Radiation therapy for clinically localized prostate cancer: Long term results of 469 patients from a single institution in the era of dose escalation

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1 Original Article Radiation therapy for clinically localized prostate cancer: Long term results of 469 patients from a single institution in the era of dose escalation ABSTRACT Aims: The aim of the following study is to analyze the long term results of veterans treated with dose escalated radiation therapy for prostate cancer. Materials and Methods: This retrospective study analyzed 469 patients who were treated between 2003 and 2010 with dose escalated radiation therapy to a minimum dose of 7560 cgy for prostate cancer at the New York Harbor Department of Veterans Affairs. Biochemical failure free survival (bffs) and distant metastatic free survival (DMFS) were compared using the Kaplan Meier method. Univariate and multivariate Cox Regression were used to measure the impact of covariates on biochemical control. Results: The median follow up was 61 months and 95.3% of patients were followed at least 2 years. The 5 year bffs for National Cancer Care Network low, intermediate and high risk disease were 90.3%, 86.9% and 77.3% respectively (P = 0.001). Patients with high risk disease were more likely to develop metastatic disease. The 5 year DMFS was 99.1% for low risk, 98.8% for intermediate risk and 94.5% for high risk (P < 0.001). There were 8 prostate cancer related deaths, of which 6 had high risk disease and 2 had intermediate risk disease. The 5 year prostate cancer specific survival was 98.4%. Toxicities were generally mild, however there were two genitourinary toxicity related deaths, though in both patients there were confounding medical issues that may have contributed to their deaths. Conclusions: Dose escalated radiation in the treatment of United States Veterans appears to be well tolerated with results in line with prior reports. Further follow up is necessary to identify any additional late toxicities as well as to assess the durability of their biochemical control beyond 5 years. KEY WORDS: Dose escalation, prostate cancer, radiation INTRODUCTION Prostate cancer is the leading cancer diagnosis among men, with an estimated >238,000 new cases to be diagnosed in the United States in 2013 and is also the second leading cause of death, after lung cancer. [1] The incidence in India appears to be increasing over time as well, with an expected large increase in the rates of prostate cancer across Asia in the future [2] Dose escalated external beam radiation therapy is a primary treatment option for patients with clinically localized prostate cancer. The evidence supporting the dose response relationship in prostate cancer has been growing since the late 1990 s, with the initial reports of improved biochemical control when doses greater than 71 Gy were given compared to doses less than 71 Gy. [3] Since then, six phase three trials have compared the historical standard doses of external beam radiation Journal of Cancer Research and Therapeutics - October-December Volume 10 - Issue 4 therapy of Gy with escalated doses of Gy. [4 9] These and other recent prospective trials, as well as retrospective series, have shown the benefits of dose escalated radiation therapy with respect to biochemical and local disease control when compared to lower doses. Investigators at Fox Chase Cancer center [10] showed an improvement in biochemical control when doses of 80 Gy were used. The 10 year data was previously reported from Memorial Sloan Kettering through which investigators showed that 81 Gy was tolerable and associated with excellent long term tumor control in patients with localized prostate cancer. [11] Results from further dose escalation studies at Memorial Sloan Kettering were recently published [12] and found a 7 year biochemical relapse free survival of 98.8% and 85.6% for low risk and intermediate risk prostate cancer patients respectively, with low rates of gastrointestinal (GI) and genitourinary (GU) toxicity when treating with 86.4 Gy. Aparna Surapaneni 1,2, David Schwartz 1,2, Emmanuel Nwokedi 1, Justin Rineer 3, Marvin Rotman 1,2, David Schreiber 1,2 1 Department of Veterans Affairs, New York Harbor Healthcare System, 2 Department of Radiation Oncology, SUNY Downstate Medical Center, Brooklyn, NY, 3 UF Orlando Health, Orlando, Florida, USA For correspondence: Dr. David Schreiber, 800, Poly Place, Suite 114A, Brooklyn, NY 11209, USA. E mail: Access this article online Website: DOI: / PMID: *** Quick Response Code: 951

