- Email: [email protected]
Long-Term Results of a Prospective, Phase II Study of Long-Term Androgen Ablation, Pelvic Radiotherapy, Brachytherapy Boost, and Adjuvant Docetaxel in Patients With High-Risk Prostate Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 3, pp. 732–736, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.06.042
CLINICAL INVESTIGATION
Prostate
LONG-TERM RESULTS OF A PROSPECTIVE, PHASE II STUDY OF LONG-TERM ANDROGEN ABLATION, PELVIC RADIOTHERAPY, BRACHYTHERAPY BOOST, AND ADJUVANT DOCETAXEL IN PATIENTS WITH HIGH-RISK PROSTATE CANCER STEVEN J. DIBIASE, M.D.,* ARIF HUSSAIN, M.D.,z RITESH KATARIA,y PRADIP AMIN, M.D.,y SUNAKSHI BASSI,y NANCY DAWSON, M.D,x AND YOUNG KWOK, M.D.y *Department of Radiation Oncology at Robert Wood Johnson School of Medicine and Cooper University Hospital, Camden, NJ; y Department of Radiation Oncology and zDivision of Hematology and Oncology at University of Maryland School of Medicine, Baltimore, MD; and xLombardi Cancer Center at Georgetown University School of Medicine, Washington, DC Purpose: We report the long-term results of a prospective, Phase II study of long-term androgen deprivation (AD), pelvic radiotherapy (EBRT), permanent transperineal prostate brachytherapy boost (PB), and adjuvant docetaxel in patients with high-risk prostate cancer. Methods and Materials: Eligibility included biopsy-proven prostate adenocarcinoma with the following: prostatespecific antigen (PSA) > 20 ng/ml; or Gleason score of 7 and a PSA >10 ng/ml; or any Gleason score of 8 to 10; or stage T2b to T3 irrespective of Gleason score or PSA. Treatment consisted of 45 Gy of pelvic EBRT, followed 1 month later by PB with either iodine-125 or Pd-103. One month after PB, patients received three cycles of docetaxel chemotherapy (35 mg/m2 per week, Days 1, 8, and 15 every 28 days). All patients received 2 years of AD. Biochemical failure was defined as per the Phoenix definition (PSA nadir + 2). Results: From August 2000 to March 2004, 42 patients were enrolled. The median overall and active follow-ups were 5.6 years (range, 0.9–7.8 years) and 6.3 years (range, 4–7.8 years), respectively. Grade 2 and 3 acute genitourinary (GU) and gastrointestinal (GI) toxicities were 50.0% and 14.2%, respectively, with no Grade 4 toxicities noted. Grade 3 and 4 acute hematologic toxicities were 19% and 2.4%, respectively. Of the patients, 85.7% were able to complete the planned multimodality treatment. The 5- and 7-year actuarial freedom from biochemical failures rates were 89.6% and 86.5%, and corresponding rates for disease-free survival were 76.2% and 70.4%, respectively. The 5- and 7-year actuarial overall survival rates were 83.3% and 80.1%, respectively. The 5- and 7-year actuarial rates of late Grade 2 GI/GU toxicity (no Grade 3–5) was 7.7%. Conclusions: The trimodality approach of using 2 years of AD, external radiation, brachytherapy, and upfront docetaxel in high-risk prostate cancer is well tolerated, produces encouraging long-term results, and should be validated in a multi-institutional setting. Ó 2011 Elsevier Inc. Prostate cancer, Radiotherapy, Brachytherapy, Adjuvant docetaxel, Multimodality.
INTRODUCTION
doses of EBRT (70 Gy), as well as the existence of androgen-insensitive tumor clonagens (3, 4). Recently, randomized trials have shown improved biochemical DFS outcomes with higher EBRT doses (5–7). Similarly, the combination of prostate brachytherapy (PB) and EBRT has been advocated by some as an effective dose-escalation strategy in intermediate- and high-risk prostate cancer, as it delivers a higher biologic dose to the prostate gland while lessening the effects of interfraction and intrafraction prostate motion (8, 9). Because biochemical relapse continues to occur in a large percentage of these patients, integrating systemic
The effective management of high-risk prostate cancer presents a significant clinical challenge to the physicians involved. The mainstay of treatment typically involves the combination of long-term androgen deprivation (AD) with external beam radiation therapy (EBRT). Randomized trials have shown improved overall survival (OS) with this combination; however, even with this approach, more than one-half of patients experience disease recurrence (1, 2). Possible explanations for the disease recurrence in this high-risk group after combined EBRT and AD include the persistence of locally resistant tumor cells in the prostate after conventional Reprint requests to: Steven J. DiBiase, M.D., Department of Radiation Oncology, Cooper University Hospital, 1 Cooper Plaza, Camden, NJ 08103. Tel: (856) 342-2038; Fax: (856) 968-8334; E-mail: [email protected] Presented at the annual meeting of the American Society of Therapeutic Radiology and Oncology September 21-25, 2008, Boston, MA.
