment area.9,11,14–16 Our study suggests that choline PET/CT improves target delineation and allows for dose escalation. For example, when patients have scans, which identify the site of disease in the prostatic fossa or pelvis, physicians may limit the dose escalation to those areas most likely harboring disease; negative scans would allow physicians to consider lower dose treatment or even consider observation. One possible limitation of this approach is that choline PET/CT scan sensitivity increases with PSA concentration so treatment should not be held until disease becomes apparent on a choline PET/CT scan.14 Patients who fail prostate radiation are usually offered ADT.1 Identifying a recurrence outside of the original or salvage radiation fields would offer these patients a second opportunity to receive local radiation treatment and provide them the option of avoiding ADT.1 Although functional radiotracers have not been effective in the initial staging of prostate cancer because of low sensitivity and specificity, there is evidence that choline PET/CT has improved value and may enhance identification of cancer recurrence in previously irradiated patients.7 This offers a potential area of future investigation. Curative therapy of prostate cancer with surgery or radiation as well as salvage prostatic fossa radiation after surgery may intentionally leave the pelvic lymph nodes untreated.17 Therefore, identification and treatment of pelvic lymph node failure may offer patients another chance for cure and defer the need for ADT.18,19 However, the optimal treatment strategies for detection and treatment of pelvic lymph node recurrence remain to be determined. Some groups have targeted only lymph nodes that show radiotracer uptake using stereotaxic radiosurgery techniques.20 We believe that this approach should be followed with caution. Rigatti reported a series of patients who underwent pelvic lymph node dissection r
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following positive pet choline scans. Pathologic examination showed many additional involved nodes that were not PET choline avid on the initial scan.12,21 Our approach to pelvic nodal recurrence has been to treat the entire nodal volume and offer increased dose to the choline PET/CT avid region.4 Our series reports 3 patients with oligometastatic disease who were treated with stereotactic body radiation therapy and were able to delay start of ADT because of a lengthened diseasefree interval following treatment. Similar findings have been reported by others.22 Although most of these patients eventually develop widespread disease, deferment of ADT is beneficial. The treatments offered in our series and in others were well tolerated with no major complications. In fact, improvement in planning, targeting, and dose delivery in conjunction with choline PET/CT should limit treatment-related side effects by reducing the volume of normal tissue irradiated, while allowing for dose escalation to areas most at risk for disease recurrence. Although our results showed that choline PET/CT had a significant effect on treatment offered to patients, these findings need to be interpreted with caution in the milieu of a small retrospective study subject to selection bias. Biopsy confirmation was obtained for all patients receiving salvage therapy to the prostate and MRI confirmed all bone lesions irradiated. Biopsies were not obtained for patients treated with salvage lymph node irradiation and the biochemical response of this group to therapy has been previously reported and may be considered a surrogate confirmation.23
CONCLUSIONS These results from this small initial study suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines improves care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning and delaying or avoiding use of ADT. Although our early results are promising, we encourage caution and careful monitoring of patients for efficacy and side effects. REFERENCES 1. Punnen S, Cooperberg MR, D’Amico AV, et al. Management of biochemical recurrence after primary treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2013;64:905–915. 2. FDA approves 11C-choline for PET in prostate cancer. J Nuclear Med. 2012;53:11n.
