HYPOFRACTIONATED VERSUS CONVENTIONAL RADIOTHERAPY IN ... · del tumore alla prostata e testicolo – Regione Campania, Italy 2Radiation Oncology, Istituto Nazionale per lo Studio

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HYPOFRACTIONATED VERSUS CONVENTIONALRADIOTHERAPY IN PATIENTS WITH LOW/INTERMEDIATE-RISK LOCALIZED PROSTATE CANCER: REVIEW OF RECTAL AND URINARY TOXICITY

WCRJ 2016; x (x): exxx

Corresponding Author: Carla Cavaliere, MD; e-mail: [email protected]

Abstract – Purpose: This review has the purpose of comparing radiation toxicity in patients with localized prostate cancer treated with conventional fractionation, hypofractionated and ex-treme hypofractionated to analyze the impact of techniques and technological innovation on the management of prostate cancer.

Materials and Methods: We searched PubMed trials that examined acute and late urinary/gas-trointestinal toxicity in patients with low/intermediate risk localized prostate cancer treated with radiotherapy. We grouped studies into 5 groups, analyzed the acute and chronic toxicity detected, and calculated mean of the percentage for toxicity ≥ G2 and odds ratio (OR) in the different groups.

Results: Regarding the gastrointestinal and genitourinary acute/late toxicity, Intensity Modu-lated Radiation Therapy (IMRT) hypofractionated technique is advantageous of 3DCRT hypofrac-tionated and IMRT with conventional fractionation. Stereotactic Body Radiation Therapy (SBRT) is advantageous of IMRT hypofractionated, only for acute and late gastrointestinal and acute geni-tourinary toxicity.

Conclusions: This preliminary analysis shows that hypofractionated scheme, especially IMRT, provides an increased tolerance of treatment. SBRT with Cyberknife system, represent in selected cases, a future challenge.

KEYWORDS: Radiotherapy, Localized prostate cancer, Rectal toxicity, Urinary toxicity.

1Progetto ONCONET2.0 – Linea progettuale 14 per l’implementazione della prevenzione e diagnosi precoce del tumore alla prostata e testicolo – Regione Campania, Italy2Radiation Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, Naples, Italy3Division of Medical Oncology, A.O.R.N. dei COLLI “Ospedali Monaldi-Cotugno-CTO”, Naples, Italy4Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy5Pathology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” – IRCCS, Naples, Italy.6Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, Naples, Italy7Psycho-Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale” – IRCCS, Naples, Italy8Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori ‘Fondazione G. Pascale’ – IRCCS, Naples, Italy

R. DI FRANCO1,2, V. BORZILLO2, V. RAVO2, G. AMETRANO1,2, S. FALIVENE2,F. CAMMAROTA2, S. ROSSETTI1, C. D’ANIELLO1,3, C. CAVALIERE1,4, F.J. ROMANO1, M.G. MALZONE1,5, M. MONTANARI1,6, D. VANACORE1, E. LA MANTIA1,5, F. CAPPUCCIO1,7, G. IOVANE1,8, M.A. PORRICELLI1,8, R. PISCITELLI1, G. FACCHINI1,8, P. MUTO2

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MATERIALS AND METHODS

Study Selection: We searched PubMed (http://www.ncbi.nlm.nhi.gov/pubmed) on June 2016 for the terms “rectal toxicity” and “urinary toxi-city” and “radiotherapy” and “localized prostate cancer”. Duplicates, studies of brachytherapy, methodology, dosimetry, old techniques, advan-ced disease, after-surgical treatment or high-risk patients studies, were excluded. Abstracts of re-maining manuscript were read. Studies concer-ning the potential relationship between acute/late urinary/gastrointestinal toxicity and prosta-te radiotherapy in patients with low/intermediate risk localized prostate cancer, were included in the final analysis.

Data Extraction and Analysis of results: Was extracted first author, year of publication, type of trial, median of follow-up, risk class, RT pro-tocol, total dose and equivalent dose, androgen deprivation therapy (ADT), Toxicity Criteria, percentage of acute/late genitourinary and gas-trointestinal toxicity. We combined the studies according to the type of technique (3DCRT, IMRT, SBRT), the type of fractionation (conven-tional, hypofractionated, extreme hypofraction-ated). We calculated the mean of the percentage for toxicity ≥ G2 and odds ratio (OR) in different groups between patients with G0-1 toxicity and patients with toxicity ≥ G2. We calculated the 95% confidence interval, considering statistical significant p-values ≤ 0.05.

RESULTS

Study Selection: Our initial search yielded 530 results. The initial removal of publications with the described criteria reduced the number to 212. Then we removed 54 studies that not evaluate both acute and chronic toxicity GU and GI. Lastly, we evaluated 158 full-text article, and we eliminated others 128 because studies assessed after-surgery treatments, old techniques, or had few data. In to-tal 30 manuscripts met all eligibility requirements and were included in this report.

We obtained three groups of studies. Group I includes 12 articles on 3DCRT treatments, in-cluding 5 with conventional fractionation, 5 with hypofractionated, 2 who used techniques 3DCRT and SBRT with Cyberknife system (Table 1). The second group includes studies of treatments with IMRT techniques (9 with conventional fraction-ation and 6 with hypofractionated) (Table 2). The third group includes studies of extreme hypofrac-tionated treatment (5 used the Linac, 8 used Cy-berknife system) (Table 3).