2 This retrospective study reviews the clinical records of patients with clinically localized prostate cancer treated with dose escalated external beam radiation therapy of doses 7560 cgy at the New York Harbor Department of Veterans Affairs. MATERIALS AND METHODS Patient characteristics After approval by the New York Harbor Department of Veterans Affairs institutional review board, we reviewed the charts of all patients who were diagnosed with prostate cancer and were treated with external beam radiation to a dose of 7560 cgy or higher from 2003 to The radiation techniques changed over time. From 2003 to 2006, all patients received treatment via 3D conformal radiation therapy (3DCRT). This typically involved a 4 field box technique for the initial 4500 cgy followed by a 6 field oblique plan for subsequent boost fields. Starting in late 2006, intensity modulated radiation therapy (IMRT) was used more often and by late 2007 all patients were treated via IMRT. Starting in 2010, all patients were treated using image guided radiation therapy (IGRT) as well, consisting of daily megavoltage cone beam computed tomography scans matched either to the bony anatomy or to gold fiducial markers. The radiation fields varied based on physician discretion, but generally the whole pelvis or true pelvis was treated for high risk disease. For intermediate risk patients, the pelvis was treated about half the time. However, this generally included the true pelvis only. Most low risk patients received treatment to the prostate and/or seminal vesicles only. Patients who received androgen deprivation were treated with a luteinizing hormone agonist. Upon completion of treatment, patients were generally followed every 3 6 months for 5 years, followed by yearly prostate specific antigen (PSA) checks. The medical records of other clinics as well as other Veterans Hospitals were also reviewed to determine any toxicity as well as to follow the PSA for patients who were lost to follow up. Biochemical failure was defined using the Phoenix definition of PSA nadir + 2 ng/ml. [13] Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. Grade 1 toxicity corresponded to minimal side effects, grade 2 toxicity corresponded to side effects requiring medications, grade 3 corresponded to side effects requiring minor procedures and grade 4 toxicity corresponded to medical admission due to life threatening complications. Survival data were gathered from the Veterans Hospital medical records as well as from social security records. If the cause of death was unknown and the patient was known to have metastatic disease at the time of recurrence, it was recorded in our database as a prostate cancer related death. If the patient had no evidence of disease at the time of death but the precise cause of death was unknown, it was recorded as unknown. PSA relapse was determined from the date of completion of radiation treatments and were analyzed using the Kaplan Meier method and compared using the log rank test. Patients were divided into risk groups based on National Cancer Care Network (NCCN) criteria ( Univariate and multivariate Cox regression modeling was performed to determine the impact of covariates on biochemical outcome. Statistical analysis was performed using the statistical package for the social sciences (SPSS) version 20.0 (IBM Inc, Armonk, New York) and statistical significance was achieved with a P RESULTS A total of 469 patients were identified with a median follow up of 61 months. Of these, nearly 95.3% were followed for at least 2 years. The median age was 70 (range: years) and the median PSA was 7.7 ng/ml at diagnosis (range: ng/ml). The median Gleason score was 7 (range: 4 10). In regards to androgen deprivation, this was generally limited to those with intermediate or high risk disease. However, five patients