Twice-Weekly Hypofractionated Intensity-Modulated Radiotherapy for Localized Prostate Cancer With Low-Risk Nodal Involvement: Toxicity and Outcome From a Dose Escalation Pilot Study

Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 2, pp. 382–389, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2010.05.057

CLINICAL INVESTIGATION

Prostate

TWICE-WEEKLY HYPOFRACTIONATED INTENSITY-MODULATED RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER WITH LOW-RISK NODAL INVOLVEMENT: TOXICITY AND OUTCOME FROM A DOSE ESCALATION PILOT STUDY THOMAS ZILLI, M.D.,* SANDRA JORCANO, M.D.,y MICHEL ROUZAUD, D.SC.,* GIOVANNA DIPASQUALE, D.SC.,* PHILIPPE NOUET, D.SC.,* JOSE´ IGNACIO TOSCAS, M.D.,y NATHALIE CASANOVA, M.D.,* HUI WANG, M.D.,* LLUI´S ESCUDE´, D.SC.,y MERITXELL MOLLA`, M.D.,y DOLORS LINERO, D.SC.,y DAMIEN C. WEBER, M.D.,* AND RAYMOND MIRALBELL, M.D.*y )

Service de Radio-oncologie, Hoˆpitaux Universitaires de Gene`ve, Geneva, Switzerland ; and yServei de Radio-oncologia, Institut Onco`logic Teknon, Barcelona, Spain Purpose: To evaluate the toxicity and preliminary outcome of patients with localized prostate cancer treated with twice-weekly hypofractionated intensity-modulated radiotherapy (IMRT). Methods and Materials: Between 2003 and 2006, 82 prostate cancer patients with a nodal involvement risk #20% (Roach index) have been treated to the prostate with or without seminal vesicles with 56 Gy (4 Gy/fraction twice weekly) and an overall treatment time of 6.5 weeks. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicities were scored according to the Radiation Therapy Oncology Group (RTOG) grading system. Median follow-up was 48 months (range, 9–67 months). Results: All patients completed the treatment without interruptions. No patient presented with Grade $3 acute GU or GI toxicity. Of the patients, 4% presented with Grade 2 GU or GI persistent acute toxicity 6 weeks after treatment completion. The estimated 4-year probability of Grade $2 late GU and GI toxicity-free survival were 94.2% ± 2.9% and 96.1% ± 2.2%, respectively. One patient presented with Grade 3 GI and another patient with Grade 4 GU late toxicity, which were transitory in both cases. The 4-year actuarial biochemical relapse-free survival was 91.3% ± 5.9%, 76.4% ± 8.8%, and 77.5% ± 8.9% for low-, intermediate-, and high-risk groups, respectively. Conclusions: In patients with localized prostate cancer, acute and late toxicity were minimal after dose-escalation administering twice-weekly 4 Gy to a total dose of 56 Gy, with IMRT. Further prospective trials are warranted to further assess the best fractionation schemes for these patients. Ó 2011 Elsevier Inc. Prostate cancer, IMRT, Hypofractionation, Acute and late radiation induced toxicity, Biochemical relapse–free survival.

higher than the standard 2 Gy/fraction may be radiobiologically effective. Furthermore, delivering a higher dose in a reduced number of fractions may be most convenient for patients and logistically advantageous for busy RT departments. In addition, reducing the number of fractions may also succeed to reduce the cost of RT for prostate cancer in ‘‘pay-per-fraction’’ reimbursement systems (i.e., ‘‘health care dollar rationale’’). Nevertheless, hypofractionated RT with moderately high dose/fraction (i.e., 2.5-3.5 Gy) to treat prostate cancer is not a novel treatment approach. Indeed, it has been standard in the United Kingdom, Canada, and Australia for years, with results much alike fractionated treatments in 1.8- to 2-Gy fractions (17–19).