INTRODUCTION

External beam radiotherapy (EBRT) is a standard treatment modality for localized and locally advan-ced prostate cancer, one of the most frequent tu-mors affecting men in the world1,2. Many publica-tions have suggested that prostate cancer has a low α/β ratio (ratio between “intrinsic radiosensitivity” and “reparative capacity”), compared to healthy tissues1-3. The organs at risk, (OARs) as rectum or bladder have an estimated α/β-level of 3-5 Gy, and then prostate cancer cells are more responsive to a larger fraction size in comparison with OARs, so there is a therapeutic gain using larger size frac-tions4. Five large randomized trials demonstrated that increased dose to the prostate of 74-80 Gray (Gy) with 1.8-2 Gy/fractions results in improved biochemical recurrence-free survival and disease specific survival5-9. Advances in radiation delivery techniques such as intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) led to greater sparing of adjacent normal tissue to reduce toxicity.

Extremely hypofractionated schemes consi-sting of 5 treatments or less have also been inve-stigated. The current approach in prostate radio-therapy trials investigating hypofractionation and extreme hypofractionation utilizes a simultaneous integrated boost (SIB) to deliver a higher dose to dominant intraprostatic lesions and a lower dose to the whole prostate. A second dose escalation strategy involves heavy ion-based irradiation such as proton therapy. Now the experience of large proton centers doesn’t show superiority in disease control or toxicity for proton therapy10-12.

Very important is patient selection, which must consider various aspects to define the risk class. Several systems have been proposed to stratify prostate cancer into differing risk groups. In 2010, the seventh edition of the AJCC Staging Manual13, added Gleason score and PSA to the TNM staging system, making these stage grou-ping roughly comparable to those of D’Amico and NCCN, with notable differences in the inter-mediate- and high-risk groups. NCCN also adds “very low-risk” and “very high-risk” categories. Nearly 50% of patients diagnosed with prostate cancer fall in prognostic AJCC Stage I, which includes patients with a clinical stage of T1-T2a, PSA<10, and Gleason 614.

Our review shows a preliminary analysis that compares acute and late radiation toxicity data detected in conventional fractionation, hypofrac-tionated and extreme hypofractionated in view of the techniques used, to analyze the impact of technical and technological innovation on the ma-nagement of prostate cancer.

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TABLE 1. Trials on 3DCRT treatments with conventional and hypofractionated treatment.

Author Year Type of FU Risk Tecnique RT (Total [EQ D2] ADT Acute GU Acute GI Late GU Late GI Toxicity(No. pt) Study (median) groups dose/n.fz) z a/b 1,5 Toxicity Toxicity Toxicity Toxicity (criteria)

(L/I/H) % (daily fz) % % % %

Schmid 2012 Prospective 74 M L:35;I: 3DCRT 70Gy/35 (2) [70 Gy] 135(+) ≥G2:22 ≥G2:15 ≥ G2:23 ≥G2:19 EORTC et al (178) phase II 34;H:30 CV 74Gy/37(2) [74 Gy] 43(-) RTOGMcCloskey 2004 Retrospective 47 M L:21;I: 3DCRT <75,6Gy/ [74 Gy] 182(+) [<75,6Gy] [<75,6Gy] [<75,6Gy] [<75,6Gy] RTOG et al (222) 27;H:52 CV 42-38(1.8-2) vs [24 Gy] G0:4;G1:69; G0:46;G1:43; G0:50;G1:33; G0:43;G1:36;

75,6 Gy /(1.8-2) [50 Gy] G2:27 G2:10;G3:1 G2:9;G4:1 G2:10;G3:3[75,6Gy] [75,6Gy] [75,6Gy] [75,6Gy]

G0:5;G1:61; G0:53; G0:35;G1:44; G0:61;G1:G2:32;G3:2 G1:41;G2:7 G2:9;G3:1 18;G2:5;G3:1

Zietman 2010 Prospective 105 M 70,2 Gy 3DCRT 70.2-79,2 Gy [70.2 Gy]+ 393(-) [70,2 Gy] [70,2 Gy] [70,2 Gy] [70,2 Gy] RTOG et al (393) randomized L:57;I:38;H:5 +boost 50.4Gy/ (1.8) [19.8Gy] G1:37; G1:39; G1:42;G2 22; G1:35;G2:13

79,2Gy protoni Boost 19.8GyE/ [79.2 Gy]+ G2:51;G3:3 G2:44;G3:1 G3:2 [79,2Gy] L:59;I:35;H:4 11(1.8) [28.8Gy] [79,2Gy] [79,2Gy] [79,2Gy] G1:41;G2:

28.8GyE/16 (1.8) G1:29;G2:60; G1:26;G2: G1:45;G2:27; 24;G3:1G3:2;G4:1 63;G3:1 G3:2

Coen 2011 Prospective 31,6 M L-I:100 Protoni 78-79 Gy/ [82 Gy] 85(-) G1:51;G2:13; G1:19;G2:1 G1:33;G2:26; G1:33;G2:26; RTOG et al (85) Phase II CV 39-40(2) G3:1 G3:11;G4:2 G3:11;G4:2 EORTCNihei 2011 Prospective 43,4 M L:77; I:74 Protoni L: 74Gy/37 (2) pros [74 Gy] 42(+) G0:30;G1:58; G0:89;G1:10; G0:87;G1:6; G0:78; CTC et al (151) phase II CV I: boost 24Gy pros [24 Gy] 109(-) G2:12 G2:0,7 G2:5;G3:1 G1:18;G2:3

after 50Gy [50 Gy]prostate+vs

White 2015 Prospective 36 M L:11;I:38; 3DCRT 57Gy/17 (3) [73,3 Gy] 71(+) G1:58,6;G2:10; G1:75,6 G1:47,3; G1:40;G2:9,3; CTCAE et al (90) H:50 Hypo 19(-) G3:1,1 G2:2,4 G3:4,7Tramacere 2015 Prospective 39M L:19;I:41; 3DCRT 62Gy/20 (3,1) [81,5Gy] 94(+) G1:43;G2:21; G1:18;G2:15 G1:11;G2:5; G1:2;G2:10; RTOG et al (97) Phase II H:40 Hypo G3:3 G3:3 G3:1 EORTCLopez 2013 Retrospective 11 M L:33;I:42; Hypo/TH 68,04Gy/27(2,52) [78.1 Gy] 35(+) G2:19;G3:6 G2:19 G2:2 G2:4 RTOG Guerra (48) H:25 70Gy/28(2,5) [80 Gy] 13(-) et al 70,2Gy/27(2,6) [82.2 Gy]Jereczek- 2013 Prospective 19 M L:40.9;I: 3DCRT 70Gy/28 (2,5) [74 Gy] 243(+) ≥G2:35; ≥G2:11.3; ≥G2:10.4; ≥G2:7.5; RTOG Fossa (337) 43.32; Hypo/IGRT [24 Gy] 94(-) ≥G3:6.2 ≥G3:1.2 ≥G3:1.6 ≥G3:1.3 et al H:14.2 [50 Gy] Martin 2007 Prospective 38 M L:32;I: 3DCRT 60Gy/20 (3) [77.1Gy] 8(+) G0:32;G1:43; G0:66;G1:22; G0:90;G1:7; G0:93;G1:2; RTOG et al (92) 61;H:8 Hypo/IGRT 84(-) G2:25 G2:11;G3:1 G2:3 G2:4Pontoriero 2016 Retrospective 21,5 M L:35;I:46; CK(boost) 38Gy/4(9.5)vs [119.4 Gy] 16(+) G1:46;G2:4 G1:23;G2:8 G1:12;G2:4 G1:4 CTCAE et al (26) H:19 + 3DCRT 9,5Gy/2(4.75) [17 Gy] 20(-)

+ 46Gy/23(2) [46 Gy]Katz 2010 Prospective 33 M I:57;H:43 EBRT + 21Gy/7(3) [27 Gy] 36(+) G0:9,4;G1:83,6; G0:15,1; G0:89;G1:5,5; G0:86,3; RTOG et al (75) CK(boost) boost 18-19,5/ [54 Gy] 39(-) G2:6,8 G1:78,1;G2:6,7 G2:4,1;G3:1,4 G1:5,5;G2:8,2

2(9-9.75) [62.7 Gy]

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TABLE 2. Trials on treatment with IMRT technique.