in the low risk group (4%) did receive androgen deprivation. For the rest of the patients, 31% of the intermediate risk disease patients and 89% of the high risk patients received androgen deprivation. Further characteristics of the patients are available in Table 1. Biochemical control The 5 year biochemical failure free survival (bffs) for the entire group of patients was 85.1%. When broken down by NCCN risk group, the 5 year bffs was 90.3% for low risk, 86.9% for intermediate risk and 77.3% for high risk (P = 0.001) [Figure 1]. On univariate and multivariate analysis, only increasing Gleason score and a PSA >20 ng/ml were associated with an increased likelihood of biochemical failure. On multivariate analysis, the addition of androgen deprivation was associated with a decreased likelihood of biochemical failure[table 2]. Figure 1: This figure depicts the biochemical control rates for patients treated with dose escalated radiation therapy by National Cancer Care Network subgroup. As can be seen, there are significant differences in biochemical control between these groups (P = 0.001) 952 Journal of Cancer Research and Therapeutics - October-December Volume 10 - Issue 4

3 Table 1: Baseline patient characteristics Characteristic Number of patients Percentage Race African American Hispanic Caucasian AJCC tumor classification T1a T1c T2a T2b T2c T3a T3b T PSA 0 10 ng/ml ng/ml >20 ng/ml Gleason score NCCN risk group Low Intermediate High Technique 3DCRT IMRT RT dose Androgen deprivation No Yes Radiation fields Prostate Prostate/SV True pelvis Whole pelvis AJCC=American Joint Committee on Cancer, PSA=Prostate specific antigen, NCCN=National Cancer Care Network, RT=Radiation therapy, 3DCRT=3D conformal radiation therapy, IMRT=Intensity modulated radiation therapy, SV=Seminal vesicles Distant control A total of 15 patients (3.2%) developed metastatic disease. Of these patients, 11 had high risk disease, three had intermediate risk disease and one had low risk disease. The median time until development of distant metastases was 32 months after completion of radiation (range: months). The 5 year distant metastatic free survival (DMFS) for the whole group was 97.6%. The 5 year DMFS by risk group was 99.1% for low risk, 98.8% for intermediate risk and 94.5% for high risk (P < 0.001) [Figure 2]. Overall survival (OS) and prostate cancer specific survival (PCSS) At total of 92 (19.6%) patients died, with a 5 year OS of 84.9%. The causes of death varied, with the most common being other Figure 2: This figure depicts the distant control rates for patients treated with dose escalated radiation therapy. Patients who were identified as having National Cancer Care Network high risk disease were at higher likelihood of develop distant metastatic disease (P < 0.001) malignancies or heart disease. The precise cause of death was unknown (obtained from social security records) in 33 patients. There were 8 prostate cancer deaths and the 5 year PCSS was 98.4%. Six of the patients who died from prostate cancer had high risk disease and two had intermediate risk disease. There were no prostate cancer related deaths in patients with low risk disease. Toxicity The incidence of acute and late GU and GI toxicities are shown in Tables 3 and 4. Most patients had grade 2 or lower urinary toxicity. An additional 8 patients (1.7%) had grade 3 toxicity that primarily consisted of acute urinary retention and/or the development of urethral stricture. In 5 of these patients, they had pre existing conditions such as a prior history of retention or transurethral resection of prostatic tissue that may have contributed to their symptoms. In terms of late toxicity, there were 23 patients (4.9%) who had grade 3 toxicity. This generally included urinary retention or stricture requiring dilation or hematuria requiring fulguration and/or transfusions. There were two patients who we identified as having grade 5 toxicity. One was treated in 2004 to a dose of 7560 cgy using 3DCRT technique. At the time of his treatment he was 77 years old and was identified as having T2b, Gleason 7 (3 + 4), PSA 11.8 ng/ ml prostate cancer. The whole pelvis was treated to a dose of 4500 cgy, followed by two successive