Cancer Investigation
ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
Acute and Late Toxicity after Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Gianluca Ingrosso, Alessandra Carosi, Elisabetta Ponti, Alessandra Murgia, Daniela di Cristino, Rosaria Barbarino, Michaela Benassi, Luana Di Murro, Emilia Giudice, Pierluigi Bove & Riccardo Santoni To cite this article: Gianluca Ingrosso, Alessandra Carosi, Elisabetta Ponti, Alessandra Murgia, Daniela di Cristino, Rosaria Barbarino, Michaela Benassi, Luana Di Murro, Emilia Giudice, Pierluigi Bove & Riccardo Santoni (2014) Acute and Late Toxicity after Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer, Cancer Investigation, 32:10, 526-532, DOI: 10.3109/07357907.2014.970193 To link to this article: http://dx.doi.org/10.3109/07357907.2014.970193
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Date: 06 November 2015, At: 01:07
Cancer Investigation, 32:526–532, 2014 ISSN: 0735-7907 print / 1532-4192 online C 2014 Informa Healthcare USA, Inc. Copyright DOI: 10.3109/07357907.2014.970193
ORIGINAL ARTICLE
Acute and Late Toxicity after Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Gianluca Ingrosso,1 Alessandra Carosi,1 Elisabetta Ponti,1 Alessandra Murgia,1 Daniela di Cristino,1 Rosaria Barbarino,1 Michaela Benassi,1 Luana Di Murro,1 Emilia Giudice,1 Pierluigi Bove,2 and Riccardo Santoni1
Cancer Investigation 2014.32:526-532.
Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University General Hospital, 00133 Rome, Italy1 Department of Urology, Tor Vergata University General Hospital, 00133 Rome, Italy2 computed tomography (CBCT) allows for online set-up corrections and for evaluation of rectal and bladder filling and prostate position. Several retrospective studies reported decreased gastrointestinal (GI) and genitourinary (GU) toxicity with image-guided radiation therapy (IGRT), and improved biochemical tumour control (17, 18). In this study we report the clinical outcome and acute and late toxicity in 142 localized prostate cancer patients treated with 3D conformal image-guided radiotherapy using a high definition micro-multileaf collimator (4 mm leaf width at the isocenter) and a linac-integrated cone-beam computed tomography.
We evaluated the clinical impact of a high definition micro-multileaf collimator and a linac-integrated cone-beam computed tomography in 142 patients treated with conformal radiotherapy for localized prostate cancer to a total dose of 76 Gy. Details on treatment toxicity and tumour control were collected. The 3 years biochemical relapse-free survival was 90%. Acute and late gastrointestinal toxicities were low (3-year actuarial late toxicity of 11.2%). Acute genitourinary toxicity was relatively high, the 3-year actuarial genitourinary late toxicity was 12%. Conformal image-guided radiotherapy for localized prostate cancer leads to low rates of late toxicity with a high rate of tumor control. Keywords: Bladder & prostate cancer, Imaging, Late effects of therapy
MATERIALS AND METHODS Between January 2008 and December 2011 142 patients were treated with conformal (3DCRT) image guided radiation therapy (IGRT) for localized prostate cancer, in our Department. Patient characteristics are summarized in Table 1. The mean and median age of patients are respectively 71 and 69 years (range 46–81 years). The median PSA level is 38.14 ng/ml (range 1.31–164 ng/ml). All patients had pathologically confirmed prostate cancer and were stratified according to the National Comprehensive Cancer Network Criteria (NCCN): 60 patients were in the low risk group, 47 in the intermediate, 30 in the high risk group and 5 patients had locally advanced disease (T3b). At the time of radiotherapy 74 patients (all in the group of intermediate/high risk or locally advanced) were on hormone therapy (23 patients on LH-RH agonist, 19 patients on anti-androgen only and 26 with total androgen blockade). All patients underwent CT under radiotherapy planning R Scanner (GE conditions obtained with a GE LightSpeed Healthcare Diagnostic Imaging, Slough, UK). The scan was to start at the level of the iliac crests and continue down through the perineum, with a 2.5 mm slice thickness. A
