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Hypofractionated Radiation Therapy (66 Gy in 22 Fractions at 3 Gy per Fraction) for Favorable-Risk Prostate Cancer: Long-term Outcomes
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Genitourinary Cancer
Hypofractionated Radiation Therapy (66 Gy in 22 Fractions at 3 Gy per Fraction) for Favorable-Risk Prostate Cancer: Long-term Outcomes Nita Patel, MD, Sergio Faria, MD, PhD, Fabio Cury, MD, Marc David, MD, Marie Duclos, MD, George Shenouda, MD, PhD, Russell Ruo, PhD, and Luis Souhami, MD Department of Radiation Oncology, McGill University Health Centre, Montreal, Quebec, Canada Received Oct 25, 2012, and in revised form Feb 3, 2013. Accepted for publication Feb 5, 2013
Summary We report updated results from a cohort of low- and intermediate-risk prostate cancer patients who received high-dose hypofractionated RT using 3-dimensional conformal radiation therapy. At a median follow-up of 90 months, biochemical-free survival rates at 5 and 8 years were 97% and 92%, respectively, with moderate toxicity. These results support the concept that high-dose hypofractionated RT may be an alternative treatment option for this cohort of patients, but the results cannot be extrapolated to the IMRT technique.
Purpose: To report long-term outcomes of low- and intermediate-risk prostate cancer patients treated with high-dose hypofractionated radiation therapy (HypoRT). Methods and Materials: Patients with low- and intermediate-risk prostate cancer were treated using 3-dimensional conformal radiation therapy to a dose of 66 Gy in 22 daily fractions of 3 Gy without hormonal therapy. A uniform 7-mm margin was created around the prostate for the planning target volume, and treatment was prescribed to the isocenter. Treatment was delivered using daily ultrasound image-guided radiation therapy. Common Terminology Criteria for Adverse Events, version 3.0, was used to prospectively score toxicity. Biochemical failure was defined as the nadir prostate-specific antigen level plus 2 ng/mL. Results: A total of 129 patients were treated between November 2002 and December 2005. With a median follow-up of 90 months, the 5- and 8-year actuarial biochemical control rates were 97% and 92%, respectively. The 5- and 8-year actuarial overall survival rates were 92% and 88%, respectively. Only 1 patient died from prostate cancer at 92 months after treatment, giving an 8-year actuarial cancer-specific survival of 98%. Radiation therapy was well tolerated, with 57% of patients not experiencing any acute gastrointestinal (GI) or genitourinary (GU) toxicity. For late toxicity, the worst grade 2 rate for GI and GU toxicity was 27% and 33%, respectively. There was no grade >3 toxicity. At last follow-up, the rate of grade 2 for both GI and GU toxicity was only 1.5%. Conclusions: Hypofractionation with 66 Gy in 22 fractions prescribed to the isocenter using 3dimensional conformal radiation therapy produces excellent biochemical control rates, with moderate toxicity. However, this regimen cannot be extrapolated to the intensity modulated radiation therapy technique. Ó 2013 Elsevier Inc.
Reprint requests to: Sergio L. Faria, MD, McGill University Health Centre, Department of Radiation Oncology, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada. Tel: (514) 934-8040; E-mail: sergio.faria@ muhc.mcgill.ca
Int J Radiation Oncol Biol Phys, Vol. 86, No. 3, pp. 534e539, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.02.010
Presented in part as a poster at the American Society of Clinical Oncology: 2013 Genitourinary Cancers Symposium, Orlando, FL. February, 2013. N.P. is a genitourinary Astra Zeneca fellow. Conflict of interest: none.
Volume 86 Number 3 2013
Introduction Several randomized trials have demonstrated that dose escalation of external beam radiation therapy with standard fractionation improves biochemical control in patients with localized prostate cancer (1-3). However, this is at the expense of prolonging overall treatment time, which adds a burden on limited resources as well as inconveniencing the patient. Moreover, radiobiologic analyses suggesting that the a/b ratio for prostate cancer can be as low as 13 Gy (4) led several investigators to develop hypofractionated radiation therapy (HypoRT) regimens (5-7). In HypoRT, fewer, larger daily fractions using an equivalent biologically effective dose (BED) to conventionally fractionated radiation therapy has the potential to improve the therapeutic ratio, with the additional benefit of shortening the overall treatment time. We previously reported preliminary results of patients with favorable-risk prostate cancer treated with HypoRT at our center (8). In this present article we present the long-term outcomes for those patients.
Methods and Materials We began a program of hypofractionated 3-dimensional conformal radiation therapy (3D-CRT) in November 2002, offered as an alternative treatment for patients with favorable-risk prostate cancer as previously reported in detail (8). In summary, eligible patients had histologically proven prostate adenocarcinoma, did not receive hormonal therapy (before, during, or after RT), and were at low or intermediate risk, defined as T1-2c, prostatespecific antigen (PSA) 20 ng/mL, and Gleason score 7 (9).
Treatment Each patient was treated with a 3D-CRT plan consisting of 5 18MV photon beams delivering 66 Gy in 22 daily fractions of 3 Gy prescribed to the isocenter, 5 treatments per week. The coverage of the planning target volume (PTV) was between 95% and 107%, as per the International Commission for Radiation Units and Measurements Report 50. Patients underwent CT scan simulation in the supine treatment position with a comfortably full bladder. A urethrogram was routinely performed to help define the prostatic apex. The clinical target volume (CTV) was the prostate gland only. The PTV consisted of the CTV plus a uniform 7-mm 3D margin. The seminal vesicles, bladder, femoral heads, penile bulb, and the whole rectum (from anus to the sigmoid) were contoured in all patients. There were no defined normal tissue constraints for the organs at risk. Daily pretreatment localization of the prostate gland was performed using ultrasound (BAT system; Nomos Corporation, Sewickley, PA) as described previously (10).