Author Year Type of FU Risk Tecnique RT (Total [EQ D2] ADT Acute GU Acute GI Late GU Late GI Toxicity (No. pt) Study (median) groups dose/n.fz) z a/b 1,5 Toxicity Toxicity Toxicity Toxicity (criteria) (L/I/H) % (daily fz) % % % % Schild 2014 Retrospective 36 M L:23;I:55;H:22 IMRT 77,4Gy/43(1.8) [73Gy] 32(+) G1:33;G2:53 G1:51;G2:19 G1:4;G2:23 G1:1;G2:1 CTCAE et al (78) SIB 83Gy/43 (1.93) [81.3Gy] 46(-)Fang 2015 Prospective 24 M L:53;I:37;H:7,4 PBT 79,2Gy/44(1.8) [74.7Gy] IMRT [IMRT] [IMRT] [IMRT] [IMRT] CTCAE et al (394) IMRT 66 (-);27(+) G0-G1:71,3; G0/G1:86,2; ≥ G2:18,3 ≥ G2:10,8 PBT G2-G3:28,7 G2/G3:13,8 [PBT] [PBT] 79 (-);15(+) [PBT] [PBT] ≥ G2:12,8 ≥ G2:12,8 G0-G1:78,7; G0-G1:95,7; G2-G3:21,3 G2-G3:4,3Petrongari 2013 Prospective 71 M I:100 IMRT 86Gy/43(2) [86Gy] 39(-) G2:51 G2:44 G2:5;G3:8 G2:18;G3- CTCAE et al (39) phase II G4:2,5%Goineau 2013 Prospective 54 M L:18;I:60; IMRT 76Gy/38(2) [76Gy] 23(+) G1:36,8;G2: G1:23,7;G2: G1:34,2;G2: G1:23,7; CTCAE et al (38) H:32 15(-) 5,3;G3:2,6 5,3 G30 5,3;G3:5,3 G2:15,8Takeda 2012 Retrospective 60 M I:26;H:74 IMRT 76Gy/38(2) [76Gy] 124(+) G1:60;G2:8,5 G1:20;G2:1,4 ≥G2:6,4 ≥G2:5,7 CTCAE et al (141) 80Gy/40(2) [80Gy] 17(-)Tomita 2012 Retrospective 35 M L:7;I:22;H:71 IMRT 74Gy/37(2) [74Gy] 233(+) G2:24,5 G2:11,2 G2:8,3;G3:1,2 G2:6,6;G3:0,8 RTOG et al (241) TH 78Gy/39(2) [78Gy] 8(-)Marchand 2010 Prospective 18 M L:18; I:60,2; IMRT 76Gy/38(2) [76Gy] 25(+) G2:38;G3:2 G2:13 G2:15 G2:11 CTCAE et al (55) H:21,8 30(-) Cahlon 2008 Retrospective 53 M L:21;I:40;H:39 IMRT 86,4 Gy/43(2) [86.4Gy] 315 (+) G2:22;G3:0,6 G2:8 G2:13;G3:3 G2:3;G3:0,1 CTCAE et al (478) 163(-)Vora 2007 Retrospective 60 M L:79;I:60; 3DCRT(271) 68.4(66-71)Gy/ [64.5 3DCRT [3DCRT] [3DCRT] [3DCRT] [3DCRT] RTOG et al (460) H:35 IMRT (145) 38-34(1.8-2) -68.4Gy] 49(+) 222(-) G0:38;G1:21; G0:27;G1: G0:66;G1:13; G0:57;G1:26; 75.6(70,2-77,4) [71.3- IMRT G2:40;G3:1 20;G2:54 G2:17;G3:5 G2:14;G3:2 Gy/42-38(1.8-2) 75.6Gy] 44(+)101(-) [IMRT] [IMRT] [IMRT] [IMRT] G0:28;G1:23; G0:16;G1:34; G0:45;G1:27; G0:56;G1:20; G2:46;G3:3 G2:49;G3:1 G2:23;G3:6 G2:23;G3:1Manabe 2014 Retrospective 47 M L:11;I:32; IMRT 74-78Gy/ [47-78Gy] 224(+) ≥G2:9,5-> G2:1,4- ≥G2:5,8- ≥G2:13- CTCAE et al (259) H:58 37-39(2) [75.6- 35(-) 18-15 4,0-0 2,0-1,2 12-3,7 vs73,5-77,7Gy/ 79.9Gy] 35-37(2.1) [76.7- vs72,6-74,8Gy/ 79.1Gy] 33-34(2.2)Wu 2012 Prospective 54 M L:25;I:75 IMRT 55 Gy/ [77.6Gy] 11(+) G2:41;G3:3 G2:34;G3:4 G2:8 G2:8 RTOG et al (73) phase II IGRT 16(3.43) 62(-) (fiducials) Zilli 2011 Prospective 48 M L:28; I:44; Hypo- 54Gy/14 [82.7Gy] 11(+) G0:74;G1 G0:88;G1: G0:86;G1: G0:84;G1: RTOG et al (82) randomized H:28 IMRT (3.85) 71 (-) :22;G2:4 8;G2:4 9;G2:5 13;G2:3 phase III Lock 2011 Retrospecitve 36 M L:27;I:36; VMAT- 63,2Gy/20 [84.1Gy] 6(+) G0:4,4; G0:19,7;G1:42,4; G0:26,6; G0:31,2; CTCAE et al (66) phase II H:1 IMRT (3.16) 60(-) G1: 51,5; G2:25; G3:10,3; G1:54,7; G1:39,1; G2:25; G2:33,8; G3:8,8 G4:1,5 G2:14,1; G3:4,7 G3:3,1; G4:1,6 Shridhar 2009 Retrospective 33 M 75 Gy 3DCRT 75Gyvs77,5Gy [42.4Gy]+ [75 Gy] [75 Gy] [75 Gy] [75 Gy] [75 Gy] RTOG et al (125) L:85,2; I:9,8; + Boost- 45Gy/25(1.8)+ [34.3Gy] 8(+)53(-) G0:77;G1: G0:85,2;G1: G0:68,9; G0:74,2;G1:21; H:4,9 77,5Gy IMRT Boost 30Gy/ Vs [77,5Gy] 16,4;G2:6,6 8,2;G2:6,6 G1:13,1;G2:18 G2:3,2;G3:1,6 L:14,1; I:62,5; 12(2.5) vs [37.1Gy] 28(+)36(-) [77,5Gy] [77,5Gy] [77,5Gy] [77,5Gy] H:23,4 Boost 32.5 G0:60,9;G1: G0:82,8; G0:70,3;G1:18,8; G0:71,4; Gy/13(2.5) 25;G2:14,1 G1:17,2 G2:10,9 G1:17,5;G2:11,1Kupelian 2007 Retrospective 45 M L:34;I:28; IMRT/IGRT 70Gy/28 (2,5) [80Gy] 459(+) G0:33;G1:48; G0:51;G1:40; G0:90,5; G0:89,6;G1:5,9; RTOG (770) H:38 311(-) G2:18;G3:1 G2:9 G1:4,3; G2:3,1; G2:5,1;G3:0,1 G3:1,3; G4:0,1

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TABLE 3. Trials on extreme hypofractionated treatment.