INTRODUCTION Although Phase III randomized trials have shown improved biochemical control rates in the treatment of localized prostate cancer with radiotherapy (RT) above 70 Gy, a significantly higher risk of late toxicity was observed for patients treated in the high-dose arms of these studies (1–4). Consequently, several strategies have been proposed to limit the radiation-induced toxicity, such as the use of intensity-modulated RT (IMRT) (5, 6) or of high-dose rate brachytherapy (7–12). Based on the assumption that the fractionation sensitivity of prostate cancer cells is characterized by a low a/b ratio in the range of 0.8 to 2.2 Gy (13–16), delivering treatment fractions Reprint requests to: Dr.med. Thomas Zilli, M.D., Radiation Oncology Department, Geneva University Hospital, CH-1211 Geneva 14, Switzerland. Tel: +41 22 38 27 090; Fax: +41 22 38 27 117; E-mail: [email protected]

Conflict of interest: none. Received Feb 22, 2010, and in revised form May 15, 2010. Accepted for publication May 25, 2010. 382

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The issue of overall treatment time (OTT) becomes also a matter of radiobiological interest when using hypofractionated RT to treat prostate cancer. Indeed, prostate cancer cells may have a relatively long doubling time with a repopulation time probably in excess of 100 days (20, 21). Thus, protracting the OTT over 7 weeks may not be relevant for local tumor control but may reduce acute toxicity incidence and intensity compared to hypofractionated-accelerated protocols with OTT of 5 weeks or less (22, 23). In addition, reducing acute toxicity may potentially lead to a decrease of late normal tissue reactions (24–26). In the present study, we aimed to evaluate the feasibility, acute and late toxicity, as well as the preliminary outcome in patients with prostate cancer, with a low risk of nodal involvement according to the Roach index (i.e., < 20%), treated with hypofractionated IMRT delivering twice-weekly fractions over a protracted OTT of 6 to 7 weeks.

METHODS AND MATERIALS Patient characteristics From June 2003 to September 2006, a total of 82 consecutive patients from Geneva (GVA) (n = 14) and Barcelona (BCN) (n = 68) with localized prostate cancer consented to be treated with a hypofractionated IMRT schedule. All patients were treated under the supervision of the same physician (R.M.). Patients were selected according to a clinical stage of cT1 to cT3 cN0 cM0 (2002 American Joint Committee on Cancer staging system) and a Roach index for a risk of nodal involvement #20% (27). All patients underwent a digital rectal examination (DRE) and pretreatment prostaticspecific antigen (PSA) determination. Contrast-enhanced endorectal magnetic resonance imaging (erMRI) was performed at diagnosis in 71 (87%) of 82 patients (4–6 weeks after the prostatic biopsy). Supplementary staging investigations included an abdominal CT and a bone scan only for patients with Gleason score $7 and/or PSA level $10 ng/mL at diagnosis. Using the National Comprehensive Cancer Network (NCCN) Guidelines risk group classification (28), 28% of the patients were considered as low risk, 44% intermediate risk, and 28% high risk. Patient and tumor characteristics are detailed in Table 1.

Treatment Five patients with high-risk features received neoadjuvant and concomitant androgen deprivation therapy (ADT) for 6 months. Six additional patients came to our department already on ADT (prescribed by the referring urologist). Their treatment was stopped in our department after having received the first trimestrial injection of LH-RH analogue. Patients were simulated in a supine position and scanned for planning purposes using 3-mm-thick CT slices from L5 through the ischial tuberosities. The clinical target volume (CTV) included the prostate with or without seminal vesicles (SV) without margins. The SV were included in the CTV when the risk of SV involvement was $15% according to the equation published by Diaz et al. (29) or when the SV were shown to be invaded on erMRI. The safety margin around the CTV to define the planning target volume (PTV) was of 10 mm in all directions except posteriorly, where a reduced margin of 6 mm was used. Organs at risks (OARs) were the bladder, rectum, penile bulb, and femoral heads.