Toxicity and follow-up Patients were seen in follow-up every 4-6 months for the first 5 years and yearly thereafter. A PSA blood test and physical examination were performed at each follow-up visit. During each visit, gastrointestinal (GI) and genitourinary (GU) toxicity were prospectively assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3 (11). Late toxicity was defined as any toxicity documented 90 days after the last radiation treatment. Patients who developed rectal bleeding that required 1 or multiple Argon plasma
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coagulation through colonoscopy were considered as having grade 3 rectal toxicity. The worst-grade toxicity documented at any time was considered as the final late toxicity even if the patient had it only once during follow-up or the complication resolved later on.
Statistics Biochemical failure was defined as nadir PSA level þ 2 ng/mL (12). The data collected are presented by descriptive statistics. Overall, cancer-specific and biochemical relapse-free survival (biochemical no evidence of disease [bNED]) were calculated by the Kaplan-Meier actuarial method (13). Statistical analyses were performed using GraphPad Prism, version 5.0 (GraphPad Software, San Diego, CA). This review was performed after approval by our institute’s review board.
Results Between November 2002 and December 2005, 129 patients were treated with our HypoRT regime and assessed for this analysis. Baseline characteristics of all patients are shown in Table 1. The median follow-up was 90 months (range, 10-116 months). All patients completed treatment without interruption in a median time of 30 days (range, 28-37 days), except for 1 patient who developed urinary retention at 60 Gy requiring catheterization and did not receive the last 2 radiation therapy fractions. The majority of patients tolerated the treatment well, with 57% of patients not experiencing any acute GI or GU toxicity. Up to 90 days after RT, 83% of patients had no GI symptoms, 13% had grade 1, 4% grade 2, and no patient had grade 3 or greater GI toxicity. Concerning acute GU toxicity, 66% had grade 0, 25% grade 1, 8% grade 2, and 1% had grade 3. The worst late toxicity score and the toxicity assessed at the last follow-up visit are summarized in Table 2. No patient ever experienced grade 4 or 5 GI or GU toxicity. As in our previous study, we have grouped grade 2 and grade 3 rectal toxicity together (grade 2). This is because the differences between grade 2 and 3 are not straightforward in the CTCAE, version 3. When the worst toxicity grade is considered during the Table 1 Patient characteristics N Age (y) Clinical stage T1a T1b T1c T2a T2b T2c PSA (ng/mL) Gleason score 6 7 Risk category Low Intermediate Abbreviation: PSA Z prostate-specific antigen. Values are number (percentage) or median (range).
129 70 (51-79) 2 2 73 38 10 4 7
(1.5) (1.5) (56.5) (29.5) (8) (3) (1.62-17.7)
111 (86) 18 (14) 93 (72) 36 (28)
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Table 2
Number (percentage) vs grade of gastrointestinal and genitourinary late toxicity Gastrointestinal toxicity
Genitourinary toxicity
Grade
0
1
2/3
0
1
2
3
Worst grade Last follow-up
50 (39) 119 (92)
44 (34) 8 (6)
35 (27) 2 (1.5)
24 (18.5) 106 (82)
63 (49) 21 (16)
36 (28) 1 (0.8)
6 (4.5) 1 (0.8)
entire period of follow-up, the rate of grade 2 toxicity was 27%. In all but 2 of these patients, the toxicity manifested itself within the first 2 years after irradiation. This is illustrated in Figure 1. Most of that toxicity resolved, and at the last follow-up visit only 2 patients (1.5%) had residual grade 2 GI toxicity. Of the 35 patients with grade 2 GI toxicity, 32 had rectal bleeding. Of these, 23 patients underwent 1 or more hemostatic thermal therapy, and 2 patients required blood transfusion. In 2 patients the bleeding stopped after discontinuation of anticoagulation medication. The 3 patients that did not have rectal bleeding were classified as having grade 2 GI toxicity by virtue of proctitis and/ or diarrhea. At last follow-up, 92% of patients did not have any late GI toxicity. The rate of the worst late GU toxicity was the following: 4.5% had grade 3, 28% grade 2, 49% grade 1, and 18.5% had no late GU toxicity. At last follow-up, the majority of toxicity had resolved, with 82% of patients having no GU toxicity, 16% having grade 1, 0.8% grade 2, and 0.8% grade 3 residual GU toxicity (Table 2). Eight out of the 129 (6%) patients developed biochemical failure, with a median time to failure of 63.5 months (range, 5-90 months). Of these 8 cases, 4 were found to have clinical failure at 11, 18, 49, and 104 months on imaging (bone scan and/or CT scan). All 4 of these patients had bone metastases, and 1 patient also had suspicious pelvic lymph node metastasis. The other 4 patients did not have any evidence of clinical failure on imaging. None of the 8 patients had developed clinical prostate failure according to digital rectal examination or pelvic CT scans. Prostate biopsies were not performed on any of these patients with biochemical failure. The 5- and 8-year actuarial biochemical control rates are 97% and 92% respectively, as shown in Figure 2. At the time of this analysis (August 2012), 17 patients had died, with a median time to death of 56 months (range, 10-107 months). Only 1 of these patients died from prostate cancer at 92 months after treatment, with the remaining 16 patients dying from other causes. One other patient, who had documented biochemical failure at 83 months after treatment, was diagnosed with esophageal cancer at 95 months and died from this disease at 107 months. There is clear documentation that the biochemical failure was well controlled at the time of death, therefore we are not classifying this as a prostate cancer death. The 5- and 8-year actuarial overall survival rates are 92% and 88%, respectively. The 5 and 8-year actuarial cancer specific survival rates are 100% and 98%, respectively, as shown in Figure 3.
patients that must be emphasized: (1) they were treated with radiation alone without any hormonal therapy; (2) the dose is one of the highest BED delivered with a HypoRT regime; (3) patients were treated with 3D-CRT planning and not intensity modulated radiation therapy (IMRT); (4) the dose was prescribed at the isocenter and not to the PTV; (5) the PTV margin (7 mm) was uniform in all directions, including the rectal margin; and (6) there were no predefined limiting dosimetric constraints for organs at risk.