Author Year Type of FU Risk SBRT RT (Total [EQ D2] ADT Acute GU Acute GI Late GU Late GI Toxicity (No. pt) Study (median) groups dose/n.fz) z a/b 1,5 Toxicity Toxicity Toxicity Toxicity (criteria) (L/I/H) % (daily fz) % % % % Rucinska 2016 Prospective 24 M L:10;I:90 Linac 33,5/5 (6,7) [78,5Gy] 16(-) 52(+) G1:32,3; G1:26,5; G1:41,2; G1:17,6; RTOG/ et al. (68) G2:35,3; G2:10,3 G2:11,8 G2:4,4 EORTC G3:1,5 Davis 2015 Retrospective 20 M L:189;I:215; SBRT 36,25Gy/5(7,25) [90,6Gy] 11%(+) G1:25;G2:4 G1:11;G2:2 G1:34;G2:12 G1:17;G2:2,2; CTCAE et al. (437) H:33 35Gy/5(7) [85Gy] G3:0,2 37Gy/5(7,4) [94,1Gy] 38Gy/4(9,5) [119,4Gy]Loblaw 2013 Prospective 55 M L:100 Linac 35Gy/5(7) [85.0Gy] 1(+) G1:71;G2:19; G1:67; G1:2;G2:5 G1:35; G2:7; CTCAE/ et al. (84) phase I/II weekly G3:1 G2:10; G3:1 G4:1 RTOG Madsen 2007 Prospective 41 M L:40 Linac 33,5Gy/5(6,7) [78,5Gy] / G0:49;G1:28; G0:61;G1:26; G0:55;G1:25; G0:62,5;G1:30; CTC et al. (40) phase I/II G2:20,5;G3:3 G2:13 G2:20 G2:7,5 Boike 2011 Prospective 30 M L:20-53-47 SBRT 45- 47,5-50Gy/5 [135Gy] (+)27-13-27% G0:53/60/33; G0:60-60-47; G0:67-60-93; G0:87-67-60; CTCAE et al (48) I:80-47-53 (9-9.5-10) [149.3Gy] (-)73-87-73% G1:20/33/33; G1:40-13-47; G1:20-20-0; G1:7-27-33; [164.3Gy] G2:27/7/33 G2:0-27-47 G2:13-13-0; G2:7-7-0; G3:0 -7-7 G4:0-0-7 Kim 2016 Retrospective 51 M L:27,3;I:72,7 CK 36,25/5 (7,25) [90,6Gy] 33(-) G2:18,2 G2:21,2 G2: 6,1 G2:9,1 et al. (33)Fuller 2014 Prospective 72 M L:51;I:49 CK 38Gy/4 (9.5) [119,4Gy] (-) G2:10 G1:0;G2:0 G2:9;G3:6 G2:1 CTCAE et al. (79) phase II Bolzicco 2013 Prospective 36 M L:41;I:42; H:17 CK 35Gy/5(7) [85.0Gy] 29(+) G1:34; G2:12 G1:27; G2:18 G1:4;G2:3 G1:2;G2:1 RTOG et al. (100)Katz 2013 Prospective 60 M L:69; I:27; H:4 CK 35Gy/5(7) [85.0Gy] 57(+) [35Gy] [35Gy] [35Gy] [35Gy] RTOG et al. (304) 36,25Gy/5(7,25) [90,6Gy] G0:24;G1:72; G0:20;G1:76; G2:4 G2:2 G2:4 G2:4 [36,25Gy] [36,25Gy] [36,25Gy] [36,25Gy] G2:9;G3:2 G2:5 G0:20,5;G1:74,8; G0:22; G2:4,7 G1:74,4; G2:3,5 Oliai 2013 Retrospective 37 M L:51;I:31;H:17 CK 37,5Gy/5(7,5) vs [96.4Gy] 23(+) G1:59vs54;G2: G1:14vs20; G1:48vs41; G1:10vs10; CTCAE et al. (70) 36,25-35Gy/5 [90,6Gy] 14vs22;G3:3vs5 G2:0vs7 G2:24vs32; G2:7vs10 (7,25-7) [85.0Gy] G3:4vs0 King 2012 Prospective 31 M L:100 CK 36,25Gy/5(7.25) [90,6Gy] 67(-) G1:23;G2:5; G1:12,5; G0:68;G1:23; G0:84;G1:14; RTOG et al. (67) phase II G3:3 G2-3:0,2 G2:5;G3:3,5 G2:2Bolzicco 2010 Prospective 20 M L:49;I:51 CK 35Gy/5(7) [85.0Gy] 17(+) G1:35,5; G1:24,4; G1:8,8;G3:2,2 G2:2,2 RTOG et al. (45) G2:11,1 G2:24,4King 2009 Prospective 33 M L:100 CK 36,25Gy/5 [90,6Gy] (-) G0:30;G1:41; G0:51;G1:33; G0:76;G1:14; G0:47;G1:28; RTOG et al. (41) phaseII (7,25) G2:24;G3:5 G2:15 G2:7;G3:3 G2:19; G3:7

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HYPOFRACTIONATED VERSUS CONVENTIONAL RADIOTHERAPY IN PATIENTS WITH LOW/ INTERMEDIATE-RISK LOCALIZED PROSTATE CANCER

• In comparison of SBRT vs. IMRT Hypo, there is a statistically significant advantage in terms of acute GU (OR 0.53; p=0.0000), acute GI (OR 0.61; p=0.0002), late GI toxicity (OR 0.60; p=0.0023);We noted that in terms of gastrointestinal and

genitourinary acute and late toxicity, 3DCRT hypofractionated is more advantageous of 3DCRT with conventional fractionation; IMRT with conventional fractionation is more advan-tageous of 3DCRT with conventional fractio-nation; IMRT hypofractionated technique is advantageous of 3DCRT hypofractionated and IMRT with conventional fractionation. SBRT is more advantageous of IMRT hypofractionated, only for acute and late gastrointestinal and acute genitourinary toxicity.