INTRODUCTION Prostate cancer is the most common male malignancy in Western countries (1, 2); three-dimensional conformal radiotherapy (3DCRT) is one of the standard therapies for localized prostate cancer (3–9). In 3DCRT steep dose gradients and narrow margins are obtained to spare organs at risk (OAR), thus the precise treatment delivery is required; image-guidance reduces geometrical uncertainties in treatment delivery improving the precision of patient repositioning, sparing organs at risk, and escalating radiation doses. Multileaf collimators (MLCs) and high definition micromultileaf collimators (m-MLCs) are well established devices used in 3DCRT to define the field shape in order to “view” the target volume and to shield OARs (10, 11). In particular, the minor leaf width of m-MLCs affects 3D dose distribution in terms of OARs sparing, planning target volume (PTV) coverage and conformity (12–16). In prostate cancer radiotherapy several image-guidance modalities have been developed. In particular cone-beam
Correspondence to: Gianluca Ingrosso, Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University General Hospital, Viale Oxford 81, 00133 Rome, Italy, email: [email protected]; www.ptvonline.it/dip immagini. asp Received 26 March 2014; revised 23 July 2014; accepted 22 September 2014.
Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Table 1. Patient Characteristics (142 Patients) Mean Median Age (years) PSA (ng/ml) at diagnosis T-stage
Gleason score
Cancer Investigation 2014.32:526-532.
Risk group
Hormonal therapy Pre-RT urinary symptoms
71 12.34
No. of patients
Range
69 46–81 38.14 1.31–164 T1c T2a T2b T2c T3b 5 (3+2) 6 (3+3) 7 (3+4) 7 (4+3) 8 (3+5) 8 (4+4) 8 (5+3) 9 (4+5) 9 (5+4) 10 (5+5) Low Intermediate High Locally advanced Yes No Yes No
101 13 8 15 5 2 76 20 13 2 18 2 3 4 2 60 47 30 5 74 68 66 76
planning MRI was obtained in 67 patients within 20 min after CT scanning with a 3.0 T Philips Achieva Intera (Philips Medical Systems, Reigate, UK); T2 TSE (turbo-spin eco) weighted images were acquired for image registration. CT and MRI scans were obtained in a supine position on a flat couch top with the arms on the chest; ankle stocks were used to prevent rotation of the hips, and localizing tattoos were used to maintain a stable position. Bowel preparation was obtained suggesting a diet in combination with a daily mild laxative to reduce intestinal gas and obtain a reproducible bowel volume during CT acquisition and treatment sessions; patients were also invited to have a comfortably full bladder during CT scan and treatment session. For each patient the clinical target volume (CTV) and organs at risk (OARs) were outlined. CTV1 consisted of the prostate and seminal vesicles, and CTV2 prostate and base of the seminal vesicles. Planning target volumes (PTV1 and PTV2 ) were generated by an asymmetric expansion of CTVs (6 mm in all directions except at the posterior margin, where a 5 mm expansion was used). Low-risk patients were treated on prostate and base of the seminal vesicles only. The rectum was contoured as solid organ from the 8th slice (2 cm) above the anal verge to the rectosigmoid junction; the bladder was contoured in its entirety. The penile bulb was defined as a pear-shaped structure comprising the proximal part of the corpus spongiosum; femurs too were outlined. Conformal treatment plans were obtained on Pinnacle3 version 8.0 m (Philips Medical System, Andover, MA); C 2014 Informa Healthcare USA, Inc. Copyright