Acute toxicity The treatment was well tolerated, and this satisfactory tolerance is reflected by the almost lack of interruption during radiation therapy, which was generally delivered within 30 consecutive days. Fifty-seven percent of patients did not experience any acute GI or GU toxicity, which is similar to other series (5, 7, 14).
Late toxicity One major concern with any hypofractionation regimen, particularly using a high BED, is potential late effects. With this in mind, toxicity was prospectively scored in every patient at each followup visit. Scores change during follow-up, and we rapidly learned how difficult it is to accurately report radiation-induced late toxicity. This topic has previously been discussed extensively (15). For instance, according to the Radiation Therapy Oncology Group (RTOG) scoring system, late grade 3 GI toxicity is when patients have “obstruction/bleeding requiring surgery.” None of our patients had this situation. The grading score to be given when an endoscopic intervention is performed, such as rectal cauterization through colonoscopy, which some of our patients received, is not
Discussion We report the long-term results of 129 patients with low/ intermediate-risk prostate cancer who underwent HypoRT to a dose of 66 Gy in 22 fractions of 3 Gy. To our knowledge, this is the longest reported follow-up in patients who have undergone high-dose HypoRT. There are characteristics of this cohort of
Fig. 1. time.
Incidence of grade 2 long-term rectal toxicity over
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Table 3 Comparison of incidence of grade 2/3 rectal toxicity among different studies First author (dose) (reference)
BED3
Grade 2/3 rectal toxicity (%)
McGill (present study) Kuban (escalated dose) (1) Martin (hypofractionation) (5) Zelefsky (escalated dose) (19) Dearnaley (escalated dose) (18) Zietman (escalated dose) (20) Kupelian (hypofractionation) (14) Pollack (hypofractionation) (21)
132 130 120 >121 123 126 128 133
27 26 6 17 33 18 6 6
Abbreviation: BED3 Z biologically equivalent dose using
a/b Z 3 Gy. Fig. 2. Biochemical relapse-free (biochemical no evidence of disease) rate, with the associated numbers of patients at risk. clear under the RTOG scoring system, and because of that different authors modified it according to different criteria, making comparisons difficult (16, 17). Our long-term results demonstrate that this HypoRT regimen was in general well tolerated. Table 3 summarizes the incidence of late rectal toxicity in several studies that used either HypoRT or standard fractionation with similar or a slightly lower BED (1, 5, 14, 18-21). It can be seen that the overall incidence of late GI toxicity is not very different, except for a few studies. Kupelian et al (14) reported a rate of 6% grade 2 late GI toxicity using 70 Gy in 28 fractions of 2.5 Gy with a 4-mm rectal margin. Martin et al (5) also reported a low incidence of 6.3% of late grade 2 GI toxicity using 60 Gy in 20 fractions of 3 Gy. Pollack et al (21) reported 5.9% late grade 2 GI toxicity using 70.2 Gy in 26 fractions of 2.7 Gy. These significant lower incidences of late toxicity may be due to the use of IMRT and/or the smaller posterior rectal margin (4 mm) that was used in some cases, or better imageguided radiation therapy (IGRT). Kupelian and Martin also reported the rate of late toxicity seen at last follow-up as 5% and 4%, respectively (5, 7), which is not very different from their rate of worst late toxicity of 6% but interestingly is higher than the rate of late toxicity at last follow-up found in our patients of only 1.5%.
Fig. 3.
Overall and cancer-specific survival rates.
The experience of the Princess Margaret Hospital (PMH) with hypofractionation for prostate cancer is worth noting. They also started their HypoRT in prostate cancer approximately 10 years ago and initially used a dose of 60 Gy in 20 fractions of 3 Gy delivered with IMRT planning, with good results (5). They used a larger PTV margin of 10 mm (reduced rectal margin of 7 mm) and had rigid constraints for organs at risk. Because of the acceptable rate of acute/late toxicity seen in this initial cohort, they treated a further 29 patients with a higher dose of 66 Gy in 22 fractions of 3 Gy (22). However, they found a significant rate of severe late GI toxicity in this cohort, with 6% of patients having RTOG grade 3 or 4 GI toxicity and 38% of patients having grade 2 GI toxicity. Considering that none of the patients in our study had RTOG grade 3 or 4 late toxicity, it is clear that despite the same nominal dose of 66 Gy in 22 fractions the 2 different techniques resulted in different outcomes. Intensity modulated radiation therapy gives better conformity, but prescribing with IMRT is more complex than with 3D-CRT, particularly because of potential hot spots in organs at risk. For instance, with our 3DCRT regimen the mean dose to the CTV was typically 66 Gy, with small hotspots concentrated in the center of the CTV. However, with the PMH IMRT technique the median dose to the CTV was >66 Gy. Moreover, with IMRT larger volumes usually receive doses between 66 Gy and 69 Gy, often at the periphery of the PTV, where the bladder and rectum are located. Thus, it is reasonable to speculate that if we are at the limit of the tolerance dose of the rectum, any small increment of total dose, even in a small volume of normal rectum, may result in more severe late toxicity. However, we cannot rule out the possibility that our high-dose regimen itself caused the late toxicity. Having a homogeneous cohort of patients treated without any dosimetric exclusion criteria and who were prospectively assessed for late toxicity allowed us to search for optimal doseevolume constraints to reduce rectal toxicity after HypoRT for prostate cancer. Despite all efforts, we could not find them, suggesting that for patients with favorable prostate cancer treated with IGRT and a small PTV margin, either there is a very small volume of normal tissue receiving the full dose, making any constraints less important, and/or there must be other unknown nondosimetric risk factors for late toxicity (23). The incidence of worst-grade late GU toxicity was a little higher than for GI toxicity, which is in keeping with other studies (5, 14). Only 18.5% of our patients did not experience any late GU toxicity, with the majority (49%) experiencing grade 1 toxicity. As with late GI toxicity, most of these symptoms resolved over time,
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usually within 6-12 months, with 82% of patients having no GU symptoms at the last follow-up visit.