Conflict of interest: This study was funded through an educational grant from Sanofi-Aventis, which had no role in the design, conduct, collection, or interpretation of the data, or in the preparation, review, or approval of the manuscript. Nancy Dawson, M.D., receives consulting fees from Sanofi-Aventis. Received March 1, 2010, and in revised form June 21, 2010. Accepted for publication June 25, 2010. 732
Multimodal therapy in high-risk prostate cancer d S. J. DIBIASE et al.
chemotherapy with radiation and AD in high-risk prostate cancer is one potential approach for improving treatment outcomes. Two randomized trials have reported an overall survival advantage with docetaxel-based chemotherapy in men with castration-resistant prostate cancer; however, no randomized trial results have been reported demonstrating the efficacy of docetaxel-based systemic therapy upfront in the treatment of nonmetastatic, high-risk localized prostate cancer (10, 11). In the present trial, PB boost after pelvic EBRT was used in an effort to deliver more accurately an escalated dose of radiation directly into the prostate to overcome radioresistent tumor clonagens, whereas docetaxel was added to potentially enhance control of any undetectable micrometastatic tumor clonagens. In this article, we report the results of a prospective, Phase II multimodal trial evaluating the efficacy of combining EBRT with permanent PB along with systemic therapy using 2 years of AD and three cycles of adjuvant docetaxel in high-risk prostate cancer patients. METHODS AND MATERIALS Eligibility The study was approved by the Institutional Review Board, and the patients were accrued and treated at the University of Maryland Medical Center. All patients were required to have a histologically confirmed adenocarcinoma of the prostate and to meet the following criteria: prostate-specific antigen (PSA) >20 ng/ml; or Gleason score of 7 and PSA >10ng/ml; or Gleason score of 8 to 10; or T2b to T3 disease (American Joint Committee on Cancer [AJCC] Staging 1997). Patients with prior chemotherapy or radiotherapy, or lymph node positive (N+) or metastatic disease (M1) were ineligible. Prior AD was allowed up to a maximum of 2 months before enrollment. All patients were required to have a Karnofsky performance status $70 and a life expectancy of >2 years. A computed tomography (CT) scan of the abdomen/pelvis and a bone scan were required to rule out metastatic disease. Comprehensive blood work was performed in all patients, including CBC, chemistries, and liver function tests. Patients were enrolled only after a thorough evaluation by a medical oncologist, urologist, and radiation oncologist.
Treatment plan The multimodality treatment protocol is depicted in Table 1. EBRT was initiated on Day 1 to a pelvic field at 1.8 Gy/fraction per day, 5 days per week, to a total dose of 45 Gy. A linear accelerator with an energy of 18 MV was used. Treatment was delivered via a four-field technique (anterior–posterior/posterior–anterior [AP/ PA] and opposed laterals). The superior edge of the field was at the L5/S1 interspace, and a urethrogram was used to identify the in-
733
ferior aspect of the prostate. Four weeks after completion of EBRT, a permanent, transperineal, PB procedure was administered using either iodine-125 isotope (108 Gy) or Pd-103 isotope (100 Gy). The target volume for the implant was defined as the prostate plus 2 mm in all dimensions except posteriorly where there was no margin. The total length of AD was 24 months. This was initiated in the first week of EBRT and consisted of an antiandrogen (flutamide 250 mg p.o. t.i.d. or bicalutamide 50 mg p.o. q.d.) for 4 weeks and luteinizing hormone-releasing hormone agonist (goserelin or leuprolide injections) for a total duration of 24 months. Four to 6 weeks after the PB procedure, docetaxel was given i.v. as a 30min infusion at 35 mg/m2 per week every 3 out of 4 weeks for a total of three cycles (thus each cycle was 3 weeks on, 1 week off). Dexamethasone 8 mg p.o. b.i.d. three doses was given beginning 12 hours before receiving docetaxel. Patients were seen every 3 months for the first 3 years after the completion of chemotherapy, then every 6 months. At each follow up visit, a history and physical and PSA value were obtained, and the toxicity was assessed by the physician and research coordinator. Furthermore, the patients completed a battery of toxicity and quality of life questionnaires that included the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and Functional Assessment of Cancer Therapy-Prostate (FACT-P) at each visit. Bone and CT scans were obtained in follow-up if clinically indicated.
Statistical analysis The primary endpoint of this study was disease-free survival (DFS). Secondary endpoints were freedom from biochemical failure (bNED), overall survival (OS), and acute and late toxicity rates. Acute toxicity was graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0, and late toxicity was scored according to the modified Radiation Therapy Oncology Group (RTOG)–Late Effects of Normal Tissue (LENT) scale (5, 12). Biochemical failure was defined by the Phoenix definition (PSA nadir + 2). DFS was defined as date of start of therapy to the date of PSA failure or distant failure (with or without PSA failure), or death from any cause. OS was defined as date of start of therapy to the date of death from any cause. Actuarial analyses were calculated using the Kaplan–Meier method. Data were analyzed and presented using the intent-to-treat principle.