DISCUSSION

The advent of image-based or image-guided RT more precisely, news algorithms and advanced technology, have permitted the use of high-dose for fraction in the prostate cancer treatment. Some tumors, such as prostate cancer have a very low α/β ratio and higher single doses can be ap-plied with a better tumor control and same side effects15,16. Randomized trials have shown a bet-ter biochemical control when higher total doses of conventionally fractionated irradiation are deliv-ered to the prostate17,18. However, dose escalation with standard fractionation improves biochemi-cal-free survival at the expense of prolonging the overall duration of the treatment19-21.

Target localization prior to daily treatments is required and can be performed using X-ray im-aging of implanted fiducials or CT; this allows a smaller PTV expansion with a lower dose to sur-rounding organs. With the CyberKnife, continu-ous image acquisition and target correction oc-curs routinely. Correction for target motion must account for translational (anterior/posterior, right/left, and superior/inferior) motion. Stereotactic body radiotherapy (SBRT) delivers a very high-dose radiotherapy to targets in the body, with treatment completed in one-five fractions.

We noted that the mean percentage of tox G2 acute urinary and gastrointestinal decreases in Hypo 3DCRT versus CV 3DCRT (22 vs. 38%, and 14 vs. 28%), and decreases in Hypo-IMRT technique (18% vs. 38%, and 11 vs. 28%). We not-ed a greater reduction in extreme hypofractionat-ed especially with the Cyberknife system (12.5 vs. 38%, and 11.3 vs. 28%). A reduction in the mean percentage of late urinary and gastrointestinal toxicity results in hypofractionated versus con-ventional fractionation 3DCRT (18-14 vs. 5-7%), and with IMRT technique (8-9% vs. 18-14%). In SBRT treatment, there is a reduction of late uri-nary toxicity (11 vs. 18%), and late gastrointesti-nal toxicity (5-5.4 vs. 14%).

Table 4 shows for each group of studies pa-tients with acute/late genitourinary and gastroin-testinal toxicity G0-G1, and patients with acute/late genitourinary and gastrointestinal toxicity ≥ G2.

Table 5 shows Odds Ratio (OR) derived by comparing patients with toxicity ≥ G2 and pa-tients with G0-1 toxicity in different groups of studies.

From the analysis of RR and OR values in comparisons between groups, we found: • In comparison of IMRT Hypo vs. IMRT CV,

there is a statistically significant advantage in terms of acute GU (OR 0.55; p=0.0000), acute GI (OR 0.50; p=0.0000), late GU (OR 0.34; p=0.0000) and late GI toxicity (OR 0.63; p=0.0003);

• In comparison of 3DCRT Hypo vs. 3DCRT CV, there is a statistically significant advanta-ge in terms of acute GI (OR 0.36; p=0.0000), late GU (OR 0.35; p=0.0000) and late GI toxi-city (OR 0.49; p=0.000);

• In comparison of IMRT CV vs. 3DCRT CV, there is a statistically significant advantage in terms of acute GU (OR 0.80; p=0.0073), acute GI (OR 0.72; p=0.0003), late GU (OR 0.79; p=0.0148) and late GI toxicity (OR 0.59; p=0.000);

• In comparison of IMRT Hypo vs. 3DCRT Hypo there is a statistically significant advan-tage in terms of acute GU toxicity (OR 0.52; p=0.0000);

TABLE 4. Number of patients with acute or late genitourinary and gastrointestinal toxicity G0-G1, and ≥ G2.

Group of Studies Tox GU acute Tox GI acute Tox GU late Tox GI late

Total number of pz G0-1 ≥G2 G0-1 ≥G2 G0-1 ≥G2 G0-1 ≥G2

1 IMRT Hypo 1375 1116 259 1222 153 1287 88 1278 972 IMRT CV 1924 1351 573 1536 388 1601 323 1718 2063 3DCRT Hypo 664 458 206 589 75 609 55 604 604 3DCRT CV 1029 655 347 761 268 819 210 856 1735 SBRT 1416 1262 154 1316 100 1258 158 1354 62

7


and 13% gastrointestinal for low-dose arm; 60 and 27% genitourinary and 63 and 24% gastro-intestinal for high-dose arm. Then, we evaluated two trials with protons with conventional fraction-ation. The first, conducted by Coen et al26, with a dose of 78-79 Gy in 85 men, reported genitouri-nary/gastrointestinal acute toxicity of 50% Grade 1, 14% 1% Grade 2 and Grade 3. Late toxicity, were 33% Grade 1, Grade 26% 2, 7% Grade 3, and 1% Grade 4. The second conducted by Nihei et al27 with 50 Gy dose of Protons and boost of 24 Gy, reported genitourinary/gastrointestinal acute toxicity of 0.7% and 12%, respectively. The Grade 2 or greater late rectal and bladder toxicity was 2.0% and 4.1%.