Cancer control The freedom from biochemical failure rate (bNED) at 5 and 8 years with a median follow-up of 90 months is encouraging at 97% and 92%, respectively. Only 1 patient died from prostate cancer at 92 months. These results compare favorably to other experiences (1, 3, 6, 7, 20, 24). Table 4 compares the bNED rates of our study with other HypoRT and conventionally fractionated studies using escalated doses. Two institutions, which compared escalated with standard radiation therapy dose using conventional fractionation, have published long-term outcomes (1, 3). Zietman et al reported a 5-year bNED rate of 91% and a 10-year bNED rate of 84% (3, 20). Kuban et al reported 5-, 8-, and 10-year bNED rates of 85%, 78%, and 73%, respectively (1).
Randomized controlled trials There are several ongoing or completed phase 3 randomized trials comparing standard versus hypofractionated radiation therapy using escalated doses. The Canadian PROstate Fractionated Irradiation Trial (PROFIT) explored the PMH regime of 60 Gy in 20 fractions (5) and compared it with 78 Gy in 39 fractions in intermediate-risk patients. Up to 6 months of hormonal treatment before radiation therapy was allowed. The RTOG 0415 trial assessed HypoRT in low-risk patients without hormonal therapy. It tested Kupelian’s (7) regime of 70 Gy in 28 fractions versus 73.8 Gy in 41 fractions. Both trials are completed, but neither has reported preliminary results as yet. The British CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer) trial recently reported data on toxicity but not biochemical failure (25). This trial compared the conventionally fractionated schedule of 74 Gy in 37 fractions with 2 hypofractionated regimes (60 Gy/20 fractions and 57 Gy/19 fractions) in patients with low-, intermediate-, and high-risk disease. Shortcourse hormonal therapy for 3-6 months was given to the majority of patients. Using the RTOG/European Organization for Research and Treatment of Cancer toxicity score, they found grade 2 GI toxicity at 2 years in the conventional versus 60-Gy group versus 57-Gy group was 4.3%, 3.6%, and 1.4%, respectively, and grade 2 GU toxicity was 2.2%, 2.2%, and 0, respectively. An Italian trial by Arcangeli et al (24) compared 62 Gy in 20 fractions, but with 4 fractions per week, versus 80 Gy in 40 fractions, including only patients with high-risk disease, without pelvic node irradiation. All patients received hormonal Table 4 Long-term freedom from biochemical failure (bNED) according to different studies using escalated doses bNED (%) First author (dose) (reference)
5-y
8-y
10-y
McGill (present study) Kupelian (hypofractionation) (7) Livsey (hypofractionation) (6) Arcangeli (hypofractionation) (24) Zietman (escalated dose) (3, 20) Kuban (escalated dose) (1)
97 88 82 80 91 85
92 78
84 73
Abbreviation: bNED Z biochemical no evidence of disease.
therapy for a total of 9 months, and radiation therapy was delivered using 3D-CRT. With a median follow-up of 70 months, the outcomes are similar in both groups, with a 5-year bNED of 80%. Pollack et al (21) updated the results of their randomized trial comparing 70.2 Gy in 2.7 Gy per fraction with the standard arm of 76 Gy in 2 Gy per fraction using IMRT. One-third of the 307 patients in this trial had high-risk disease, with 45% of patients receiving hormonal therapy. At a median follow-up of 60 months, there were no significant differences in the outcomes, with a bNED rate of 85.6% in the conventional compared with 86.1% in the HypoRT arm and no statistically significant differences between the arms for GI and GU toxicity.
Conclusion Long-term results from our cohort of 129 patients who underwent HypoRT to a dose of 66 Gy in 22 fractions using 3D-CRT demonstrate moderate rates of late GU and GI toxicity, with an excellent biochemical-free survival rate of 92% and a cancerspecific survival rate of 98% at 8 years. However, caution should be exercised if IMRT is to be used, because our data cannot be safely extrapolated to this technique. This study supports the concept that HypoRT with a high equivalent BED may be an alternative treatment option for patients with favorable risk prostate cancer but highlights the need to use IMRT, better IGRT techniques, and tighter margins to the PTV to potentially lower the risk of toxicity. However, results from completed randomized phase 3 trials will be necessary to allow us to define the a/b ratio of prostate cancer more accurately and confirm whether hypofractionation is a safe method of delivering dose-escalated curative radiation therapy.
References 1. 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. 2. Peeters ST, Heemsbergen WD, Koper PC, et al. Dose-response in radiotherapy for localized prostate cancer: Results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006;24:1990-1996. 3. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: Long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol 2010;28:1106-1111. 4. Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021-1031. 5. Martin JM, Rosewall T, Bayley A, et al. Phase II trial of hypofractionated image-guided intensity-modulated radiotherapy for localized prostate adenocarcinoma. Int J Radiat Oncol Biol Phys 2007;69:1084-1089. 6. Livsey JE, Cowan RA, Wylie JP, et al. Hypofractionated conformal radiotherapy in carcinoma of the prostate: Five-year outcome analysis. Int J Radiat Oncol Biol Phys 2003;57:1254-1259. 7. Kupelian PA, Thakkar VV, Khuntia D, et al. Hypofractionated intensity-modulated radiotherapy (70 gy at 2.5 Gy per fraction) for localized prostate cancer: Long-term outcomes. Int J Radiat Oncol Biol Phys 2005;63:1463-1468. 8. Rene N, Faria S, Cury F, et al. Hypofractionated radiotherapy for favorable risk prostate cancer. Int J Radiat Oncol Biol Phys 2010;77: 805-810.