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3. Detti B, Scoccianti S, Franceschini D, et al. Predictive factors of [18F]-Choline PET/CT in 170 patients with increasing PSA after primary radical treatment. J Cancer Res Clin Oncol. 2013;139: 521–528. 4. Schwarzenbock SM, Kurth J, Gocke C, et al. Role of choline PET/ CT in guiding target volume delineation for irradiation of prostate cancer. Eur J Nuclear Med Mol Imag. 2013;40(suppl 1):28–35. 5. Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 1.2014. J Nat Comp Cancer Network. 2013;11:1471–1479. 6. Rischke HC, Knippen S, Kirste S, et al. Treatment of recurrent prostate cancer following radical prostatectomy: the radiationoncologists point of view. Quarter J Nuclear Med Mol Imaging. 2012;56:409–420. 7. Chondrogiannis S, Marzola MC, Ferretti A, et al. Role of F-choline PET/CT in suspicion of relapse following definitive radiotherapy for prostate cancer. Eur J Nuclear Med Mol Imaging. 2013;40:1356–1364. 8. Crehange G, Chen CP, Hsu CC, et al. Management of prostate cancer patients with lymph node involvement: a rapidly evolving paradigm. Cancer Treat Rev. 2012;38:956–967. 9. Fortuin AS, Deserno WM, Meijer HJ, et al. Value of PET/CT and MR lymphography in treatment of prostate cancer patients with lymph node metastases. Int J Radiat Oncol Biol Phys. 2012;84:712–718. 10. Mamede M, Ceci F, Castellucci P, et al. The role of 11C-Choline PET imaging in the early detection of recurrence in surgically treated prostate cancer patients with very low PSA level < 0.5 ng/ mL. Clin Nucl Med. 2013;38:e342–e345. 11. Chang JH, Lim Joon D, Lee ST, et al. Intensity modulated radiation therapy dose painting for localized prostate cancer using (1)(1)C-choline positron emission tomography scans. Int J Radiat Oncol Biol Phys. 2012;83:e691–e696. 12. Passoni NM, Suardi N, Abdollah F, et al. Utility of [C]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. 2013;32:38.e9–e16. 13. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190:441–449.
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14. Kitajima K, Murphy RC, Nathan MA. Choline PET/CT for imaging prostate cancer: an update. Ann Nucl Med. 2013;27:581–591. 15. Poortmans P, Bossi A, Vandeputte K, et al. Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother Oncol. 2007;84:121–127. 16. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;76:361–368. 17. Abdollah F, Cozzarini C, Suardi N, et al. Indications for pelvic nodal treatment in prostate cancer should change. Validation of the Roach formula in a large extended nodal dissection series. Int J Radiat Oncol Biol Phys. 2012;83:624–629. 18. Casamassima F, Masi L, Menichelli C, et al. Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients. Tumori. 2011;97:49–55. 19. Jereczek-Fossa BA, Beltramo G, Fariselli L, et al. Robotic imageguided stereotactic radiotherapy, for isolated recurrent primary, lymph node or metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:889–897. 20. Reske SN, Moritz S, Kull T. [11C]Choline-PET/CT for outcome prediction of salvage radiotherapy of local relapsing prostate carcinoma. Quarter J Nuclear Med Mol Imag. 2012;56:430–439. 21. Rigatti P, Suardi N, Briganti A, 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;60:935–943. 22. Schick U, Jorcano S, Nouet P, et al. Androgen deprivation and high-dose radiotherapy for oligometastatic prostate cancer patients with less than five regional and/or distant metastases. Acta Oncologica (Stockholm, Sweden). 2013;52:1622–1628. 23. Symon Z, Ben-Bezalel G, Spieler B, et al. A retrospective feasibility study of salvage pelvic nodal radiation in 6 patients with biochemical failure following prostate fossa radiation: an alternative to androgen deprivation therapy (ADT) [In press]. Am J Clin Oncol. 2014;’:’.