RESULTS From August 2000 to March 2004 a total of 42 patients were accrued to this prospective, Phase II study. The median age of the patients was 62.5 years (range, 47–75 years). Approximately 29% of patients in our cohort had bulky clinical disease (T2b–T3, AJCC 2002), whereas 45% of the patients had Gleason 8 to 9 cancers. The median PSA at trial entry was 17.7 ng/ml (range, 1.2–84.6 ng/ml). Clinical characteristics of the patients are summarized in Table 2. The median
Table 1. Treatment schema Week 1 (Day 1)
Week 9
Week 13
Pelvic EBRT 45 Gy (5 weeks) LHRH agonist (2 years) Anti-androgen (4 weeks)
Brachytherapy boost (I-125–108 Gy) or (Pd-103–100 Gy)
Adjuvant docetaxel 3 cycles (1 cycle = 35 mg/m2 i.v., Days 1, 8, 15 Q 28 days)
Abbreviations: EBRT = external beam radiation; LHRH = luteinizing hormone-releasing hormone.
I. J. Radiation Oncology d Biology d Physics
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Table 2. Baseline patient characteristics (n = 42) Characteristic
Value n = 42
Follow-up, median (range), y Follow-up, active (range), y Age, median (range), y Stage (AJCC 2002) T1c T2a T2b T2c T3a T3b Gleason 6 3+4 4+3 8 9 PSA, median Brachytherapy source Pd–103 I-125 No boost
5.6 years (0.9–7.8) 6.3 years (4–7.8) 62.5 years (47–75) 20 (47.6%) 10 (23.8%) 5 (11.9%) 4 (9.4%) 2 (4.8%) 1 (2.4%) 2 (4.8%) 9 (21.4%) 13 (31.0%) 8 (19.0%) 11 (26.2%) 17.8 ng/ml (1.2-–84.6) 24 (57.1%) 16 (38.1%) 2 (4.8%)
Fig. 2. Actuarial disease-free survival (DFS).
Efficacy The 5-year and 7-year actuarial bNED rates were 89.6% and 86.5%, respectively (Fig. 1). The corresponding rates for DFS were 76.2% and 70.4% (Fig. 2). For the entire cohort, 5-year and 7-year OS were 83.3% and 80.1%, respectively (Fig. 3). Six patients experienced disease failure, including 4 patients who had biochemical-only failure and 2 patients who had biochemical plus distant clinical failure. One patient died of metastatic disease.
Toxicity During the course of EBRT and PB the most common acute toxicity was genitourinary (GU) followed by gastrointestinal (GI). The acute Grade 2 and Grade 3 GU toxicity rates were 24% and 26%, respectively. The acute Grade 2 and Grade 3 GI toxicity rates were 10% and 4.2%, respectively. No patient experienced acute Grade 4 or Grade 5 GI/GU toxicity. During chemotherapy, 8 patients (19%) experienced acute Grade 3 anemia (5%), leukopenia (7%) and neutropenia (7%), and 1 patient (2.4%) had Grade 4 leukopenia. There was no acute Grade 3 or Grade 4 thrombocytopenia. In addition, no Grade 5 toxicities were observed during the entire course of treatment. Three patients experienced late Grade 2 GI/GU toxicity; 1 patient experienced intermittent rectal bleeding treated conservatively with rectal steroids; and two had nocturia and increased frequency. No late Grade 3 or Grade 4 GI/GU toxicity was seen. The
Fig. 1. Actuarial freedom from biochemical failure (bNED).
Fig. 3. Actuarial overall survival (OS).
Abbreviations: AJCC = american joint committee on cancer; PSA = prostate-specific antigen.
overall follow-up was 5.6 years (range, 0.9–7.8 years), and the median active follow-up for alive patients was 6.3 years (range, 4–7.8 years).
Multimodal therapy in high-risk prostate cancer d S. J. DIBIASE et al.
Fig. 4. Late Grade $2 gastrointestinal (GI)/genitourinary (GU) toxicity (modified Radiation Therapy Oncology Group [RTOG]–Late Effects of Normal Tissue [LENT]). The 5-year actuarial incidence was 7.7%.