Volume 86 Number 3 2013 9. Lukka H, Warde P, Pickles T, et al. Controversies in prostate cancer radiotherapy: Consensus development. Can J Urol 2001;8:1314-1322. 10. Poli ME, Parker W, Patrocinio H, et al. An assessment of PTV margin definitions for patients undergoing conformal 3D external beam radiation therapy for prostate cancer based on an analysis of 10,327 pretreatment daily ultrasound localizations. Int J Radiat Oncol Biol Phys 2007;67:1430-1437. 11. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at: http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Accessed July 1, 2012. 12. Roach M 3rd, Hanks G, Thames H Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965-974. 13. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-481. 14. Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;68:1424-1430. 15. Faria SL, Souhami L, Joshua B, et al. Reporting late rectal toxicity in prostate cancer patients treated with curative radiation treatment. Int J Radiat Oncol Biol Phys 2008;72:777-781. 16. Peeters ST, Heemsbergen WD, van Putten WL, et al. Acute and late complications after radiotherapy for prostate cancer: Results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005;61:1019-1034. 17. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the
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outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998; 41:491-500. Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: First results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007; 8:475-487. Zelefsky MJ, Cowen D, Fuks Z, et al. Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer 1999;85:2460-2468. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: A randomized controlled trial. JAMA 2005;294:1233-1239. Pollack A, Walker G, Buyyounouski M, et al. Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2011;81:S1. Vesprini D, Sia M, Lockwood G, et al. Role of principal component analysis in predicting toxicity in prostate cancer patients treated with hypofractionated intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:e415-e421. Faria S, Joshua B, Patrocinio H, et al. Searching for optimal dosevolume constraints to reduce rectal toxicity after hypofractionated radiotherapy for prostate cancer. Clin Oncol (R Coll Radiol) 2010;22: 810-817. Arcangeli S, Strigari L, Gomellini S, et al. Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2012;84:1172-1178. Dearnaley D, Syndikus I, Sumo G, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: Preliminary safety results from the CHHiP randomised controlled trial. Lancet Oncol 2012;13:43-54.
Radiation Oncology biology
physics
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Clinical Investigation: Genitourinary Cancer
Hypofractionated Radiation Therapy (66 Gy in 22 Fractions at 3 Gy per Fraction) for Favorable-Risk Prostate Cancer: Long-term Outcomes Nita Patel, MD, Sergio Faria, MD, PhD, Fabio Cury, MD, Marc David, MD, Marie Duclos, MD, George Shenouda, MD, PhD, Russell Ruo, PhD, and Luis Souhami, MD Department of Radiation Oncology, McGill University Health Centre, Montreal, Quebec, Canada Received Oct 25, 2012, and in revised form Feb 3, 2013. Accepted for publication Feb 5, 2013
Summary We report updated results from a cohort of low- and intermediate-risk prostate cancer patients who received high-dose hypofractionated RT using 3-dimensional conformal radiation therapy. At a median follow-up of 90 months, biochemical-free survival rates at 5 and 8 years were 97% and 92%, respectively, with moderate toxicity. These results support the concept that high-dose hypofractionated RT may be an alternative treatment option for this cohort of patients, but the results cannot be extrapolated to the IMRT technique.
Purpose: To report long-term outcomes of low- and intermediate-risk prostate cancer patients treated with high-dose hypofractionated radiation therapy (HypoRT). Methods and Materials: Patients with low- and intermediate-risk prostate cancer were treated using 3-dimensional conformal radiation therapy to a dose of 66 Gy in 22 daily fractions of 3 Gy without hormonal therapy. A uniform 7-mm margin was created around the prostate for the planning target volume, and treatment was prescribed to the isocenter. Treatment was delivered using daily ultrasound image-guided radiation therapy. Common Terminology Criteria for Adverse Events, version 3.0, was used to prospectively score toxicity. Biochemical failure was defined as the nadir prostate-specific antigen level plus 2 ng/mL. Results: A total of 129 patients were treated between November 2002 and December 2005. With a median follow-up of 90 months, the 5- and 8-year actuarial biochemical control rates were 97% and 92%, respectively. The 5- and 8-year actuarial overall survival rates were 92% and 88%, respectively. Only 1 patient died from prostate cancer at 92 months after treatment, giving an 8-year actuarial cancer-specific survival of 98%. Radiation therapy was well tolerated, with 57% of patients not experiencing any acute gastrointestinal (GI) or genitourinary (GU) toxicity. For late toxicity, the worst grade 2 rate for GI and GU toxicity was 27% and 33%, respectively. There was no grade >3 toxicity. At last follow-up, the rate of grade 2 for both GI and GU toxicity was only 1.5%. Conclusions: Hypofractionation with 66 Gy in 22 fractions prescribed to the isocenter using 3dimensional conformal radiation therapy produces excellent biochemical control rates, with moderate toxicity. However, this regimen cannot be extrapolated to the intensity modulated radiation therapy technique. Ó 2013 Elsevier Inc.
Reprint requests to: Sergio L. Faria, MD, McGill University Health Centre, Department of Radiation Oncology, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada. Tel: (514) 934-8040; E-mail: sergio.faria@ muhc.mcgill.ca
Int J Radiation Oncol Biol Phys, Vol. 86, No. 3, pp. 534e539, 2013 0360-3016/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.02.010
Presented in part as a poster at the American Society of Clinical Oncology: 2013 Genitourinary Cancers Symposium, Orlando, FL. February, 2013. N.P. is a genitourinary Astra Zeneca fellow. Conflict of interest: none.
Volume 86 Number 3 2013
Introduction Several randomized trials have demonstrated that dose escalation of external beam radiation therapy with standard fractionation improves biochemical control in patients with localized prostate cancer (1-3). However, this is at the expense of prolonging overall treatment time, which adds a burden on limited resources as well as inconveniencing the patient. Moreover, radiobiologic analyses suggesting that the a/b ratio for prostate cancer can be as low as 13 Gy (4) led several investigators to develop hypofractionated radiation therapy (HypoRT) regimens (5-7). In HypoRT, fewer, larger daily fractions using an equivalent biologically effective dose (BED) to conventionally fractionated radiation therapy has the potential to improve the therapeutic ratio, with the additional benefit of shortening the overall treatment time. We previously reported preliminary results of patients with favorable-risk prostate cancer treated with HypoRT at our center (8). In this present article we present the long-term outcomes for those patients.