66 Gy were prescribed to PTV1 and 76 Gy to PTV2 ; a criterion of 95% of the target volume receiving the 95% of prescribed dose was satisfied for all plans. Daily fractions of 2 Gy (5 days a week) were delivered with 6 conformal shaped treatment fields (15 MV) using the micro-multi-leaf collimator (m-MLC Beam ModulatorTM ; 4 mm leaf width at the isocenter) of an Elekta Synergy linear accelerator (Elekta Synergy S) equipped with a kilovolt (kV) imaging system capable of acquiring 3D X-ray volume images based on kV cone-beam computed tomography (CBCT). All the images were stored and processed on a control work station (XVI). For every patient, planning CT images, with OARs, PTV and marker isocenter were transferred from Pinnacle to XVI. Daily CBCT scans were acquired for every patient before each treatment session, during the first 5 days of radiotherapy; planning CT images were matched online with the daily CBCT images using bone-matching algorithm for 3D image registration (chamfer matching); an alignment clip-box for volumes matching was defined by the physicians. The registration was evaluated by a physician using a “cut” display modality and rectal and bladder volumes were checked, in order to define prostate and OARs position and to perform on-line corrections before the treatment session; set-up errors greater than 3 mm were corrected. Thereafter CBCT was practiced 2 times a week; in patients with problems in obtaining an empty rectum CBCT was performed 3 or 4 times a week. Acute (within 90 days from the start of radiotherapy) and late genitourinary (GU) and gastrointestinal (GI) toxicities were scored by the radiation oncologist, according to the RTOG/EORTC toxicity scale. For biochemical failure definition we referred to the Phoenix definition, revised by ASTRO and RTOG in Phoenix, as a rise in PSA by 2 ng/ml or more above the nadir PSA (defined as the lowest PSA achieved) (19). Follow-up visits with PSA measurement were scheduled every 3 months during the first 2 years and every 6 months thereafter. The follow-up started from the date of the end of radiotherapy. Dose-Volume-Histograms (DVHs) were used to provide a quantitative analysis. Maximum, mean, minimum doses and a set of appropriate Vx (percent of OAR volume receiving the x dose) were evaluated for rectum and bladder; in particular we recorded V50 , V60 , V66 and V70 for the rectum and V50 , V60 and V70 for the bladder (20, 21). Statistical analysis was carried out using a commercial statistical software package (SPSS 9.0; SPSS Inc, Chicago, IL). Correlation between dose volume parameters considered as continuous variables and grade ≥ 2 toxicities were assessed by Student’s t-test for independent samples in case of normal distribution, otherwise by non-parametric Mann-Whitney test. Data were tested for normality with the KolmogorovSmirnov test. Correlation between grade ≥ 2 late toxicities and clinical parameters was performed using the χ 2 -test for categorial variables. The survival analysis was performed with Kaplan-Meier method.
G. Ingrosso et al.
Table 2. Mean values and Range of Variability of Dose-Volume-Histogram Parameters (142 Conformal Plans) Organ volume (cc) Rectum V76 V70 V66 V60 V50 Bladder V70 V60 V50 PTV1 PTV2
Volume (%)
Maximum dose (Gy)
Mean dose (Gy)
Minimum dose (Gy)
76.3 (66.0–84.9)
42.5 (23.9–54.2)
7.5 (1.6–25.4)
78.3 (66.4–84.6)
40.1 (8.6–66.8)
4.2 (1.3–24.8)
40.6 (19.4–45.0) 1.8 (0–20) 14.0 (0–30) 20.0 (3–38) 26.8 (8–48) 36.2 (12–60) 170.5 (82.4–559) 23.1 (7–55) 33.8 (11–70) 42.0 (16–73) 150.5 (92.3–258.9) 107.6 (57.2–212.0)
Cancer Investigation 2014.32:526-532.