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Table 1. Patient demographics and tumor characteristics (n = 82) n Age (y) Median Range Clinical T-stage* T1 T2 T3 Endorectal MRI Yes No Gleason score #6 7 PNI Yes No Unknown PSA at diagnosis (ng/ml) <10 10–20 >20 NCCN risk groups Low Intermediate High Roach index for nodal involvement risk #10 11–20 ADT Yesy No

%

67 51–86 34 24 24

42 29 29

71 11

87 13

55 27

67 33

8 51 23

10 62 28

66 15 1

81 18 1

23 36 23

28 44 28

52 30

63 37

11 71

13 87

Abbreviations: ADT = androgen deprivation therapy; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; PNI = perineural infiltration; PSA = prostatespecific antigen. * MRI staging was used to confirm extracapsular extension or seminal vesicle invasion. y In 6 patients, ADT consisted of a unique trimestrial injection of analogue LH-RH.

The dose escalation hypofractionated IMRT schedule consisted of a total dose of 56 Gy in 4-Gy fractions, twice-weekly (i.e., 14  4 Gy) for an OTT of 6.5 weeks. The estimated equivalent normalized total dose at 2 Gy/fraction (NTD2Gy) assuming an a/b ratio of 1.5 Gy (13–16) for prostate cancer cells was 88 Gy. The dose was prescribed at the International Commission on Radiation Units and Measurements (ICRU) reference point. The PTV was planned to receive a minimum (Dmin) and a maximum dose (Dmax) of 95% and 110% of the prescribed dose, respectively. Priority was given to normal OAR dose–volume constraints rather than the 95% dose coverage of the PTV. Dmax for the rectum and bladder was #95% of the prescribed dose, #30% of the rectum or bladder was to receive 90% of the prescribed dose, and #50% of the rectum or bladder was to receive 50% of the prescribed dose. The femoral heads were planned to receive a Dmax of 30 Gy to #5% and a dose of 20 Gy to #50% of their volumes. To limit the maximal dose to the bladder and the rectum, overlap volumes (i.e., PTVbladder and PTV-rectum) were created in GVA but not in BCN. The PTV-bladder and PTV-rectum overlaps were constrained to receive a Dmin of 92.8% and 85.7% of the prescribed dose,

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respectively. In GVA and BCN, patients were treated with a five nonopposed 6 MV and seven to 11 (median, nine) 6-MV photon beam technique, respectively, delivered by a linear accelerator with dynamic multileaf collimation (MLC).

Quality assurance Portal images of the setup fields were taken before every treatment session and compared with the digitally reconstructed images. In BCN, all patients were treated with a commercially available extracranial stereotactic system based on an infrared guided repositioning device with the patient immobilized in a customized vacuum body cast (30). To ensure optimal treatment reproducibility, all patients from both centers were instructed to empty their bladder before simulation and successively before every IMRT fraction. At the beginning of the study a rectal enema was prescribed to all patients before simulation and before each treatment fraction to reduce inter- and intrafraction target motion. Later on, rectal purging before treatment was done only in patients with medium-to-large rectal volumes at simulation (i.e., >60 cc). The first 22 patients in BCN included in the protocol were simulated and treated using a rectal balloon inflated with 60 cc of air after purging the rectum as part of an optimization study for internal organ motion reduction. All patients in BCN underwent a weekly repositioning control CT before treatment (i.e., every second fraction) thus allowing to control for prostate motion and for stability of rectal and bladder volumes. CTV displacements $1 cm were corrected by replanning the treatment and controlling closely for rectal purging and/or for balloon insertion and inflation before every fraction. In GVA, standard portal vision was performed before every fraction with weekly CTs only for those patients with large rectal volumes at simulation (>60 cc).