Methods and Materials We began a program of hypofractionated 3-dimensional conformal radiation therapy (3D-CRT) in November 2002, offered as an alternative treatment for patients with favorable-risk prostate cancer as previously reported in detail (8). In summary, eligible patients had histologically proven prostate adenocarcinoma, did not receive hormonal therapy (before, during, or after RT), and were at low or intermediate risk, defined as T1-2c, prostatespecific antigen (PSA) 20 ng/mL, and Gleason score 7 (9).
Treatment Each patient was treated with a 3D-CRT plan consisting of 5 18MV photon beams delivering 66 Gy in 22 daily fractions of 3 Gy prescribed to the isocenter, 5 treatments per week. The coverage of the planning target volume (PTV) was between 95% and 107%, as per the International Commission for Radiation Units and Measurements Report 50. Patients underwent CT scan simulation in the supine treatment position with a comfortably full bladder. A urethrogram was routinely performed to help define the prostatic apex. The clinical target volume (CTV) was the prostate gland only. The PTV consisted of the CTV plus a uniform 7-mm 3D margin. The seminal vesicles, bladder, femoral heads, penile bulb, and the whole rectum (from anus to the sigmoid) were contoured in all patients. There were no defined normal tissue constraints for the organs at risk. Daily pretreatment localization of the prostate gland was performed using ultrasound (BAT system; Nomos Corporation, Sewickley, PA) as described previously (10).
Toxicity and follow-up Patients were seen in follow-up every 4-6 months for the first 5 years and yearly thereafter. A PSA blood test and physical examination were performed at each follow-up visit. During each visit, gastrointestinal (GI) and genitourinary (GU) toxicity were prospectively assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 3 (11). Late toxicity was defined as any toxicity documented 90 days after the last radiation treatment. Patients who developed rectal bleeding that required 1 or multiple Argon plasma
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coagulation through colonoscopy were considered as having grade 3 rectal toxicity. The worst-grade toxicity documented at any time was considered as the final late toxicity even if the patient had it only once during follow-up or the complication resolved later on.
Statistics Biochemical failure was defined as nadir PSA level þ 2 ng/mL (12). The data collected are presented by descriptive statistics. Overall, cancer-specific and biochemical relapse-free survival (biochemical no evidence of disease [bNED]) were calculated by the Kaplan-Meier actuarial method (13). Statistical analyses were performed using GraphPad Prism, version 5.0 (GraphPad Software, San Diego, CA). This review was performed after approval by our institute’s review board.
Results Between November 2002 and December 2005, 129 patients were treated with our HypoRT regime and assessed for this analysis. Baseline characteristics of all patients are shown in Table 1. The median follow-up was 90 months (range, 10-116 months). All patients completed treatment without interruption in a median time of 30 days (range, 28-37 days), except for 1 patient who developed urinary retention at 60 Gy requiring catheterization and did not receive the last 2 radiation therapy fractions. The majority of patients tolerated the treatment well, with 57% of patients not experiencing any acute GI or GU toxicity. Up to 90 days after RT, 83% of patients had no GI symptoms, 13% had grade 1, 4% grade 2, and no patient had grade 3 or greater GI toxicity. Concerning acute GU toxicity, 66% had grade 0, 25% grade 1, 8% grade 2, and 1% had grade 3. The worst late toxicity score and the toxicity assessed at the last follow-up visit are summarized in Table 2. No patient ever experienced grade 4 or 5 GI or GU toxicity. As in our previous study, we have grouped grade 2 and grade 3 rectal toxicity together (grade 2). This is because the differences between grade 2 and 3 are not straightforward in the CTCAE, version 3. When the worst toxicity grade is considered during the Table 1 Patient characteristics N Age (y) Clinical stage T1a T1b T1c T2a T2b T2c PSA (ng/mL) Gleason score 6 7 Risk category Low Intermediate Abbreviation: PSA Z prostate-specific antigen. Values are number (percentage) or median (range).
129 70 (51-79) 2 2 73 38 10 4 7
(1.5) (1.5) (56.5) (29.5) (8) (3) (1.62-17.7)
111 (86) 18 (14) 93 (72) 36 (28)
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Table 2
Number (percentage) vs grade of gastrointestinal and genitourinary late toxicity Gastrointestinal toxicity
Genitourinary toxicity
Grade
0
1
2/3
0
1
2
3
Worst grade Last follow-up
50 (39) 119 (92)
44 (34) 8 (6)
35 (27) 2 (1.5)
24 (18.5) 106 (82)
63 (49) 21 (16)
36 (28) 1 (0.8)
6 (4.5) 1 (0.8)
entire period of follow-up, the rate of grade 2 toxicity was 27%. In all but 2 of these patients, the toxicity manifested itself within the first 2 years after irradiation. This is illustrated in Figure 1. Most of that toxicity resolved, and at the last follow-up visit only 2 patients (1.5%) had residual grade 2 GI toxicity. Of the 35 patients with grade 2 GI toxicity, 32 had rectal bleeding. Of these, 23 patients underwent 1 or more hemostatic thermal therapy, and 2 patients required blood transfusion. In 2 patients the bleeding stopped after discontinuation of anticoagulation medication. The 3 patients that did not have rectal bleeding were classified as having grade 2 GI toxicity by virtue of proctitis and/ or diarrhea. At last follow-up, 92% of patients did not have any late GI toxicity. The rate of the worst late GU toxicity was the following: 4.5% had grade 3, 28% grade 2, 49% grade 1, and 18.5% had no late GU toxicity. At last follow-up, the majority of toxicity had resolved, with 82% of patients having no GU toxicity, 16% having grade 1, 0.8% grade 2, and 0.8% grade 3 residual GU toxicity (Table 2). Eight out of the 129 (6%) patients developed biochemical failure, with a median time to failure of 63.5 months (range, 5-90 months). Of these 8 cases, 4 were found to have clinical failure at 11, 18, 49, and 104 months on imaging (bone scan and/or CT scan). All 4 of these patients had bone metastases, and 1 patient also had suspicious pelvic lymph node metastasis. The other 4 patients did not have any evidence of clinical failure on imaging. None of the 8 patients had developed clinical prostate failure according to digital rectal examination or pelvic CT scans. Prostate biopsies were not performed on any of these patients with biochemical failure. The 5- and 8-year actuarial biochemical control rates are 97% and 92% respectively, as shown in Figure 2. At the time of this analysis (August 2012), 17 patients had died, with a median time to death of 56 months (range, 10-107 months). Only 1 of these patients died from prostate cancer at 92 months after treatment, with the remaining 16 patients dying from other causes. One other patient, who had documented biochemical failure at 83 months after treatment, was diagnosed with esophageal cancer at 95 months and died from this disease at 107 months. There is clear documentation that the biochemical failure was well controlled at the time of death, therefore we are not classifying this as a prostate cancer death. The 5- and 8-year actuarial overall survival rates are 92% and 88%, respectively. The 5 and 8-year actuarial cancer specific survival rates are 100% and 98%, respectively, as shown in Figure 3.