r
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Does Choline PET/CT Change the Management of Prostate Cancer Patients With Biochemical Failure? Jeffrey Goldstein, MD,* Einat Even-Sapir, MD,w Simona Ben-Haim, MD,* Akram Saad, MD,* Benjamin Spieler, BA,z Tima Davidson, MD,* Raanan Berger, MD, PhD,* Ilana Weiss, MA,* Sarit Appel, MD,* Yaacov R. Lawrence, MD,* and Zvi Symon, MD* Purpose: The FDA approved C-11 choline PET/computed tomography (CT) for imaging patients with recurrent prostate cancer in 2012. Subsequently, the 2014 NCCN guidelines have introduced labeled choline PET/CT in the imaging algorithm of patients with suspected recurrent disease. However, there is only scarce data on the impact of labeled choline PET/CT findings on disease management. We hypothesized that labeled-choline PET/CT studies showing local or regional recurrence or distant metastases will have a direct role in selection of appropriate patient management and improve radiation planning in patients with disease that can be controlled using this mode of therapy. Methods: This retrospective study was approved by the Tel Aviv Sourasky and Sheba Medical Center’s Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and pre-PET choline treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with labeled choline PET/CT. Treatment recommendations post-PET/CT were compared with pre-PET/CT ones. Pathologic confirmation was obtained before prostate retreatment. A nonparametric w2 test was used to compare the initial and final treatment recommendations following choline PET/CT. Results: Between June 2010 and January 2014, 34 labeled-choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy (RP) (n = 6), radiation therapy (RT) (n = 6), brachytherapy (n = 2), RP + salvage prostate fossa RT (n = 14), and RP + salvage prostate fossa/lymph node RT (n = 6). Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Labeled choline PET/CT showed prostate, prostate fossa, or pelvic lymph node increased uptake in 17 studies, remote metastatic disease in 9 studies, and failed to identify the cause for biochemical failure in 7 scans. PET/CT altered treatment approach in 18 of 33 (55%) patients (P = 0.05). Sixteen of 27 patients (59%) treated previously with radiation were retreated with RT and delayed or eliminated androgen deprivation therapy: 1 received salvage brachytherapy, 10 received salvage pelvic lymph node or prostate fossa irradiation, 2 brachytherapy failures received salvage prostate and lymph nodes IMRT, and 3 with solitary bone metastasis were treated with radiosurgery. Eleven of 16 patients retreated responded to salvage therapy with a significant
From the *Departments of Radiation Oncology, Nuclear Medicine, Medical Oncology, Urology, Chaim Sheba Medical Center; wDepartment of Nuclear Medicine, Tel Aviv Sourasky Medical Center, both affiliated with the Sackler School of Medicine, Tel Aviv University, Israel; and zMt Sinai School of Medicine, New York, NY. Accepted for Presentation: American Society of Therapeutic Radiation and Oncology (ASTRO) September, 2014 San Francisco, CA. Supported by an unrestricted grant from the Leroy Schechter Foundation. The authors declare no conflicts of interest. Reprints: Zvi Symon, MD, Department of Radiation Oncology, Chaim Sheba Medical Center, Tel Hashomer, Israel. E-mail: [email protected]. gov.il. Copyright r 2014 by Lippincott Williams & Wilkins ISSN: 0277-3732/14/000-000 DOI: 10.1097/COC.0000000000000139
American Journal of Clinical Oncology
PSA response (< 0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500 ± 447 days. Two of 6 patients with no prior RT were referred for salvage prostatic fossa RT: 1 received dose escalation for disease identified in the prostate fossa and another had inclusion of “hot” pelvic lymph nodes in the treatment volume. Conclusions: These early results suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines may change management and improve care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning, and delaying or avoiding use of androgen deprivation therapy. Key Words: prostate cancer, radiation therapy, salvage, PET choline
(Am J Clin Oncol 2014;00:000–000)
O
ptimal management of prostate cancer patients with rising PSA following definitive treatment with surgery, external beam radiation, or brachytherapy is unknown.1 Imaging studies using computed tomography (CT), magnetic resonance imaging (MRI), bone scan, or 18F FDG PET/CT often fail to identify the cause for biochemical failure. Uncertainty in location and extent of recurrent disease may adversely impact disease management and patients may undergo futile treatment. Improved imaging is warranted for determination of the cause for biochemical failure and tailoring the optimal treatment approach with consequent improved outcome. Recently, 11C choline PET/CT was approved by the US Food and drug Administration (FDA) as an imaging agent for detection of recurrent disease in patients with rising PSA following definitive treatment.2 Although labeled-choline PET/CT has limited utility in the initial staging of prostate cancer, it has been shown to locate sites of recurrence in patients with biochemical failure.3,4 Updated 2014 NCCN guidelines5 now suggest the use of labeled-choline PET/CT in patients with biochemical failure. The goal of optimal imaging in this clinical scenario is to assist in patient selection for observation or targeted radiotherapy avoiding or delaying androgen deprivation therapy (ADT).3,6 In addition, patients with metastatic disease will be diagnosed and offered ADT rather than salvage radiation.3,6 Few studies describe how labeled choline PET/CT imaging impacts decision making and treatment of patients with biochemical failure following definitive therapy.3,7–10 In this study we report the impact of labeled choline PET/CT scans on management decisions and subsequent treatment for 33 patients with rising PSA after failed primary or salvage therapy.