Follow-up and statistical analysis All patients were seen on routine follow-up once a week while on treatment and thereafter 6 weeks after treatment completion, every 3 months for the first year, and every 6 months successively. PSA measurement, DRE, and toxicity evaluation were assessed at each visit and reported by the attending physician (R.M.). All but 1 patient (who died after 9 months of follow-up of a lung cancer) had a follow-up period >25 months. Acute and late genitourinary (GU) and low-gastrointestinal (GI) toxicities were assessed using the Radiation Therapy Oncology Group (RTOG) acute and late radiation morbidity scoring criteria (31). Biochemical failure was defined using the Phoenix consensus criteria (PSA nadir + 2 ng/ml) (32). GU and GI late toxicity free-survival and biochemical outcome were assessed using the Kaplan–Meier method. The effect of different clinical and treatment related variables on the occurrence of late GU and GI of any RTOG grade was also analyzed. The following categorical variables were considered in the analysis: age (<65 vs. $65 years), IMRT technique (five-field IMRT vs. ninefield IMRT), inclusion of SV in the CTV, use of a rectal enema or balloon, use of ADT, and the presence of a previous acute toxicity of any grade at the end of the RT. The area under the curve of rectal dose–volume histograms was analyzed as a continuous variable. Proportions were compared with GI and GU late toxicities using the Chi-square test and Fisher exact test or Student t test for categorical and continuous variables, respectively. Statistical significance was defined as p # 0.05. All analyses were performed using the SPSS statistical package (SPSS 17.0, Chicago, IL).

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RESULTS Acute toxicity All patients completed the treatment without interruptions. Acute toxicity scores are summarized in Table 2. During the course of IMRT, Grade 1 and Grade 2 GU toxicity was observed in 33% and 35% of patients, respectively (Table 2). Patients with Grade 2 GU toxicity were treated with selective a-1 blockers or nonsteroidal anti-inflammatory drugs. In addition, 21% and 12% of patients presented with Grade 1 and Grade 2 GI toxicity scores, respectively (Table 2). Six weeks after treatment completion, 88% and 74% of patients were free of any GI and GU toxicity, respectively, and only 4% presented with persistent Grade 2 GU or GI toxicity. No patient in this series experienced Grade 3 or greater GU or GI toxicity either during treatment or 6 weeks after treatment completion. Late toxicity Table 3 provides details of the late GU and GI toxicity. The median follow-up was 48 months (range, 9–67 months). Of the patients, 19% and 24% presented with late GU and GI toxicity, respectively. The 4-year probabilities of Grade $1 and Grade $2 late GU toxicity-free survival were 80.9%  4.7% and 94.2%  2.9%, respectively (Fig. 1). The 4-year probability rate of Grade $3 late GU toxicity-free survival was 98.7%  1.3%. One patient developed a temporary urinary retention (Grade 4 GU toxicity) 32 months after treatment, which reverted to normal urinary flow 6 months after urethral catheterization. The 4-year probability rates of Grade $1 and Grade $2 late GI toxicity–free survival were 76.3%  5% and 96.1%  2.2%, respectively (Fig. 2). The 4-year probability rate of Grade $3 late GI toxicity–free survival was 98.6%  1.4%. Only 1 patient presented with Grade 3 late rectal toxicity (persistent rectal bleeding), 30 months after IMRT, which evolved to Grade 0 after argon plasma coagulation of rectal wall telangiectasiae. None of the variables evaluated for a potential correlation with late toxicity reached statistical significance on univariate analysis (i.e., age, ADT, IMRT technique, use of a rectal enema or balloon, acute toxicity, and area under the curve of rectal dose–volume histograms). Table 2. Acute genitourinary (GU) and gastrointestinal (GI) toxicities (RTOG scoring): Maximum score during IMRT and 6 weeks after treatment completion Acute RTOG toxicity (% of patients) GI Grade 0 1 2 3 4

GU

Treatment

6 Weeks

Treatment

6 Weeks

55 (67) 17 (21) 10 (12) — —

72 (88) 7 (8) 3 (4) — —

26 (32) 27 (33) 29 (35) — —

61 (74) 18 (22) 3 (4) — —

Abbreviation: RTOG = Radiation Therapy Oncology Group.