cone downs to the final prescription dose. Approximately 14 months after his radiation treatments he started reporting persistent hematuria. He subsequently developed a bladder perforation at the dome of the bladder that required an emergent cystoprostatectomy. He ultimately died about 2.5 months later in the post operative period from an acute myocardial infarction. It was not clear from the medical records that the perforation was related to radiation related damage but it was decided to identify this side effect as such. The second patient was 85 years old at the time of his treatment. He was diagnosed with T1c, Gleason 7 (4 + 3), Journal of Cancer Research and Therapeutics - October-December Volume 10 - Issue 4 953

4 Table 2: Univariate and multivariate analysis of bffs Variable Univariate analysis Multivariate analysis HR (95% CI) P value HR (95% CI) P value Age (continuous) 1.03 ( ) ( ) 0.19 Race White 1 1 African American 1.02 ( ) ( ) 0.87 Hispanic 0.59 ( ) ( ) 0.35 Year of treatment (continuous) 1.19 ( ) ( ) 0.21 T classification (continuous) 1.20 ( ) ( ) 0.33 Prostate specific antigen 10 ng/ml ng/ml 1.50 ( ) ( ) 0.12 >20 ng/ml 2.43 ( ) ( ) Gleason score ( ) ( ) ( ) ( ) ( ) < ( ) Androgen deprivation No months 0.38 ( ) ( ) >12 months 1.38 ( ) ( ) 0.03 Radiation technique 3D conformal IMRT 1.71 ( ) ( ) Radiation fields Prostate 1 1 Prostate/SV 2.28 ( ) ( ) 0.35 True pelvis 1.76 ( ) ( ) 0.46 Whole pelvis 3.02 ( ) ( ) 0.52 IMRT=Intensity modulated radiation therapy, SV=Seminal vesicles, bffs=biochemical failure free survival, CI=Confidence interval, HR=Hazard ratio Table 3: Acute and late genitourinary toxicity, N=469 Grade No. of patients (%) Acute Late (36.2) 368 (78.5) (22.8) 3 (0.6) (39.2) 73 (15.6) 3 8 (1.7) 23 (4.9) 4 0 (0) 0 (0) 5 0 (0) 2 (0.4) Table 4: Acute and late gastrointestinal toxicity, N=469 Grade No. of patients (%) Acute Late (61.2) 408 (87) 1 40 (8.5) 16 (3.4) (30.3) 13 (2.8) 3 0 (0) 32 (6.8) PSA 13.4 ng/ml prostate cancer and received a dose of 7920 cgy to the prostate via IMRT. He ultimately died 29 months after his radiation treatments from urosepsis and persistent hematuria. Approximately 1 year after he completed his treatments, he was diagnosed with multiple myeloma and myelodysplastic syndrome. Subsequent to that diagnosis, he was treated several times for both hematuria as well as epistacis, but his treatment course was complicated by a persistent coagulopathy. In fact, his platelet count was 29 at the time of his expiration. In terms of acute GI toxicity, all patients had grade 2 or lower side effects. In terms of late GI toxicity, 32 patients (6.8%) had grade 3 toxicity that consisted of rectal bleeding requiring argon plasma coagulation and/or blood transfusions. The remaining patients all had grade 2 or less toxicity. The late rectal toxicity was further analyzed by year of treatment, as we hypothesized that with the use of IMRT the rectal toxicity will have improved over time. In fact, we found that with the advent of IMRT our rectal toxicity initially went up and only improved after the advent of our IGRT use. The grade 3 rectal toxicity from years 2003 to 2006 (representing 3DCRT) was 5.4%, years (IMRT) was 9.7% and year 2010 (IMRT with image guidance) was 2.7%. CONCLUSION In this study of well followed veterans, the 5 year biochemical control rates with dose escalated radiation are comparable to previously published data. [5 9] Table 5 illustrates previously published single institution series and randomized controlled trials showing the benefit of dose escalation in terms of biochemical control. This series shows excellent biochemical control across all risk groups, with 5 year biochemical control rates of 90.3%, 86.9% and 77.3% for low, intermediate and high risk disease. Radiation therapy oncology group (RTOG) conducted a phase I/II dose escalation trial and registered patients on five sequential dose levels: 68.4 Gy, 73.8 Gy, 79.2 Gy (levels I III) and 74 Gy and 78 Gy (levels IV V). With a median follow up time of years, 5 year disease free survivals were 67 80%, (low risk); 69 70%, (intermediate risk); and 67 68%, (high risk) for radiation doses > 74 Gy. [14] Despite the high overall survival and cause specific survival rates seen in 954 Journal of Cancer Research and Therapeutics - October-December Volume 10 - Issue 4