5-year actuarial rate of late Grade 2 GI/GU toxicity (modified RTOG-LENT) was 7.7% (Fig. 4). The majority of patients were able to complete their planned therapy. Planned radiation was completed in 40 of 42 patients (95.2%). One patient refused PB after EBRT, and 1 patient was discovered to have lung cancer during preoperative chest imaging and therefore did not receive the planned PB. The full 24-month of AD was completed by 92.9% of the patients (39 of 42 patients). Three patients died before receiving the full AD course. In all, 86% of the patients received all three planned cycles of docetaxel without dose modifications. One patient refused to undergo any chemotherapy. DISCUSSION With more than 5 years of follow-up, this Phase II study has shown that multimodality treatment, using a radiation dose escalation approach combined with both hormonal therapy and chemotherapy as specified in this study, is well tolerated and produces encouraging efficacy results. With a median PSA of 17.7 ng/ml and almost one-half the patients having a Gleason score of 8 to 9 at trial entry, the actuarial 7-year bNED rate was 86.5% in this prospective study. Although continued failures will likely occur with additional followup, the tumor control rates revealed in this pilot study are encouraging in a patient population that typically has bNED rates of 50% to 60% at a comparable follow-up interval. One of the initial concerns before the initiation of this trial was the possible morbidity risk involved with a radiation dose escalation approach combined with chemotherapy. However, only 7.7% had late Grade 2 GI/GU morbidity, with no patients experiencing Grade 3 to 5 toxicity. This rate compares favorably to EBRT dose escalation trials (5–7). Furthermore the overall compliance on this study
735
was high, with 85.7% of patients completing the combined radiation protocol as well as the three cycles of docetaxel. Although it is difficult to draw firm conclusions based on a single-arm pilot trial, when one compares the bNED rates of this high-risk population with other comparable series, it appears that the inclusion of docetaxel in the treatment regimen may have contributed to the overall tumor control efficacy. The role of docetaxel in prostate cancer is clearly defined in the castration-resistant metastatic setting, as demonstrated by the two pivotal trials TAX 327 and Southwestern Oncology Group (SWOG)/Intergroup 99-16, which showed OS benefit with docetaxel-based therapy compared with mitoxantrone-based therapy (10, 11). However, there continues to be a relative dearth of experience regarding the utility of upfront chemotherapy and radiation in nonmetastatic high-risk prostate cancer. Although there have been several trials of neoadjuvant chemotherapy before prostatectomy, none have been randomized, and the results of these small series thus far have been disappointing (13–16). Currently, Cancer and Leukemia Group B (CALGB) 90203 is randomizing high-risk patients to prostatectomy alone vs. neoadjuvant docetaxel and AD followed by prostatectomy (17). Even fewer studies have combined docetaxel-based regimens with radiation for high-risk prostate cancer, and all have short follow-ups (18–20). To our knowledge, the current trial is the first report of a multimodal radiation regimen incorporating EBRT plus PB with an adjuvant docetaxel regimen. Recently, the RTOG protocol 0521 closed to accrual. This trial evaluated definitive EBRT and 28 months of AD with adjuvant docetaxel in high-risk prostate cancer. Hopefully, the mature results of this protocol will begin to clarify the utility of adjuvant docetaxel-based regimens in high-risk prostate cancer. One limitation this study arises mainly from when the patients were accrued. Pelvic IMRT was not used. Furthermore transrectal magnetic resonance imaging (MRI) was not routinely available. Although the utility of transrectal MRI is debatable in patients with low-risk disease, it is potentially beneficial in determining the extent of possible extracapsular and seminal vesicle involvement that could preclude an effective implant (21). The docetaxel dosing schedule (3 weeks on, 1 week off) would be considered nonstandard by the current practices of administering this agent every 3 weeks. Despite these limitations, patients tolerated the entire multimodality treatment well, with the vast majority completing all of the therapy as planned. CONCLUSION In conclusion, based on the findings of this trial, multimodality treatment integrating EBRT, brachytherapy boost, adjuvant docetaxel, and long-term androgen deprivation is feasible, producing a high level of disease control with acceptable toxicity. Additional follow-up as well as a Phase III comparison of this approach vs. conventional treatment is warranted.
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REFERENCES 1. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): A phase III randomised trial. Lancet 2002;360:103–106. 2. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: A phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497–2504. Epub 2008 Apr 14. 3. Zagars GK, Pollack A, Smith LG. Conventional external-beam radiation therapy alone or with androgen ablation for clinical stage III (T3, NX/N0, M0) adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1999;44:809–819. 4. Zelefsky MJ, Kelly WK, Scher HI, et al. Results of a phase II study using estramustine phosphate and vinblastine in combination with high-dose three-dimensional conformal radiotherapy for patients with locally advanced prostate cancer. J Clin Oncol 2000;18:1936–1941. 5. Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M.D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008;70:67–74. 6. Al-Mamgani A, van Putten WL, Heemsbergen WD, et al. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72:980–988. 7. Zietman AL. Correction: Inaccurate analysis and results in a study of radiation therapy in adenocarcinoma of the prostate. JAMA 2008;299:898–900. 8. Zelefsky MJ, Kuban DA, Levy LB, et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys 2007;67:327–333. 9. Sylvester JE, Grimm PD, Blasko JC, et al. 15-Year biochemical relapse free survival in clinical Stage T1–T3 prostate cancer following combined external beam radiotherapy and brachytherapy; Seattle experience. Int J Radiat Oncol Biol Phys 2007; 67:57–64. 10. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 2008;26:242–245.
11. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351: 1513–1520. 12. Hanlon AL, Schultheiss TE, Hunt MA, et al. Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 1997;387:59–63. 13. Pettaway CA, Pisters LL, Troncoso P, et al. Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: Feasibility and preliminary results. J Clin Oncol 2000;18: 1050–1057. 14. Mellado B, Font A, Alcaraz A, et al. Phase II trial of short-term neoadjuvant docetaxel and complete androgen blockade in high-risk prostate cancer. Br J Cancer 2009;101:1248–1252. 15. Vuky J, Porter C, Isacson C, et al. Phase II trial of neoadjuvant docetaxel and gefitinib followed by radical prostatectomy in patients with high-risk, locally advanced prostate cancer. Cancer 2009;115:784–791. 16. Shepard DR, Dreicer R, Garcia J, et al. Phase II trial of neoadjuvant nab-paclitaxel in high risk patients with prostate cancer undergoing radical prostatectomy. J Urol 2009;181:1672– 1677:discussion 1677. 17. Eastham JA, Kelly WK, Grossfeld GD, et al. Cancer and Leukemia Group B (CALGB) 90203: A randomized phase 3 study of radical prostatectomy alone versus estramustine and docetaxel before radical prostatectomy for patients with high-risk localized disease. Urology 2003;62(Suppl 1):55–62. 18. Ryan CJ, Zelefsky MJ, Heller G, et al. Five-year outcomes after neoadjuvant chemotherapy and conformal radiotherapy in patients with high-risk localized prostate cancer. Urology 2004; 64:90–94. 19. Kumar P, Perrotti M, Weiss R, et al. Phase I trial of weekly docetaxel with concurrent three-dimensional conformal radiation therapy in the treatment of unfavorable localized adenocarcinoma of the prostate. J Clin Oncol 2004;22:1909–1915. 20. Perrotti M, Doyle T, Kumar P, et al. Phase I/II trial of docetaxel and concurrent radiation therapy in localized high risk prostate cancer (AGUSG 03-10). Urol Oncol 2008;26:276–280. 21. Carey B, Swift S. The current role of imaging for prostate brachytherapy. Cancer Imaging 2007;7:27–33.
doi:10.1016/j.ijrobp.2010.06.042
CLINICAL INVESTIGATION
Prostate
LONG-TERM RESULTS OF A PROSPECTIVE, PHASE II STUDY OF LONG-TERM ANDROGEN ABLATION, PELVIC RADIOTHERAPY, BRACHYTHERAPY BOOST, AND ADJUVANT DOCETAXEL IN PATIENTS WITH HIGH-RISK PROSTATE CANCER STEVEN J. DIBIASE, M.D.,* ARIF HUSSAIN, M.D.,z RITESH KATARIA,y PRADIP AMIN, M.D.,y SUNAKSHI BASSI,y NANCY DAWSON, M.D,x AND YOUNG KWOK, M.D.y *Department of Radiation Oncology at Robert Wood Johnson School of Medicine and Cooper University Hospital, Camden, NJ; y Department of Radiation Oncology and zDivision of Hematology and Oncology at University of Maryland School of Medicine, Baltimore, MD; and xLombardi Cancer Center at Georgetown University School of Medicine, Washington, DC Purpose: We report the long-term results of a prospective, Phase II study of long-term androgen deprivation (AD), pelvic radiotherapy (EBRT), permanent transperineal prostate brachytherapy boost (PB), and adjuvant docetaxel in patients with high-risk prostate cancer. Methods and Materials: Eligibility included biopsy-proven prostate adenocarcinoma with the following: prostatespecific antigen (PSA) > 20 ng/ml; or Gleason score of 7 and a PSA >10 ng/ml; or any Gleason score of 8 to 10; or stage T2b to T3 irrespective of Gleason score or PSA. Treatment consisted of 45 Gy of pelvic EBRT, followed 1 month later by PB with either iodine-125 or Pd-103. One month after PB, patients received three cycles of docetaxel chemotherapy (35 mg/m2 per week, Days 1, 8, and 15 every 28 days). All patients received 2 years of AD. Biochemical failure was defined as per the Phoenix definition (PSA nadir + 2). Results: From August 2000 to March 2004, 42 patients were enrolled. The median overall and active follow-ups were 5.6 years (range, 0.9–7.8 years) and 6.3 years (range, 4–7.8 years), respectively. Grade 2 and 3 acute genitourinary (GU) and gastrointestinal (GI) toxicities were 50.0% and 14.2%, respectively, with no Grade 4 toxicities noted. Grade 3 and 4 acute hematologic toxicities were 19% and 2.4%, respectively. Of the patients, 85.7% were able to complete the planned multimodality treatment. The 5- and 7-year actuarial freedom from biochemical failures rates were 89.6% and 86.5%, and corresponding rates for disease-free survival were 76.2% and 70.4%, respectively. The 5- and 7-year actuarial overall survival rates were 83.3% and 80.1%, respectively. The 5- and 7-year actuarial rates of late Grade 2 GI/GU toxicity (no Grade 3–5) was 7.7%. Conclusions: The trimodality approach of using 2 years of AD, external radiation, brachytherapy, and upfront docetaxel in high-risk prostate cancer is well tolerated, produces encouraging long-term results, and should be validated in a multi-institutional setting. Ó 2011 Elsevier Inc. Prostate cancer, Radiotherapy, Brachytherapy, Adjuvant docetaxel, Multimodality.