RESULTS With a median and mean follow-up periods of 35.8 months and 35.05 months, respectively, (range 10–61.1 months) 88.73% (126/142) of patients were free from biochemical relapse, 2 patients were dead for other diseases and 9.8% (14/142) had active prostate cancer disease (5 with biochemical relapse; 7 with pelvic or lumbar-aortic lymphatic metastases and 2 with bony metastases). The 3 years biochemical relapse-free survival was 90% (Figure 1). Dose–volume histograms parameters of 142 treatment plans are reported in Table 2. All patients completed the prescribed radiation treatment, with no interruption. Table 3 reports acute and late toxicity rates. Acute GI toxicity was observed only in 34 patients: G1 in 2.1% (3/142), G2 in 20.4% (29/142), and G3 in 1.4% (2/142); acute GU toxicity was observed in 100 patients: G1 in 3.5% (5/142), G2 in 63.38% (90/142), and G3 in 3.5% (5/142). No RTOG grade 4–5 late toxicity was recorded; 5 patients (3.5%) had late G3 gastrointestinal toxicity and 1 of these presented heavy bleeding managed with laser photocoagulation; 8 pts (5.6%) had late G2 gastrointestinal toxicity. Five patients (3.5%) showed late G3 genitourinary toxicity consisting in urethral stricture (in 3 patients) and in hematuria (in 2 pa-
tients); 9 patients (6.3%) had late G2 genitourinary toxicity. Table 4 summarizes toxicity rates from different studies using IGRT. In our series the 3-year actuarial late grade ≥ 2 GI and GU toxicity rates were 11.2% and 12%, respectively (Figure 2). Table 5 summarizes the correlation analysis between dose volume parameters and grade ≥ 2 late GU and GI toxicity; while there was no correlation between DVH parameters and late GU toxicity, for late GI toxicity the mean rectal dose (D mean ) and V 50 rectal dose parameter were statistically significant (p = .03 and p = .02, respectively). Finally, we found a correlation between acute and late GI toxicity (p = .03) while no other clinical variable was statistically significant (Table 6). DISCUSSION To our knowledge this is one of the few studies demonstrating the clinical effect of 3D conformal image-guided radiotherapy using a high definition micro-multileaf collimator and a linac-integrated cone-beam computed tomography; the total dose of 76 Gy (2 Gy per fraction) can be safely delivered obtaining a 90% 3-year biochemical-free survival with a 3-year actuarial rate of late GI and GU toxicity of 11.2% and 12%, respectively. Acute grade ≥ 2 GI toxicity was observed in 21.8% of the patients (G2 in 20.4 and G3 in 1.4%). Data in literature show that a transient moderate-severe acute GI toxicity may occur in about 25% of patients (Table 4). Martin et al. (22) reported a lower acute GI toxicity rate, with a G2 toxicity of 10.1% in 259 men treated with IGRT to a total dose of 79.8 Gy (1.9 Gy per fraction). Guckenberger et al. (18) analyzed 100
Table 3. Radiation Therapy Oncology Group (RTOG) Toxicity in 142 Patients G1 GI GU
Figure 1. Biochemical relapse-free survival curve.
GI GU
G2
Acute toxicity 20.4% (29/142) 63.3% (90/142) Late toxicity 1.4% (2/142) 5.6% (8/142) 9.1% (13/142) 6.3% (9/142) 2.1% (3/142) 3.5% (5/142)
G3 1.4% (2/142) 3.5% (5/142) 3.5% (5/142) 3.5% (5/142)
Cancer Investigation
Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Table 4. Toxicity Rate from Different Studies Using IGRT G ≥ 2 acute toxicity
G ≥ 2 late toxicity
Patients
RT
Total
Fractions
Toxicity
Author
(n)
technique
dose (Gy)
(n)
scoring
GI (%)
GU (%)
GI (%)
GU (%)
Ghadjar [25] 2008 Lips [23] 2008 Martin [22] 2009
39 331 259
80 76 79.8
40 35 42
CTCAE v3.0 CTC/RTOG RTOG
3 30 10.1
64 51 33
8 10.3 4.3
31 25.3 8.6
Guckenberger [18] 2010 Gill [44] 2011 Takeda [45] 2012 Present series
75 249 141 142
IMRT IMRT 3DCRT/ IMRT IMRT IMRT IMRT 3DCRT
76.31 78 76/80 76
33 39 38/40 38
CTCAE v3.0 CTCAE v3.0 CTCAE v4.0 RTOG
12 9 1.4 21.8
41 63 9 66.8
— — 5.7 9.1
— — 6.4 9.8
Table 5. Correlation Between DVH Parameters and Late Toxicity. (Student’s t test /Mann-Whitney test)
Cancer Investigation 2014.32:526-532.