METHODS This retrospective review of a prospective database was approved by the Tel Aviv Sourasky Medical Center and Sheba
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1
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American Journal of Clinical Oncology
Goldstein et al
Medical Center’s Helsinki ethical review committees. Patient characteristics including age, PSA, stage, prior treatments, and precholine PET/CT treatment recommendations based on NCCN guidelines were recorded. Patients with biochemical failure and without evidence of recurrence on physical examination or standard imaging were offered the option of additional imaging with a labeled choline PET/CT scan or treatment based on NCCN guidelines. All radiation treatments were given under the direction of a single radiation oncologist (Z.S.) in the Department of Radiation Oncology at Chaim Sheba Medical Center, Ramat Gan, Israel. When patients were treated with radiation, the scan results were incorporated into the planning process. Prostate recurrences were offered brachytherapy and brachytherapy recurrences were offered prostate irradiation. Lymph node recurrences in patients with prior treatment to the prostate or prostate fossa were offered lymph node salvage therapy. Patients with oligometastatic disease were offered ADT or radiation therapy. Scan results and revised treatment recommendations were compared with prescan recommendations. Pathologic confirmation was obtained before prostate retreatment. Thirty 11C Choline PET/CT studies were performed at the Department of Nuclear Medicine, Sourasky Medical Center, Tel Aviv, and four 18F Choline PET/CT studies were performed at the Department of Nuclear Medicine, Chaim Sheba Medical Center, Tel Hashomer. Tracer was supplied from the cyclotron at Hadassah Medical Center in Jerusalem, Israel. Whole-body PET/CT scanning was performed with a 64-row helical detector Discovery PET/CT 690, GE Healthcare at Sourasky, and 16 row helical detector Gemini GXL Discovery PET/CT, Phillips Medical at Sheba. Both scanners allow acquisition of PET and CT without changing the patient’s positioning and provide head to thigh images with multiple bed positions. Acquisition started soon after IV injection of 370 Mbq of either 11C-Choline or 18F-Choline and was repeated at 60 minutes after the injection of 18FCholine. Fusion of PET and CT data is done using the GE Healthcare Xeleris workstation at Sourasky or the Phillips Portal computer workstation at Sheba. A nonparametric w2 test was used to compare the effect of PET choline CT on the change in treatment recommendations.
RESULTS Between June 2010 and January 2014, 34 labeled choline PET/CT studies were performed on 33 patients with biochemical failure following radical prostatectomy, prostate radiation therapy, brachytherapy, and radical prostatectomy followed by salvage prostate fossa radiation therapy or salvage prostate fossa/lymph node radiation therapy. One patient had undergone 2 scans. Patients were asymptomatic at time of referral and suffered only from biochemical failure. Median PSA level before imaging was 2 ng/mL (range, 0.16 to 79). Patient characteristics and results of the labeled choline PET/ CT studies are shown in Table 1. Local recurrence in the prostate, prostate fossa, or pelvic lymph nodes was seen in 17 patients, metastatic disease was seen in 9 patients, and failed to identify the cause for biochemical failure in 7 patients. Table 2 summarizes the initial management options offered to patients and the revised options when the results of the PET/CT were considered. Choline PET/CT altered treatment recommendation in 18 of 33 patients. A w2 test comparing the initial and final treatment recommendations for all 33 patients showed that use of choline PET/CT imaging significantly altered patient management (P = 0.05).