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Table 3. Late genitourinary (GU) and gastrointestinal (GI) toxicities (RTOG scoring): Maximum score $6 months after treatment completion and toxicity at time of last follow-up Late RTOG toxicity (% of patients) GI Grade 0 1 2 3 4

GU

Worse score

Persistent

Worse score

Persistent

62 (76) 16 (19) 3 (4) 1 (1) —

69 (84) 11 (13) 2 (3) — —

66 (81) 10 (12) 5 (6) — 1 (1)

71 (86) 7 (9) 4 (5) — —

Abbreviation: RTOG = Radiation Therapy Oncology Group

Outcomes Biochemical, clinical failure, and salvage treatments are summarized in Table 4. The 4-year actuarial biochemical relapse-free survival (bRFS) was 91.3%  5.9%, 76.4%  8.8% and 77.5%  8.9% for low-, intermediate-, and highrisk groups, respectively (p = 0.548) (Fig. 3). Two patients were lost to follow-up while in remission 3 and 4 years after treatment. Among the 13 biochemical recurrences, 2 occurred in low-risk, 6 in intermediate-risk and 5 in high-risk patients. In two patients, the exact failure sites were impossible to determine neither with bone scan nor with 11C-acetate or 18F-choline positron emission tomography-CT studies. One patient with biochemical recurrence died of a metachronic lung cancer. The 4-year overall local failure–free and distant metastasis–free survivals were 85.7%  4.7% and 96.3%  2.1%, respectively. There were 2 deaths from lung cancer at 9 and 59 months after diagnosis but not related to prostate cancer. The 4-year estimated overall survival rate was 98.8%  1.2%. DISCUSSION Based on the evidence that higher doses of radiation may improve biochemical relapse-free survival (1–4) and

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assuming that the a/b value for prostate cancer control is lower than the corresponding values for late effects in normal tissues (13–16), a dose-escalated hypofractionated regimen may improve tumor control rates without increasing the risk of severe late side effects. Several dose escalation studies using hypofractionated schedules have been conducted in the last few years reporting acceptable short-term levels of toxicity and biochemical control (17–19, 33–39). In our study, we used a treatment schedule delivering a NTD2Gy of 88 Gy (a/b = 1.5 Gy) based on our goal of exploring the threshold above which no gain in biochemical tumor control would be expected. From dose escalation reports with high-dose-rate brachytherapy, one can estimate this threshold to be approximately 84 to 90 Gy (7–12). For this study, we selected patients with a relatively low risk of nodal disease at diagnosis according to the Roach index and consequently with no need for pelvic irradiation. Indeed, in our practice, patients with a higher risk of nodal metastases would have been treated with standard fractionated RT to the pelvic region up to 50.4 Gy, followed by a hypofractionated boost to the prostate and SV. However, regardless of the risk of harboring regional disease, some of our patients in the study received ADT because of a potentially aggressive local tumor phenotype based on clinical stage (locally advanced disease), and/or on tumor density (>1/3 of positive biopsy results), and/or on existing perineural invasion in the biopsied material. Most hypofractionated treatment strategies reported so far have been simultaneously accelerated (i.e., treatment delivered in 4–5 weeks) with total weekly doses much above 10 Gy (range, 11.8–33.6 Gy), thus potentially increasing patient acute toxicity risk (22, 23). Assuming that there is no significant repopulation of tumor prostatic cells during at least the first 7 weeks of treatment, we deliberately decided to protract the treatment time to 6 to 7 weeks in the present study by delivering a total weekly dose of 8 Gy to the tumor, aiming to optimally protect acute responding normal tissues from excessive radiation. Keeping the weekly dose <10 Gy, and despite the high total prescribed dose to the

Fig. 1. Actuarial (Kaplan–Meier) late genitourinary toxicity free–survival probability for Radiation Therapy Oncology Group (RTOG) Grade $1 (a) and Grade $2 (b) side effects.