INTRODUCTION
doses of EBRT (70 Gy), as well as the existence of androgen-insensitive tumor clonagens (3, 4). Recently, randomized trials have shown improved biochemical DFS outcomes with higher EBRT doses (5–7). Similarly, the combination of prostate brachytherapy (PB) and EBRT has been advocated by some as an effective dose-escalation strategy in intermediate- and high-risk prostate cancer, as it delivers a higher biologic dose to the prostate gland while lessening the effects of interfraction and intrafraction prostate motion (8, 9). Because biochemical relapse continues to occur in a large percentage of these patients, integrating systemic
The effective management of high-risk prostate cancer presents a significant clinical challenge to the physicians involved. The mainstay of treatment typically involves the combination of long-term androgen deprivation (AD) with external beam radiation therapy (EBRT). Randomized trials have shown improved overall survival (OS) with this combination; however, even with this approach, more than one-half of patients experience disease recurrence (1, 2). Possible explanations for the disease recurrence in this high-risk group after combined EBRT and AD include the persistence of locally resistant tumor cells in the prostate after conventional Reprint requests to: Steven J. DiBiase, M.D., Department of Radiation Oncology, Cooper University Hospital, 1 Cooper Plaza, Camden, NJ 08103. Tel: (856) 342-2038; Fax: (856) 968-8334; E-mail: [email protected] Presented at the annual meeting of the American Society of Therapeutic Radiology and Oncology September 21-25, 2008, Boston, MA.
Conflict of interest: This study was funded through an educational grant from Sanofi-Aventis, which had no role in the design, conduct, collection, or interpretation of the data, or in the preparation, review, or approval of the manuscript. Nancy Dawson, M.D., receives consulting fees from Sanofi-Aventis. Received March 1, 2010, and in revised form June 21, 2010. Accepted for publication June 25, 2010. 732
Multimodal therapy in high-risk prostate cancer d S. J. DIBIASE et al.
chemotherapy with radiation and AD in high-risk prostate cancer is one potential approach for improving treatment outcomes. Two randomized trials have reported an overall survival advantage with docetaxel-based chemotherapy in men with castration-resistant prostate cancer; however, no randomized trial results have been reported demonstrating the efficacy of docetaxel-based systemic therapy upfront in the treatment of nonmetastatic, high-risk localized prostate cancer (10, 11). In the present trial, PB boost after pelvic EBRT was used in an effort to deliver more accurately an escalated dose of radiation directly into the prostate to overcome radioresistent tumor clonagens, whereas docetaxel was added to potentially enhance control of any undetectable micrometastatic tumor clonagens. In this article, we report the results of a prospective, Phase II multimodal trial evaluating the efficacy of combining EBRT with permanent PB along with systemic therapy using 2 years of AD and three cycles of adjuvant docetaxel in high-risk prostate cancer patients. METHODS AND MATERIALS Eligibility The study was approved by the Institutional Review Board, and the patients were accrued and treated at the University of Maryland Medical Center. All patients were required to have a histologically confirmed adenocarcinoma of the prostate and to meet the following criteria: prostate-specific antigen (PSA) >20 ng/ml; or Gleason score of 7 and PSA >10ng/ml; or Gleason score of 8 to 10; or T2b to T3 disease (American Joint Committee on Cancer [AJCC] Staging 1997). Patients with prior chemotherapy or radiotherapy, or lymph node positive (N+) or metastatic disease (M1) were ineligible. Prior AD was allowed up to a maximum of 2 months before enrollment. All patients were required to have a Karnofsky performance status $70 and a life expectancy of >2 years. A computed tomography (CT) scan of the abdomen/pelvis and a bone scan were required to rule out metastatic disease. Comprehensive blood work was performed in all patients, including CBC, chemistries, and liver function tests. Patients were enrolled only after a thorough evaluation by a medical oncologist, urologist, and radiation oncologist.