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TABLE 1. Characteristics of Patients Referred for Choline PET-CT
Parameters
Values
No. patients N = 33 Median age in years (range) 72 (57-81) Clinical T stage (%) T1 2 (7) T2 15 (52) T3 11 (38) T4 1 (3.5) Tx 4 patients Gleason score (%) 6 7 (22.5) 7 13 (42) 8 9 (29) 9 2 (6.5) Unknown 2 patients Median PSA ng/mL (range) at referral for scan 2 ng/mL (0.16-79) Androgen deprivation therapy (ADT) No 29 Yes 4 Prior therapy* Radical prostatectomy 6 Radical prostatectomy + prostate fossa radiation 14 Radical prostatectomy + pelvic radiation 6 Prostate external beam radiation 6 Brachytherapy 1 Brachytherapy + pelvic radiation 1 *n = 34, 1 patient had 2 prior therapies and was scanned twice.
Sixteen of 27 patients treated previously with radiation benefited by receiving RT and delaying or eliminating ADT: 1 received salvage brachytherapy after confirmation by biopsy, 10 received salvage pelvic lymph node or prostate fossa margin irradiation, 2 brachytherapy failures received salvage IMRT to the prostate (confirmed by positive biopsy) and pelvic nodes, and 3 patients with solitary bone metastasis (confirmed by MRI) were treated with radiosurgery. For these patients, 11 of 16 responded to salvage therapy with a significant PSA response (< 0.2 ng/mL), 2 patients had partial biochemical responses, and 3 patients failed. The median duration of response was 500 ± 447 days. Two of 6 patients with no prior radiation treatment who were offered salvage prostatic fossa RT benefited from choline PET/CT: 1 received dose escalation for disease identified in the prostate fossa and 1 had the treatment volume increased to include involved pelvic lymph nodes along with the prostate fossa. Three patients with elevated PSA’s and nondiagnostic scans selected observation rather than ADT or other salvage therapy. One of these patients had initial prostate radiation followed by a PSA elevation 3 years after treatment. As evaluation with choline PET/CT was nondiagnostic, the patient declined ADT. This patient’s PSA subsequently declined and he continues to do well without intervention three years later.
DISCUSSION The patients in our series were strongly motivated to avoid ADT as their initial salvage treatment and were willing to shoulder the cost of the study. The use of choline PET/CT scans had a significant impact on disease management (Table 2): when scans showed metastatic disease, patients received either targeted radiosurgery or ADT and avoided salvage prostatic fossa radiation; when scans showed local or regional disease, patients received salvage radiation and delayed or avoided ADT. Several patients with nondiagnostic scans selected observation and r
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Choline PET CT in Management of Prostate Cancer
TABLE 2. Treatment Offered Before and After Choline PET-CT Imaging
Prior Therapy
Changew in Plan (n)
Treatment Delivered Following Choline PET-CT Imaging
Prostate fossa radiation
2
14
ADT or observation
7
6
ADT or observation
2
6
ADT or local salvage or observation ADT or observation
4
Dose escalation n = 1 Inclusion of pelvic lymph nodes n = 1 Salvage lymph node RT n = 6 RT to bone metastasis n = 1 SRT to marginal recurrence n = 1 RT to bone metastasis n = 1 Salvage brachytherapy n = 1 Salvage lymph node RT n = 3 Salvage prostate and lymph node RT n = 2 RT to bone metastasis n = 1z
Scans
Radical prostatectomy Radical prostatectomy + prostate fossa RT Radical prostatectomy + prostate fossa and lymph node RT Prostate RT
6
Brachytherapy
2
Proposed Treatment Before Choline PET-CT
3
*P = 0.05. wObserved versus expected change in treatment plan Chi test. zOne patient had a second course of RT. ADT indicates androgen deprivation therapy; PF, prostatic fossa; RP, radical prostatectomy; RT, radiation therapy; SRT, SRT stereotactic radiation therapy.