GI toxicity
GU toxicity
DVH parameter
G 0-1 (mean + sd)
G ≥ 2 (mean + sd)
p-value
G 0-1 (mean + sd)
G ≥ 2 (mean + sd)
p-value
Dmax (Gy) Dmean (Gy) Dmin (Gy) V(50) (%) V(60) (%) V(66) (%) V(70) (%) CTV (cc)
76.4 ± 2.2 42.3 ± 6.5 7.5 ± 5.0 35.7 ± 10.7 26.5 ± 8.6 19.9 ± 7.3 14.3 ± 6.5 151.0 ± 39.3
75.7 ± 3.1 45.3 ± 3.6 7.7 ± 6.9 42.0 ± 9.0 30.0 ± 7.2 22.3 ± 9.9 16.0 ± 8.6 145.5 ± 34.1
0.47 0.02∗ 0.67 0.03∗ 0.12 0.41 0.50 0.59
78.4 ± 2.3 40.2 ± 13.3 4.3 ± 4.0 42.5 ± 16.2 34.0 ± 15.6 — 23.1 ± 11.9 149.7 ± 38.8
78.3 ± 1.9 39.4 ± 7.6 2.8 ± 1.6 39.5 ± 12.1 32.6 ± 11.0 — 22.7 ± 9.4 157.3 ± 39.8
0.90 0.74 0.21 0.41 0.68 — 0.87 0.51
sd = standard deviation. ∗ p-value ≤ 0.05.
patients treated with simultaneous integrated boost (SIB) IMRT (total dose 76.23 Gy) and IGRT obtained with conebeam computed tomography; acute GI ≥ 2 toxicity was 12%. Lips et al. collected data from 331 patients with localized prostate cancer that received 76 Gy in 35 fractions using IMRT combined with IGRT; acute grade 2 GI toxicity was 30% (23). The late grade ≥ 2 GI toxicity reported in literature for patients treated with IGRT for localized prostate cancer varies from 6% to 12% (18, 23–25). In our study late grade 2 and grade 3 GI toxicity were respectively 5.6% and 3.5%, and the actuarial late grade ≥ 2 toxicity rate at 3 years was 11.2%. We found a statistically significant correlation between the rectal dose-volume parameter V50 and late toxicity and between mean rectal dose and late toxicity (Table 5). In fact, not only high but also intermediate doses delivered to the Table 6. Correlation Analysis Between Late Toxicity and Clinical Variables. (χ 2 -test)
Smoke Hypertension Age ≥ 70 Hormonal therapy Diabetes Acute toxicity Pre-RT urinary symptoms ∗
G ≥ 2 late GI toxicity
G ≥ 2 late GU toxicity
p-value
p-value
0.09 0.54 0.31 0.30
0.07 0.54 0.69
0.53 0.03∗ —
— 0.37 0.39
p-value ≤ .05.
C 2014 Informa Healthcare USA, Inc. Copyright
rectum are correlated with late GI toxicity; data in literature show that a total dose of 40–50 Gy to a large part of the rectal volume increases the incidence of late toxicity (ie rectal bleeding) (26–28) and it is important to respect dose-volume constraints in the V40 - V50 region of the DVH in order to reduce the risk of rectal toxicity. A reproducible empty rectal volume and position during CT acquisition and daily treatment session, achieved suggesting a diet in combination with a daily mild laxative, may reduce the risk of late toxicity; in fact, several studies demonstrate that also the spatial distribution of the dose, depending mainly on rectal volume and position, is important as well (27, 29, 30–33). Munbdoh et al. found that late rectal toxicity is related to the irradiation of the upper part of the rectum and to rectal size on the planning CT (33). In previous reports we reported that a daily bowel preparation is useful to control the physiological changes of the rectum during the radiation treatment (34) and that in empty rectum condition, with the upper tract of the rectum far from the posterior surface of the prostate, the use of mMLC in 3DCRT helps to respect dose-volume constraints in the V60 and V50 DVH region (35); in fact, m-MLC better protect the rectum from radiation by better adapting every beam to the shape of the PTV because of the small leaf width, with evident advantages in the development of 3D conformal treatment plans. Finally, the use of on-board cone-beam CT allows to check rectal volume and position just before the treatment session. Using the χ 2 -test we found no significant correlation between all but one clinical variable and late GI toxicity and data in literature are controversial about this issue (36); some author reports a correlation between diabetes (37) or
Cancer Investigation 2014.32:526-532.