5 Table 5: Outcomes of previous dose escalation trials Study Number of patients Trial design Median follow up Risk group Results Kuban et al. [4] 301 RCT 8.7 years LR, IR, HR 8 years FFF favored 78 Gy compared to 70 Gy: 78% versus 59% (P=0.04) Dearnaley et al. [7] 843 RCT 5.2 years LR, IR, HR 5 years bpfs favored 74 Gy compared to 64 Gy: 71% versus 60%, with a hazard ratio for clinical progression free survival of 0.69 (P=0.064) Beckendorf et al. [8] 306 RCT 5.1 years LR, HR, HR 5 years brr was higher in the 70 Gy arm compared to 80 Gy: 39% s 28% (P=0.036) ASTRO definition; Phoenix definition: 5 years brr was 32% and 23.5%, respectively (P=0.09) Al Mamgani et al. [6] 669 RCT 5.8 years LR, HR, HR 7 years FFF was significantly better in the 78 Gy than in the 68 Gy arm: 54% versus 47%, respectively, P=0.04; using the phoenix definition was also better in the 78 Gy arm than in the 68 Gy arm 7 years FFF rate: 56% versus 45%, respectively, (P=0.03) Zietman 393 RCT 8.9 years LR, HR, HR The 10 years American Society for Therapeutic Radiology and et al. [5] Oncology BF rates were 32.4% for conventional dose and 16.7% for high dose radiation therapy (P<0.0001) Alicikus 170 Retro 8.25 years LR, IR, HR 10 year actuarial PSA RFS was 81% (95% CI, 64 97%), 78% (95% CI, et al. [10] 66 91%) and 62% (95% CI, 44 80%) for the LR, IR and HR groups, respectively (P=0.013) Spratt et al. [11] 1002 Retro 5.5 years Very LR, LR, IR, HR For LR, IR, HR groups, 7 years brfs outcomes were 98.8%, 85.6% and 67.9%, respectively (P<0.001) Michalski et al. [13] 1055 Phase I/II years LR, IR, HR 5 years DFS were 67 80%, (LR); 69 70%, (IR); and 67 68%, (HR) for radiation doses >74 Gy RCT=Randomized controlled trial, Retro=Retrospective, LR=Low risk, IR=Intermediate risk, HR=High risk, brr=biochemical relapse rate, PSA RFS=Prostate specific antigen relapse free survival, brfs=biochemical relapse free survival, CI=Confidence interval, BF=Biochemical failure this study, the 10 year biochemical control rates are lower than expected and lower compared to other series, including this study. This indicates the need for continued long term follow up for these patients as there can be late recurrences. RTOG 9406 has longer follow up time compared to other previously published studies evaluating dose escalation and it is suspected that with longer follow up, a decrease in biochemical control could be expected with the detection of late recurrences. A recently published study suggests that at least 15 years of follow up is necessary to fully evaluate the efficacy of radiation therapy. [15] In terms of distant control, the patients in this study had a 5 year DMFS of 97.6%. The 5 year DMFS by risk group was 99.1% for low risk, 98.8% for intermediate risk and 94.5% for high risk. These results in terms of distant control are comparable to other studies. Using 86.4 Gy, Spratt et al. [12] in their study showed 7 year actuarial DMFS rates of 99.4%, 94.1% and 82.0% for low, intermediate and high risk groups. A previous report from Memorial Sloan Kettering evaluating 81 Gy had a 10 year DMFS rate for all patients of 95%. [11] Dose escalation leads to decreased biochemical failure and a reduction in biochemical failure, which is related to a decrease in distant metastases. [16] Eade et al. [9] showed that for every increase in 1 Gy delivered an 8% reduction in the risk of distant metastases was seen. In terms of OS the results from this study are also comparable to previously published data. In this study the 5 year OS was 84.8% and the 5 year rate of PCSS was 98.5%. A study at Fox Chase Cancer Center was able to show that higher radiation doses translated into a survival advantage with overall mortality rates at 10 years, of 49%, 37%, 31% and 26% for the <70 Gy, Gy, Gy and 80 Gy dose groups, respectively (P = ). [10] The majority of patients in this series had Grade 1 2 acute GU toxicity and 78.5% had Grade 0 late GU toxicity. For the 1.7% of patients who experienced Grade 3 GU toxicity, 5 out of 8 patients had pre existing conditions that likely contributed to their increased urinary