delayed all treatment. In one of these patients the PSA declined and the patient remains free of recurrence. In addition to assisting with treatment selection, choline PET/CT scans also improved radiation therapy planning and delivery. As the scans identified sites of suspected recurrence, radiation planning was able to target sites of macroscopic disease for dose escalation. Several authors have described the benefits of using imaging studies including choline PET/CTs for initial radiation therapy planning11 and for salvage treatments.3,4,12 In postprostatectomy patients with biochemical recurrence, radiation treatment of the prostatic fossa has been shown to improve biochemical survival.13 Imaging studies, which have the potential to detect the location of recurrent disease in the prostate fossa, should allow for improved results through targeted dose escalation13,14 and better delineation of the treatment area.9,11,14–16 Our study suggests that choline PET/CT improves target delineation and allows for dose escalation. For example, when patients have scans, which identify the site of disease in the prostatic fossa or pelvis, physicians may limit the dose escalation to those areas most likely harboring disease; negative scans would allow physicians to consider lower dose treatment or even consider observation. One possible limitation of this approach is that choline PET/CT scan sensitivity increases with PSA concentration so treatment should not be held until disease becomes apparent on a choline PET/CT scan.14 Patients who fail prostate radiation are usually offered ADT.1 Identifying a recurrence outside of the original or salvage radiation fields would offer these patients a second opportunity to receive local radiation treatment and provide them the option of avoiding ADT.1 Although functional radiotracers have not been effective in the initial staging of prostate cancer because of low sensitivity and specificity, there is evidence that choline PET/CT has improved value and may enhance identification of cancer recurrence in previously irradiated patients.7 This offers a potential area of future investigation. Curative therapy of prostate cancer with surgery or radiation as well as salvage prostatic fossa radiation after surgery may intentionally leave the pelvic lymph nodes untreated.17 Therefore, identification and treatment of pelvic lymph node failure may offer patients another chance for cure and defer the need for ADT.18,19 However, the optimal treatment strategies for detection and treatment of pelvic lymph node recurrence remain to be determined. Some groups have targeted only lymph nodes that show radiotracer uptake using stereotaxic radiosurgery techniques.20 We believe that this approach should be followed with caution. Rigatti reported a series of patients who underwent pelvic lymph node dissection r
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following positive pet choline scans. Pathologic examination showed many additional involved nodes that were not PET choline avid on the initial scan.12,21 Our approach to pelvic nodal recurrence has been to treat the entire nodal volume and offer increased dose to the choline PET/CT avid region.4 Our series reports 3 patients with oligometastatic disease who were treated with stereotactic body radiation therapy and were able to delay start of ADT because of a lengthened diseasefree interval following treatment. Similar findings have been reported by others.22 Although most of these patients eventually develop widespread disease, deferment of ADT is beneficial. The treatments offered in our series and in others were well tolerated with no major complications. In fact, improvement in planning, targeting, and dose delivery in conjunction with choline PET/CT should limit treatment-related side effects by reducing the volume of normal tissue irradiated, while allowing for dose escalation to areas most at risk for disease recurrence. Although our results showed that choline PET/CT had a significant effect on treatment offered to patients, these findings need to be interpreted with caution in the milieu of a small retrospective study subject to selection bias. Biopsy confirmation was obtained for all patients receiving salvage therapy to the prostate and MRI confirmed all bone lesions irradiated. Biopsies were not obtained for patients treated with salvage lymph node irradiation and the biochemical response of this group to therapy has been previously reported and may be considered a surrogate confirmation.23
CONCLUSIONS These results from this small initial study suggest that labeled choline PET/CT imaging performed according to current NCCN guidelines improves care in prostate cancer patients with biochemical failure by identifying patients for referral for salvage radiation therapy, improving radiation planning and delaying or avoiding use of ADT. Although our early results are promising, we encourage caution and careful monitoring of patients for efficacy and side effects. REFERENCES 1. Punnen S, Cooperberg MR, D’Amico AV, et al. Management of biochemical recurrence after primary treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2013;64:905–915. 2. FDA approves 11C-choline for PET in prostate cancer. J Nuclear Med. 2012;53:11n.