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Fig. 2. Actuarial (Kaplan–Meier) late gastrointestinal toxicity free–survival probability for Radiation Therapy Oncology Group (RTOG) Grade $1 (a) and Grade $2 (b) side effects.

tumor in our study, the rates of acute Grade $2 GU and GI toxicity scores, as shown in Table 2, are comparable to results reported by other hypofractionated series (22, 23, 33–40), the later with lower NTD2Gy dose prescription values. Despite the use of large fractions and of a high equivalent total tumor dose we observed a low incidence of late side effect compared with other standard fractionated doseescalation protocols with patients treated with 3D-CRT techniques (26, 41). Thus, not only differences in fractionation sensitivity between the prostatic tumor cells and the late responding normal cells of the rectum but, in addition, the use of safely dose escalation with IMRT techniques may have helped to make the difference in succeeding to reduce to acceptable levels moderate to severe late rectal toxicity in our study. As shown in Table 5, the benefit of IMRT in reducing rectal toxicity with standard fractionated RT >81 Gy has been reported by Cahlon et al. and Zelefsky et al. with

a 5- and 10-year Grade $2 late rectal toxicity rate of 4% and 5%, respectively (5, 26). These figures are similar to our 4-year rater of 3.9% for a NTD2Gy of 88 Gy to the tumor, or to the 5-year 6% reported by Kupelian et al. for a NTD2Gy of 80 Gy (33). Is IMRT or is hypofractionation the parameter with the strongest influence in reducing late toxicity rates at the low-GI level after dose escalation? Zelefsky et al. observed for patients treated to 75.6 Gy with 3D-CRT and to 81 Gy with IMRT a 10-year Grade $2 GI toxicity of 18% and 5%, respectively (26). Thus, for these authors, IMRT would make the difference in the optimization of the dose distribution in the rectum, thereby reducing late rectal toxicity by a factor of 3.6 despite a higher prescribed dose to the tumor

Table 4. Characteristics of biochemical failures Risk group

Clinical failure

Salvage treatment

Type of salvage treatment

1 2 3 4 5 6 7 8 9 10

Intermediate High High High Intermediate Intermediate High High Intermediate Intermediate

No Yes Yes Yes Yes No Yes Yes Yes Yes

— CRIO iADT RP iADT — CRIO HIFU iADT iADT

11 12* 13

Low Intermediate Low

— Local Distant Local Local — Local Local Local Local and distant Local — Local and distant

Yes No Yes

iADT — CRIO/iADT/ LA-RT

Patient

Abbreviations: CRIO = cryotherapy; HIFU = high-intensity focused ultrasound; iADT = intermittent androgen deprivation therapy; LA-RT = lombo-aortic radiotherapy; RP = radical prostatectomy. * Patient died before further investigation.

Fig. 3. Actuarial (Kaplan–Meier) biochemical relapse–free survival (bRFS) according to the ‘‘nadir + 2 ng/ml’’ definition by National Comprehensive Cancer Network risk group.

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Table 5. Late toxicities of dose-escalation trials (normo- and hypofractionated) $ Grade 2 maximum Late Toxicity (% risk)

NTD2Gy for a/b ratio Median follow-up (mo)

Total dose (Gy) (no. of fractions  dose/fraction)

OTT (wk)

1.5 Gy

3 Gy

Technique

GI

GU

92 40 472 741 Zietman et al. (2) 197 195 Kupelian et al. (33) 770 Ritter et al. (39) 110 Leborgne et al. (38) 52 37 Cahlon et al. (5) 478 Tsuji et al. (37) 201

38 41 96 78 66

60 (20  3 Gy) 33.5 (5  6.7 Gy) 75.6 (42  1.8 Gy) 81 (45  1.8 Gy) 70.2 (39  1.8 GyE) 79.2 (44  1.8 GyE) 70 (28  2.5 Gy) 64.7 (22  2.94 Gy) 60 (20  3 Gy) 63 (20  3.15 Gy) 86.4 (48  1.8 Gy) 66 (20  3.3 GyE)