patients that must be emphasized: (1) they were treated with radiation alone without any hormonal therapy; (2) the dose is one of the highest BED delivered with a HypoRT regime; (3) patients were treated with 3D-CRT planning and not intensity modulated radiation therapy (IMRT); (4) the dose was prescribed at the isocenter and not to the PTV; (5) the PTV margin (7 mm) was uniform in all directions, including the rectal margin; and (6) there were no predefined limiting dosimetric constraints for organs at risk.
Acute toxicity The treatment was well tolerated, and this satisfactory tolerance is reflected by the almost lack of interruption during radiation therapy, which was generally delivered within 30 consecutive days. Fifty-seven percent of patients did not experience any acute GI or GU toxicity, which is similar to other series (5, 7, 14).
Late toxicity One major concern with any hypofractionation regimen, particularly using a high BED, is potential late effects. With this in mind, toxicity was prospectively scored in every patient at each followup visit. Scores change during follow-up, and we rapidly learned how difficult it is to accurately report radiation-induced late toxicity. This topic has previously been discussed extensively (15). For instance, according to the Radiation Therapy Oncology Group (RTOG) scoring system, late grade 3 GI toxicity is when patients have “obstruction/bleeding requiring surgery.” None of our patients had this situation. The grading score to be given when an endoscopic intervention is performed, such as rectal cauterization through colonoscopy, which some of our patients received, is not
Discussion We report the long-term results of 129 patients with low/ intermediate-risk prostate cancer who underwent HypoRT to a dose of 66 Gy in 22 fractions of 3 Gy. To our knowledge, this is the longest reported follow-up in patients who have undergone high-dose HypoRT. There are characteristics of this cohort of
Fig. 1. time.
Incidence of grade 2 long-term rectal toxicity over
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Table 3 Comparison of incidence of grade 2/3 rectal toxicity among different studies First author (dose) (reference)
BED3
Grade 2/3 rectal toxicity (%)
McGill (present study) Kuban (escalated dose) (1) Martin (hypofractionation) (5) Zelefsky (escalated dose) (19) Dearnaley (escalated dose) (18) Zietman (escalated dose) (20) Kupelian (hypofractionation) (14) Pollack (hypofractionation) (21)
132 130 120 >121 123 126 128 133
27 26 6 17 33 18 6 6
Abbreviation: BED3 Z biologically equivalent dose using
a/b Z 3 Gy. Fig. 2. Biochemical relapse-free (biochemical no evidence of disease) rate, with the associated numbers of patients at risk. clear under the RTOG scoring system, and because of that different authors modified it according to different criteria, making comparisons difficult (16, 17). Our long-term results demonstrate that this HypoRT regimen was in general well tolerated. Table 3 summarizes the incidence of late rectal toxicity in several studies that used either HypoRT or standard fractionation with similar or a slightly lower BED (1, 5, 14, 18-21). It can be seen that the overall incidence of late GI toxicity is not very different, except for a few studies. Kupelian et al (14) reported a rate of 6% grade 2 late GI toxicity using 70 Gy in 28 fractions of 2.5 Gy with a 4-mm rectal margin. Martin et al (5) also reported a low incidence of 6.3% of late grade 2 GI toxicity using 60 Gy in 20 fractions of 3 Gy. Pollack et al (21) reported 5.9% late grade 2 GI toxicity using 70.2 Gy in 26 fractions of 2.7 Gy. These significant lower incidences of late toxicity may be due to the use of IMRT and/or the smaller posterior rectal margin (4 mm) that was used in some cases, or better imageguided radiation therapy (IGRT). Kupelian and Martin also reported the rate of late toxicity seen at last follow-up as 5% and 4%, respectively (5, 7), which is not very different from their rate of worst late toxicity of 6% but interestingly is higher than the rate of late toxicity at last follow-up found in our patients of only 1.5%.
Fig. 3.
Overall and cancer-specific survival rates.