Treatment plan The multimodality treatment protocol is depicted in Table 1. EBRT was initiated on Day 1 to a pelvic field at 1.8 Gy/fraction per day, 5 days per week, to a total dose of 45 Gy. A linear accelerator with an energy of 18 MV was used. Treatment was delivered via a four-field technique (anterior–posterior/posterior–anterior [AP/ PA] and opposed laterals). The superior edge of the field was at the L5/S1 interspace, and a urethrogram was used to identify the in-
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ferior aspect of the prostate. Four weeks after completion of EBRT, a permanent, transperineal, PB procedure was administered using either iodine-125 isotope (108 Gy) or Pd-103 isotope (100 Gy). The target volume for the implant was defined as the prostate plus 2 mm in all dimensions except posteriorly where there was no margin. The total length of AD was 24 months. This was initiated in the first week of EBRT and consisted of an antiandrogen (flutamide 250 mg p.o. t.i.d. or bicalutamide 50 mg p.o. q.d.) for 4 weeks and luteinizing hormone-releasing hormone agonist (goserelin or leuprolide injections) for a total duration of 24 months. Four to 6 weeks after the PB procedure, docetaxel was given i.v. as a 30min infusion at 35 mg/m2 per week every 3 out of 4 weeks for a total of three cycles (thus each cycle was 3 weeks on, 1 week off). Dexamethasone 8 mg p.o. b.i.d. three doses was given beginning 12 hours before receiving docetaxel. Patients were seen every 3 months for the first 3 years after the completion of chemotherapy, then every 6 months. At each follow up visit, a history and physical and PSA value were obtained, and the toxicity was assessed by the physician and research coordinator. Furthermore, the patients completed a battery of toxicity and quality of life questionnaires that included the International Index of Erectile Function (IIEF), International Prostate Symptom Score (IPSS), and Functional Assessment of Cancer Therapy-Prostate (FACT-P) at each visit. Bone and CT scans were obtained in follow-up if clinically indicated.
Statistical analysis The primary endpoint of this study was disease-free survival (DFS). Secondary endpoints were freedom from biochemical failure (bNED), overall survival (OS), and acute and late toxicity rates. Acute toxicity was graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0, and late toxicity was scored according to the modified Radiation Therapy Oncology Group (RTOG)–Late Effects of Normal Tissue (LENT) scale (5, 12). Biochemical failure was defined by the Phoenix definition (PSA nadir + 2). DFS was defined as date of start of therapy to the date of PSA failure or distant failure (with or without PSA failure), or death from any cause. OS was defined as date of start of therapy to the date of death from any cause. Actuarial analyses were calculated using the Kaplan–Meier method. Data were analyzed and presented using the intent-to-treat principle.
RESULTS From August 2000 to March 2004 a total of 42 patients were accrued to this prospective, Phase II study. The median age of the patients was 62.5 years (range, 47–75 years). Approximately 29% of patients in our cohort had bulky clinical disease (T2b–T3, AJCC 2002), whereas 45% of the patients had Gleason 8 to 9 cancers. The median PSA at trial entry was 17.7 ng/ml (range, 1.2–84.6 ng/ml). Clinical characteristics of the patients are summarized in Table 2. The median
Table 1. Treatment schema Week 1 (Day 1)
Week 9
Week 13
Pelvic EBRT 45 Gy (5 weeks) LHRH agonist (2 years) Anti-androgen (4 weeks)
Brachytherapy boost (I-125–108 Gy) or (Pd-103–100 Gy)
Adjuvant docetaxel 3 cycles (1 cycle = 35 mg/m2 i.v., Days 1, 8, 15 Q 28 days)
Abbreviations: EBRT = external beam radiation; LHRH = luteinizing hormone-releasing hormone.
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Table 2. Baseline patient characteristics (n = 42) Characteristic
Value n = 42
Follow-up, median (range), y Follow-up, active (range), y Age, median (range), y Stage (AJCC 2002) T1c T2a T2b T2c T3a T3b Gleason 6 3+4 4+3 8 9 PSA, median Brachytherapy source Pd–103 I-125 No boost
5.6 years (0.9–7.8) 6.3 years (4–7.8) 62.5 years (47–75) 20 (47.6%) 10 (23.8%) 5 (11.9%) 4 (9.4%) 2 (4.8%) 1 (2.4%) 2 (4.8%) 9 (21.4%) 13 (31.0%) 8 (19.0%) 11 (26.2%) 17.8 ng/ml (1.2-–84.6) 24 (57.1%) 16 (38.1%) 2 (4.8%)
Fig. 2. Actuarial disease-free survival (DFS).
Efficacy The 5-year and 7-year actuarial bNED rates were 89.6% and 86.5%, respectively (Fig. 1). The corresponding rates for DFS were 76.2% and 70.4% (Fig. 2). For the entire cohort, 5-year and 7-year OS were 83.3% and 80.1%, respectively (Fig. 3). Six patients experienced disease failure, including 4 patients who had biochemical-only failure and 2 patients who had biochemical plus distant clinical failure. One patient died of metastatic disease.
Toxicity During the course of EBRT and PB the most common acute toxicity was genitourinary (GU) followed by gastrointestinal (GI). The acute Grade 2 and Grade 3 GU toxicity rates were 24% and 26%, respectively. The acute Grade 2 and Grade 3 GI toxicity rates were 10% and 4.2%, respectively. No patient experienced acute Grade 4 or Grade 5 GI/GU toxicity. During chemotherapy, 8 patients (19%) experienced acute Grade 3 anemia (5%), leukopenia (7%) and neutropenia (7%), and 1 patient (2.4%) had Grade 4 leukopenia. There was no acute Grade 3 or Grade 4 thrombocytopenia. In addition, no Grade 5 toxicities were observed during the entire course of treatment. Three patients experienced late Grade 2 GI/GU toxicity; 1 patient experienced intermittent rectal bleeding treated conservatively with rectal steroids; and two had nocturia and increased frequency. No late Grade 3 or Grade 4 GI/GU toxicity was seen. The
Fig. 1. Actuarial freedom from biochemical failure (bNED).