For the group of studies with the 3DCRT tech-nique, we evaluated four prospective and one retrospective studies with the hypofractionated scheme. White et al28 evaluated 90 patients treat-ed with 57 Gy in 17 fz of 3Gy and have reported acute genitourinary toxicity G 1, 2 and 3 to 58.6, 10 and 1.1% respectively; acute gastrointestinal toxicity to 75.6, 9 and 0% respectively. The grade 1, 2 and 3 GU and GI late toxicity were 47.3, 2.4, 0%, and 40, 9.3 and 4.7%, respectively. Trama-cere et al29 evaluated 97 patients treated with a schedule of 62 Gy in 20 fractions over 5 weeks, 4 fractions of 3.1 Gy each per week, and reported genitourinary (GU) and gastrointestinal (GI) ≥ G2 acute toxicities of 21% and 15%, late of 8% and 11%.

Jereczek et al30 evaluated 337 patients treated with 70 Gy in 28 fz of 2.5 Gy and reported a G2 urinary and acute rectal toxicity of 35 and 11.3%, a late toxicity of 10.4 and 7.5%.

The Quantitative Analysis of Normal Tissue Radiation Effects in the Clinic (QUANTEC)22 emphasizes the importance of adequate organ volume delineation to get a radiation dose-vol-ume parameters and OAR radiation tolerance constraints. In this work we have analyzed the acute and late urinary and gastrointestinal toxic-ity detected in studies of radiotherapy in patients with low-intermediate risk localized prostate can-cer and we analyzed changes of toxicity related to fractionation, and technique used. In the first group, we evaluated studies using the 3DCRT technique. Schmid et al23 conducted a prospective phase II study of 178 primary prostate-cancer pa-tients, including 123 patients with low/intermedi-ate risk.

McCloskey24 has conducted a retrospective study on 222 patients treated with 3DCRT con-ventional fractionation. He has assessed the toxic-ity compared to two types of treatment, one with a total dose <75.6 Gy and another of 75.6Gy. In the first arm, the percentage of G2 acute urinary and rectal toxicity were respectively of 27 and 10%, late toxicity were 9 to 10%; to 75.6 Gy the percentage of G2 acute urinary and rectal toxicity were 32 e 7%, late toxicity there were 9 e 5%. Au-thors conclude that toxicity was not significantly correlated with a higher dose radiotherapy. Ziet-man et al25 evaluated 393 men randomized to 50.4 Gy and a boost of 19.8Gy protons in 11 fz, or 28.8 Gy in 16 fz. Two percent of patients in both arms experienced late grade 3 genitourinary toxicity, 1% of patients in the high-dose arm experienced late grade 3 GI toxicity. Acute and late toxicity of grade 2 were 51 and 22% genitourinary and 44

TABLE 5. Values of Odds Ratio (OR) of toxicity > G2 and G0-1 in different groups of studies.

Groups of studies compared OR (95%CI) p

1 vs. 2 Acute GU 0.55 (0.46-0.65) 0.0000 (IMRT Hypo vs. IMRT CV) Acute GI 0.50 (0.41-0.61) 0.0000 Late GU 0.34 (0.26-0.43) 0.0000 Late GI 0.63 (0.49-0.81) 0.0003 3 vs. 4 Acute GU 0.85 (0.69-1.05) 0.1259 (3DCRT Hypo vs. 3DCRT CV) Acute GI 0.36 (0.27-0.48) 0.0000 GU late 0.35 (0.26-0.48) 0.0000 GI late 0.49 (0.36-0.67) 0.0000 2 vs. 4 Acute GU 0.80 (0.68-0.94) 0.0073 (IMRT CV vs. 3DCRT CV) Acute GI 0.72 (0.60-0.86) 0.0003 Late GU 0.79 (0.65-0.95) 0.0148 Late GI 0.59 (0.48-0.74) 0.0000 1 vs. 3 Acute GU 0.52 (0.42-0.64) 0.0000 (IMRT Hypo vs. 3DCRT Hypo) Acute GI 0.98 (0.73-1.32) 0.9102 Late GU 0.76 (0.53-1.07) 0.1187 Late GI 0.76 (0.55-1.07) 0.1157 5 vs. 1 Acute GU 0.53 (0.42-0.65) 0.0000 (SBRT vs. IMRT Hypo) Acute GI 0.61 (0.47-0.79) 0.0002 Late GU 1.84 (1.40-2.41) 0.0000 Late GI 0.60 (0.43-0.84) 0.0023

8


Vora et al43 in a retrospective study evaluated tox-icity in 271 patients treated with 3DCRT technique and 145 patients treated with IMRT technique, all with conventional fractionation. The percentage of acute urinary and gastrointestinal G2 toxicity in two groups were 40 and 37% respectively in 3DCRT, 46 and 23% in the IMRT; late toxicity were 54 and 14% in 3DCRT, 49 and 23% in IMRT.

Of the studies with the hypofractionated scheme, Kupelian et al44 evaluated a 2.5Gy/fraction for a total dose of 70 Gy; Manabe et al45 evaluated a dose of 2-2.2Gy/fraction for a total dose of 72.6-78 Gy. The acute G2 toxicity in the two studies were 18-5.1% and18-5.8%; the late G2 toxicities were 9-3.1% and 4-12%. In three studies, the dose/frac-tion was greater than 3 Gy. Wu et al46 have evalu-ated a dose/fraction of 3.43Gy for a total dose of 55Gy, Zilli et al47 a dose/fraction of 3.85 Gy for a total dose of 54 Gy, Lock et al48 a dose/fraction of 3.16Gy for a total dose of 63.2 Gy. They recorded acute urinary and gastrointestinal G2 toxicity of 41-8; 22-2.5; 33.8-14.1 % respectively, and late G2 toxicity of 34-8; 4-3; 25-25% respectively. Shridhar et al49 evaluated 125 patients treated with 75-77.5 Gy, with mixed techniques, 3DCRT with fractions of 1.8 Gy and IMRT with 2.5 Gy/fraction to 30-32 Gy for the boost dose. In the first group the acute urinary and gastrointestinal G2 toxicity were of 6.6-18%; the late toxicity was of 6.6-3.2%; in the second group acute G2 toxicity were 14.1-10.9%; late G2 toxicity were 17.2-11.1%.