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3. Detti B, Scoccianti S, Franceschini D, et al. Predictive factors of [18F]-Choline PET/CT in 170 patients with increasing PSA after primary radical treatment. J Cancer Res Clin Oncol. 2013;139: 521–528. 4. Schwarzenbock SM, Kurth J, Gocke C, et al. Role of choline PET/ CT in guiding target volume delineation for irradiation of prostate cancer. Eur J Nuclear Med Mol Imag. 2013;40(suppl 1):28–35. 5. Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 1.2014. J Nat Comp Cancer Network. 2013;11:1471–1479. 6. Rischke HC, Knippen S, Kirste S, et al. Treatment of recurrent prostate cancer following radical prostatectomy: the radiationoncologists point of view. Quarter J Nuclear Med Mol Imaging. 2012;56:409–420. 7. Chondrogiannis S, Marzola MC, Ferretti A, et al. Role of F-choline PET/CT in suspicion of relapse following definitive radiotherapy for prostate cancer. Eur J Nuclear Med Mol Imaging. 2013;40:1356–1364. 8. Crehange G, Chen CP, Hsu CC, et al. Management of prostate cancer patients with lymph node involvement: a rapidly evolving paradigm. Cancer Treat Rev. 2012;38:956–967. 9. Fortuin AS, Deserno WM, Meijer HJ, et al. Value of PET/CT and MR lymphography in treatment of prostate cancer patients with lymph node metastases. Int J Radiat Oncol Biol Phys. 2012;84:712–718. 10. Mamede M, Ceci F, Castellucci P, et al. The role of 11C-Choline PET imaging in the early detection of recurrence in surgically treated prostate cancer patients with very low PSA level < 0.5 ng/ mL. Clin Nucl Med. 2013;38:e342–e345. 11. Chang JH, Lim Joon D, Lee ST, et al. Intensity modulated radiation therapy dose painting for localized prostate cancer using (1)(1)C-choline positron emission tomography scans. Int J Radiat Oncol Biol Phys. 2012;83:e691–e696. 12. Passoni NM, Suardi N, Abdollah F, et al. Utility of [C]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. 2013;32:38.e9–e16. 13. Thompson IM, Valicenti RK, Albertsen P, et al. Adjuvant and salvage radiotherapy after prostatectomy: AUA/ASTRO Guideline. J Urol. 2013;190:441–449.
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14. Kitajima K, Murphy RC, Nathan MA. Choline PET/CT for imaging prostate cancer: an update. Ann Nucl Med. 2013;27:581–591. 15. Poortmans P, Bossi A, Vandeputte K, et al. Guidelines for target volume definition in post-operative radiotherapy for prostate cancer, on behalf of the EORTC Radiation Oncology Group. Radiother Oncol. 2007;84:121–127. 16. Michalski JM, Lawton C, El Naqa I, et al. Development of RTOG consensus guidelines for the definition of the clinical target volume for postoperative conformal radiation therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2010;76:361–368. 17. Abdollah F, Cozzarini C, Suardi N, et al. Indications for pelvic nodal treatment in prostate cancer should change. Validation of the Roach formula in a large extended nodal dissection series. Int J Radiat Oncol Biol Phys. 2012;83:624–629. 18. Casamassima F, Masi L, Menichelli C, et al. Efficacy of eradicative radiotherapy for limited nodal metastases detected with choline PET scan in prostate cancer patients. Tumori. 2011;97:49–55. 19. Jereczek-Fossa BA, Beltramo G, Fariselli L, et al. Robotic imageguided stereotactic radiotherapy, for isolated recurrent primary, lymph node or metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:889–897. 20. Reske SN, Moritz S, Kull T. [11C]Choline-PET/CT for outcome prediction of salvage radiotherapy of local relapsing prostate carcinoma. Quarter J Nuclear Med Mol Imag. 2012;56:430–439. 21. Rigatti P, Suardi N, Briganti A, 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;60:935–943. 22. Schick U, Jorcano S, Nouet P, et al. Androgen deprivation and high-dose radiotherapy for oligometastatic prostate cancer patients with less than five regional and/or distant metastases. Acta Oncologica (Stockholm, Sweden). 2013;52:1622–1628. 23. Symon Z, Ben-Bezalel G, Spieler B, et al. A retrospective feasibility study of salvage pelvic nodal radiation in 6 patients with biochemical failure following prostate fossa radiation: an alternative to androgen deprivation therapy (ADT) [In press]. Am J Clin Oncol. 2014;’:’.
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