Fig. 3. Actuarial overall survival (OS).
Abbreviations: AJCC = american joint committee on cancer; PSA = prostate-specific antigen.
overall follow-up was 5.6 years (range, 0.9–7.8 years), and the median active follow-up for alive patients was 6.3 years (range, 4–7.8 years).
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Fig. 4. Late Grade $2 gastrointestinal (GI)/genitourinary (GU) toxicity (modified Radiation Therapy Oncology Group [RTOG]–Late Effects of Normal Tissue [LENT]). The 5-year actuarial incidence was 7.7%.
5-year actuarial rate of late Grade 2 GI/GU toxicity (modified RTOG-LENT) was 7.7% (Fig. 4). The majority of patients were able to complete their planned therapy. Planned radiation was completed in 40 of 42 patients (95.2%). One patient refused PB after EBRT, and 1 patient was discovered to have lung cancer during preoperative chest imaging and therefore did not receive the planned PB. The full 24-month of AD was completed by 92.9% of the patients (39 of 42 patients). Three patients died before receiving the full AD course. In all, 86% of the patients received all three planned cycles of docetaxel without dose modifications. One patient refused to undergo any chemotherapy. DISCUSSION With more than 5 years of follow-up, this Phase II study has shown that multimodality treatment, using a radiation dose escalation approach combined with both hormonal therapy and chemotherapy as specified in this study, is well tolerated and produces encouraging efficacy results. With a median PSA of 17.7 ng/ml and almost one-half the patients having a Gleason score of 8 to 9 at trial entry, the actuarial 7-year bNED rate was 86.5% in this prospective study. Although continued failures will likely occur with additional followup, the tumor control rates revealed in this pilot study are encouraging in a patient population that typically has bNED rates of 50% to 60% at a comparable follow-up interval. One of the initial concerns before the initiation of this trial was the possible morbidity risk involved with a radiation dose escalation approach combined with chemotherapy. However, only 7.7% had late Grade 2 GI/GU morbidity, with no patients experiencing Grade 3 to 5 toxicity. This rate compares favorably to EBRT dose escalation trials (5–7). Furthermore the overall compliance on this study
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was high, with 85.7% of patients completing the combined radiation protocol as well as the three cycles of docetaxel. Although it is difficult to draw firm conclusions based on a single-arm pilot trial, when one compares the bNED rates of this high-risk population with other comparable series, it appears that the inclusion of docetaxel in the treatment regimen may have contributed to the overall tumor control efficacy. The role of docetaxel in prostate cancer is clearly defined in the castration-resistant metastatic setting, as demonstrated by the two pivotal trials TAX 327 and Southwestern Oncology Group (SWOG)/Intergroup 99-16, which showed OS benefit with docetaxel-based therapy compared with mitoxantrone-based therapy (10, 11). However, there continues to be a relative dearth of experience regarding the utility of upfront chemotherapy and radiation in nonmetastatic high-risk prostate cancer. Although there have been several trials of neoadjuvant chemotherapy before prostatectomy, none have been randomized, and the results of these small series thus far have been disappointing (13–16). Currently, Cancer and Leukemia Group B (CALGB) 90203 is randomizing high-risk patients to prostatectomy alone vs. neoadjuvant docetaxel and AD followed by prostatectomy (17). Even fewer studies have combined docetaxel-based regimens with radiation for high-risk prostate cancer, and all have short follow-ups (18–20). To our knowledge, the current trial is the first report of a multimodal radiation regimen incorporating EBRT plus PB with an adjuvant docetaxel regimen. Recently, the RTOG protocol 0521 closed to accrual. This trial evaluated definitive EBRT and 28 months of AD with adjuvant docetaxel in high-risk prostate cancer. Hopefully, the mature results of this protocol will begin to clarify the utility of adjuvant docetaxel-based regimens in high-risk prostate cancer. One limitation this study arises mainly from when the patients were accrued. Pelvic IMRT was not used. Furthermore transrectal magnetic resonance imaging (MRI) was not routinely available. Although the utility of transrectal MRI is debatable in patients with low-risk disease, it is potentially beneficial in determining the extent of possible extracapsular and seminal vesicle involvement that could preclude an effective implant (21). The docetaxel dosing schedule (3 weeks on, 1 week off) would be considered nonstandard by the current practices of administering this agent every 3 weeks. Despite these limitations, patients tolerated the entire multimodality treatment well, with the vast majority completing all of the therapy as planned. CONCLUSION In conclusion, based on the findings of this trial, multimodality treatment integrating EBRT, brachytherapy boost, adjuvant docetaxel, and long-term androgen deprivation is feasible, producing a high level of disease control with acceptable toxicity. Additional follow-up as well as a Phase III comparison of this approach vs. conventional treatment is warranted.
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