symptoms. Prior transurethral resection of the prostate and significant pre treatment urinary symptoms have been previously shown to predict for increased urinary morbidity. [16] Grade 2 3 late GI toxicity occurred in 9.6% of patients in this series which, included patients treated with both 3DCRT and IMRT. Zelefsky et al. in their study reported outcomes for 772 patients treated exclusively with IMRT and showed a 4% 3 year actuarial likelihood of late Grade 2 or higher rectal toxicity. [17] In our study, we found that, in fact, our toxicity rate went up with the advent of IMRT use and has only started improving since the initiation of IGRT as well. This indicates the importance of image guidance in our patients. This also emphasizes the perils of using new technology, as despite our strict adherence to all recommended dose constraints we found worsening rectal toxicity. A recently published study from Australia evaluated late toxicity and biochemical control in patients with prostate cancer treated with and without dose escalated fiducial marker image guided radiotherapy. A retrospective comparison of patients treated without implanted fiducial marker dose escalated image guided radiation versus those treated with image guidance had a hazard ratio for moderate to severe late GI toxicity of 3.52 (95% confidence interval: ). [18] There was no difference with regards to GU toxicity. This study supports our findings that image guidance leads to a reduced incidence of moderate to severe late GI toxicity. A study done by Zelefsky et al. [19] recently reported on toxicity comparing patients treated with 86.4 Gy using image guidance to a similar cohort treated to the same dose with IMRT without image guidance and found a significant reduction in late urinary toxicity in Journal of Cancer Research and Therapeutics - October-December Volume 10 - Issue 4 955

6 those treated with image guidance. In addition, a significant improvement in biochemical control at 3 years was observed in high risk patients treated with image guidance (97% versus 77.7%, P = 0.05). [19] These studies support our findings that image guidance leads to a decreased likelihood of late toxicity. The interaction of hormone use and toxicity has also been evaluated in previous studies. This study did not show a difference in terms of toxicity rates and the use of androgen suppression therapy. This finding in concordance with a study by Zelefsky et al. [20] that showed that hormone usage did not have an apparent effect on late toxicity. A more recent report by Alicikus et al. [11] showed that hormone usage was not associated with developing late grade 2 or greater GU toxicity. In addition Jani and Gratzie [21] reviewed the records of 445 patient treated at the University of Chicago and found that hormonal therapy did not predict for late GI or GU toxicity. Limitations to this study are its retrospective nature. In addition, patients were treated with different modalities and the use and duration of androgen suppression was not consistent among all patients, making comparisons difficult. However, despite the limitations, this series shows that patients undergoing dose escalation radiation therapy are experiencing biochemical control rates that are at least equivalent to previous dose escalation reports across all risk groups. This provides evidence that the standard of care can be delivered to patients at any radiation therapy center and does not necessarily require treatment in medical institutions that are considered as highly specialized only in prostate cancer. With the expected further increase in prostate cancer diagnosis, particularly in Asia, these supportive data may take on more importance in the future. Continued follow up is needed to determine the durability of these biochemical control rates beyond 5 years. REFERENCES 1. 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Radiation therapy for clinically localized prostate cancer: Long-term results of 469 patients from a single institution in the era of dose escalation. J Can Res Ther 2014;10: Source of Support: Nil, Conflict of Interest: None declared. 956 Journal of Cancer Research and Therapeutics - October-December Volume 10 - Issue 4