The experience of the Princess Margaret Hospital (PMH) with hypofractionation for prostate cancer is worth noting. They also started their HypoRT in prostate cancer approximately 10 years ago and initially used a dose of 60 Gy in 20 fractions of 3 Gy delivered with IMRT planning, with good results (5). They used a larger PTV margin of 10 mm (reduced rectal margin of 7 mm) and had rigid constraints for organs at risk. Because of the acceptable rate of acute/late toxicity seen in this initial cohort, they treated a further 29 patients with a higher dose of 66 Gy in 22 fractions of 3 Gy (22). However, they found a significant rate of severe late GI toxicity in this cohort, with 6% of patients having RTOG grade 3 or 4 GI toxicity and 38% of patients having grade 2 GI toxicity. Considering that none of the patients in our study had RTOG grade 3 or 4 late toxicity, it is clear that despite the same nominal dose of 66 Gy in 22 fractions the 2 different techniques resulted in different outcomes. Intensity modulated radiation therapy gives better conformity, but prescribing with IMRT is more complex than with 3D-CRT, particularly because of potential hot spots in organs at risk. For instance, with our 3DCRT regimen the mean dose to the CTV was typically 66 Gy, with small hotspots concentrated in the center of the CTV. However, with the PMH IMRT technique the median dose to the CTV was >66 Gy. Moreover, with IMRT larger volumes usually receive doses between 66 Gy and 69 Gy, often at the periphery of the PTV, where the bladder and rectum are located. Thus, it is reasonable to speculate that if we are at the limit of the tolerance dose of the rectum, any small increment of total dose, even in a small volume of normal rectum, may result in more severe late toxicity. However, we cannot rule out the possibility that our high-dose regimen itself caused the late toxicity. Having a homogeneous cohort of patients treated without any dosimetric exclusion criteria and who were prospectively assessed for late toxicity allowed us to search for optimal doseevolume constraints to reduce rectal toxicity after HypoRT for prostate cancer. Despite all efforts, we could not find them, suggesting that for patients with favorable prostate cancer treated with IGRT and a small PTV margin, either there is a very small volume of normal tissue receiving the full dose, making any constraints less important, and/or there must be other unknown nondosimetric risk factors for late toxicity (23). The incidence of worst-grade late GU toxicity was a little higher than for GI toxicity, which is in keeping with other studies (5, 14). Only 18.5% of our patients did not experience any late GU toxicity, with the majority (49%) experiencing grade 1 toxicity. As with late GI toxicity, most of these symptoms resolved over time,
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usually within 6-12 months, with 82% of patients having no GU symptoms at the last follow-up visit.
Cancer control The freedom from biochemical failure rate (bNED) at 5 and 8 years with a median follow-up of 90 months is encouraging at 97% and 92%, respectively. Only 1 patient died from prostate cancer at 92 months. These results compare favorably to other experiences (1, 3, 6, 7, 20, 24). Table 4 compares the bNED rates of our study with other HypoRT and conventionally fractionated studies using escalated doses. Two institutions, which compared escalated with standard radiation therapy dose using conventional fractionation, have published long-term outcomes (1, 3). Zietman et al reported a 5-year bNED rate of 91% and a 10-year bNED rate of 84% (3, 20). Kuban et al reported 5-, 8-, and 10-year bNED rates of 85%, 78%, and 73%, respectively (1).
Randomized controlled trials There are several ongoing or completed phase 3 randomized trials comparing standard versus hypofractionated radiation therapy using escalated doses. The Canadian PROstate Fractionated Irradiation Trial (PROFIT) explored the PMH regime of 60 Gy in 20 fractions (5) and compared it with 78 Gy in 39 fractions in intermediate-risk patients. Up to 6 months of hormonal treatment before radiation therapy was allowed. The RTOG 0415 trial assessed HypoRT in low-risk patients without hormonal therapy. It tested Kupelian’s (7) regime of 70 Gy in 28 fractions versus 73.8 Gy in 41 fractions. Both trials are completed, but neither has reported preliminary results as yet. The British CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer) trial recently reported data on toxicity but not biochemical failure (25). This trial compared the conventionally fractionated schedule of 74 Gy in 37 fractions with 2 hypofractionated regimes (60 Gy/20 fractions and 57 Gy/19 fractions) in patients with low-, intermediate-, and high-risk disease. Shortcourse hormonal therapy for 3-6 months was given to the majority of patients. Using the RTOG/European Organization for Research and Treatment of Cancer toxicity score, they found grade 2 GI toxicity at 2 years in the conventional versus 60-Gy group versus 57-Gy group was 4.3%, 3.6%, and 1.4%, respectively, and grade 2 GU toxicity was 2.2%, 2.2%, and 0, respectively. An Italian trial by Arcangeli et al (24) compared 62 Gy in 20 fractions, but with 4 fractions per week, versus 80 Gy in 40 fractions, including only patients with high-risk disease, without pelvic node irradiation. All patients received hormonal Table 4 Long-term freedom from biochemical failure (bNED) according to different studies using escalated doses bNED (%) First author (dose) (reference)
5-y
8-y
10-y
McGill (present study) Kupelian (hypofractionation) (7) Livsey (hypofractionation) (6) Arcangeli (hypofractionation) (24) Zietman (escalated dose) (3, 20) Kuban (escalated dose) (1)
97 88 82 80 91 85
92 78
84 73
Abbreviation: bNED Z biochemical no evidence of disease.
therapy for a total of 9 months, and radiation therapy was delivered using 3D-CRT. With a median follow-up of 70 months, the outcomes are similar in both groups, with a 5-year bNED of 80%. Pollack et al (21) updated the results of their randomized trial comparing 70.2 Gy in 2.7 Gy per fraction with the standard arm of 76 Gy in 2 Gy per fraction using IMRT. One-third of the 307 patients in this trial had high-risk disease, with 45% of patients receiving hormonal therapy. At a median follow-up of 60 months, there were no significant differences in the outcomes, with a bNED rate of 85.6% in the conventional compared with 86.1% in the HypoRT arm and no statistically significant differences between the arms for GI and GU toxicity.
Conclusion Long-term results from our cohort of 129 patients who underwent HypoRT to a dose of 66 Gy in 22 fractions using 3D-CRT demonstrate moderate rates of late GU and GI toxicity, with an excellent biochemical-free survival rate of 92% and a cancerspecific survival rate of 98% at 8 years. However, caution should be exercised if IMRT is to be used, because our data cannot be safely extrapolated to this technique. This study supports the concept that HypoRT with a high equivalent BED may be an alternative treatment option for patients with favorable risk prostate cancer but highlights the need to use IMRT, better IGRT techniques, and tighter margins to the PTV to potentially lower the risk of toxicity. However, results from completed randomized phase 3 trials will be necessary to allow us to define the a/b ratio of prostate cancer more accurately and confirm whether hypofractionation is a safe method of delivering dose-escalated curative radiation therapy.
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