Finally, we evaluated 13 studies of the extreme hypofractionated scheme with SBRT technique, 5 with Linac, 8 with Cyberknife system. The first 5 have evaluated treatments with dose/fraction of 6.7- 10 Gy for a total dose 33.5-50 Gy and number of fractions between 4 and 5.

The mean of percentage of acute urinary and rec-tal G2 toxicity was between 21 and 16%, the late G2 toxicity between 11-5%50-54. Regarding the studies that evaluated treatment using SBRT technique with Cyberknife system, were made by 7-9.5 Gy dose/fraction for a total dose of 35-38 Gy and number of fractions between 4-5. The mean percentage of acute urinary and rectal G2 toxicity was 12.5 and 11.3%; the late G2 toxicity was 11 and 5.4%55-62.

CONCLUSIONS

Our review suggests that hypofractionated scheme, especially with advanced techniques such as IMRT, provides a greater advantage, with an increased tolerance of treatment. The new treatment systems combined with high technolo-gy, as SBRT with Cyberknife system, represent in selected classes of the risk of prostate cancer a fu-

Martin et al31 evaluated 92 patients treated with 60 Gy in 20 fz of 3Gy, reported a G2 acute urinary and rectal toxicity of 25 and 3%, a late urinary and rectal toxicity of 11 and 4%.

Lopez Guerra et al32 conducted a retrospec-tive study of 48 patients treated with hypofrac-tionated regimens included: 68.04 Gy at 2.52 Gy/fraction, 70 Gy at 2.5 Gy/fraction, and 70.2 Gy at 2.6 Gy/fraction. Multivariate analysis showed that patients treated at 2.6 Gy/fraction or those who received a total radiation dose of 70 Gy had higher rates of grade C2 acute GU toxicity. Two inter-esting studies have used the 3DCRT technique, one with conventional fractionation and one with hypofractionated, followed by a SBRT-boost with Cyberknife system to 9.5-4.75/fz the first, 9-9.75/fz the second. The mean percentage of acute geni-tourinary and gastrointestinal toxicity was 5 and 7%; the mean percentage of late toxicity was 4 and 08% respectively33,34.

Another group of studies has considered the use of IMRT technique 9 with conventional frac-tionation (4 prospective and 5 retrospective), 6 with the hypofractionated scheme. In a prospec-tive study with conventional fractionation, Fang et al35 evaluated 394 patients treated with 79.2 Gy in 44 fractions of 1.8Gy (213 treated with IMRT photon, 181 with protons). The urinary and gastrointestinal acute G2 toxicity were re-spectively 28.7, 18.3% in IMRT, 21.3, and 12.8% in PBT; G2 late toxicities were 13.8, 10.8% in IMRT, 4.3, and 12.8% in PBT. The prospective study of Goineau et al36 evaluated 38 patients treated with 76 Gy with conventional fraction-ation and reported acute urinary and gastroin-testinal G2 toxicity of 5.3%, and late G2 toxicity of 5.3 and 15.8%. Marchand et al37 evaluated the same doses in 55 patients and reported acute uri-nary and gastrointestinal G2 toxicity of 38 and 15%, late G2 toxicities of 13 and 11%. The pro-spective study of Petrongari et al38 evaluated 39 patients treated with 86 Gy dose escalation, in 43 fractions of 2 Gy. They recorded acute uri-nary and gastrointestinal G2 toxicity of 51 and 5%, and late G2 toxicities of 44 and 18%. In a retrospective study, Schild et al39 evaluated 78 patients treated with the IMRT technique and a simultaneous boost for a total dose of 81.3 Gy. They presented acute urinary and gastrointesti-nal G2 toxicity of 52 and 23%, late G2 toxicity of 12 and 1%. Takeda et al40, Tomita et al41, Cahlon et al42 have evaluated retrospectively treatments with conventional fractionation but with differ-ent dose escalation, 76-80 Gy, 74-78 Gy, 86.4Gy respectively, recording acute urinary and gas-trointestinal G2 toxicity of 8.5-6.4; 24.5-8.3; 22-13%; late G2 toxicity of 1.4-5.7; 11.2-6.6; 8-3%.

9


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ture challenge and a way to achieve a greater con-trol of radiation-related toxicity. We cannot make definitive conclusions because most studies are retrospective and prospective studies are mainly non-randomized. Next purpose of our study will be an exclusive assessment of prospective studies and an extension of the research criteria for eval-uation of any randomized studies.

ConfliCt of interests: The Authors declare that they have no conflict of interests.

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HYPOFRACTIONATED VERSUS CONVENTIONAL RADIOTHERAPY IN ... · del tumore alla prostata e testicolo – Regione Campania, Italy 2Radiation Oncology, Istituto Nazionale per lo Studio