4 1 8.5 9 8 9 5.5 5.5 5 5 9.5 5

77.1 78.5 — — — — 80 82.1 77.1 83.7 — 90.5

72 65 — — — — 77 76.9 72 77.5 — 83.2

6.3* 9.4y 18z 5z 9x 18x 6{ — 5.5{ 5.5{ 4{ 1x

10* 16.1y 12z 20z 19{ 18{ 7{ 8.5k 5.6{ 5.6{ 16{ 6x

Current study

48

6.5

88

78.4

IMRT SHARP 3D-CRT IMRT 3D-CRT (photons + protons) IMRT IMRT/TOMO 3D-CRT 3D-CRT IMRT 3D-CRT (Carbon Ions) IMRT

3.9y

5.8y

Authors (Reference)

n

Martin et al. (35) Madsen et al. (34) Zelefsky et al. (26)

82

45 19 49 53 30

56 (14  4 Gy)

Abbreviations: 3D-CRT = 3D-conformal radiotherapy; GI = gastrointestinal; GU = genitourinary; IMRT = intensity-modulated radiotherapy; NTD2Gy = normalized total dose (Gy) for 2-Gy fractionation; OTT = overall treatment time; SHARP = stereotactic hypofractionated accurate radiotherapy; TOMO = tomotherapy. * 3-Year estimate. y 4-Year estimate. z 10-Year estimate. x Crude value. { 5-Year estimate. k 2-Year estimate.

with IMRT. Nevertheless, Leborgne et al. suggested that hypofractionation might have a strongest influence than IMRT in the protection of the surrounding normal tissues, based on their observation in a series of 89 patients treated with a hypofractionated schedule using 3D-CRT (38). These authors observed approximately the same late toxicity rates reported by other hypofractionated trials, the later using IMRT (Table 5). Thus, if the ‘‘biological’’ effect of hypofractionation were stronger than the ‘‘physical’’ effect of IMRT in reducing the late toxicity rate of the rectum, simple nonoptimized RT techniques might be sufficient to successfully escalate the dose for prostate cancer. According to these authors, less treatment fractions with standard 3D-CRT may therefore be an acceptable alternative for countries with limited resources to optimally treat prostate cancer with RT while reducing expenses. The preliminary biochemical control figures in our series compare favorably with other hypofractionated doseescalation series despite a relatively longer OTT (33–35, 37–39). This is despite the fact that a protraction in the OTT, because of unplanned breaks, has been identified by some as an adverse factor correlated with a higher PSA failure after normofractionated RT (42). On the other hand, dose-escalated protocols using standard fractionation with treatment times of 9 weeks have been unable to show a reduction in long-term tumor control and survival compared with less protracted RT strategies (5). Some limitations of this study deserve to be highlighted. First, our study represents a retrospective chart review of

a small patient’s cohort treated in a pilot study started in 2003 aiming to develop IMRT and, in addition, to establish the basis for a randomized Phase-II trial on hypofractionated RT. Therefore, toxicity scoring may have been potentially biased by the inherent limitations of a physician-based assessment without patient self-assessment on toxicity, as well as of a prospective quality of life evaluation. Second, as no fiducial-based image-guided systems able to track the daily prostate motion were available at our institutions at the time of the study, we tried to improve the accuracy in the treatment delivery using different patient repositioning and organ immobilization methods and by repeating CTs in treatment conditions every second fraction to monitor for target and rectal motion. It is reasonable to expect that the use of modern image guidance and real-time tracking systems will help to further reduce PTV margins and the risk of toxicity as a consequence. CONCLUSION In summary, the present IMRT dose escalation protocol of 14  4 Gy, twice weekly over a 6.5-week period is, to the best of our knowledge, the first nonaccelerated hypofractionated regimen reported in the literature for the treatment of prostate cancer with low regional nodal involvement risk. Patients treated on this protocol have shown good tolerance and promising outcomes. Further prospective trials are warranted to explore optimal time–dose–fractionation strategies, especially those proposing strong hypofractionation with dose fractions >6 Gy.

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Volume 81, Number 2, 2011

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