G. Ingrosso et al.
Figure 2. (a) Actuarial late grade ≥ 2 gastrointestinal toxicity. (b) Actuarial late grade ≥ 2 genitourinary toxicity.
androgen deprivation (30) and the onset of late rectal toxicity. The only significant correlation we obtained with the χ 2 test is between acute and late GI toxicity (Table 6; p = .03), as reported in literature (38, 39). We observed an acute grade ≥ 2 GU toxicity in 66.8% of the patients (G2 toxicity of 63.38% and a G3 toxicity of 3.5%); however, it is to say that in these patients pre-existing urinary symptoms may influence GU toxicity, misleading to the analysis of urinary tract complications, which may be erroneously registered as acute events related to radiotherapy (40–42). Since 2012 we use the International Prostate Score System (IPSS) in order to score lower urinary tract symptoms prior to radiotherapy and in follow-up. Many authors in literature (Table 4) reported an acute grade ≥ 2 GU toxicity ranging between 30% to 60% after IGRT for localized prostate cancer (18, 23, 25); this wide range of GU side effects across different reports may be due to different target margins, organs at risk definition, plan development (dose constraints and treatment delivery techniques) and toxicity assessment tools.
In our series late grade 2 and grade 3 GU toxicity were respectively 6.3% and 3.5%, and the actuarial late grade ≥ 2 toxicity rate at 3 years was 12%. The late ≥ 2 GU toxicity in patients treated with IGRT for localized prostate cancer varies from 10% to 30% (18, 23–25). We found no correlation between bladder dose-volume parameters and late toxicity (Table 5). Other studies report a little or no correlation between bladder DVH constraints and toxicity (22) and it is also interesting to notice that no dose-escalation trial has shown a significant difference in GU toxicity with higher dose of radiotherapy (43). These results may be due to the fact that urinary toxicities after radiotherapy could be attributed to dose exposure to the urethra and bladder neck. In fact during radiotherapy all of the prostatic urethra receives the full dose; on the other hand, IGRT decrease the volume of the bladder neck region exposed to high doses, reducing the incidence of late toxicity (17). We believe that our low GU late toxicity rate is due to the combination of 3DCRT with a m-MLC, that allows better bladder shielding (35), and of CBCT repositioning, that reduces geometrical uncertainties in treatment delivery. Using the χ 2 -test we obtained no significant correlation between clinical variables and late GU toxicity (Table 6). Many of the issues in the literature investigating the impact of IGRT on clinical outcome refer to patients treated with IMRT (18, 23, 25, 44–45); their comparison is difficult for the different toxicity scoring system, target margins, organs at risk definition and plan development. In spite of the limitations of our study (ie retrospective analysis, short length of follow-up) it is one of few the issues investigating the combination soft tissue image-guidance and m-MLC 3D conformal radiotherapy for localized prostate cancer; we obtained low 3-year toxicity rates, as reported in other works (23, 25, 45), and comparable disease control rates (17, 46). Toxicity is a serious concern in radiotherapy and new technologies are available allowing dose escalation and sparing organs at risk at the same time. Three-dimensional conformal IGRT for localized prostate cancer, using a high definition micro-multileaf collimator and a linac-integrated CBCT, is feasible and leads to low rates of late rectal and urinary toxicity without impairment of tumour control probabilities. DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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marker-based position verification: acute and late toxicity in 331 patients. Radiat Oncol 2008;21;3:15. Marchand V, Bourdin S, Charbonnel C, et al. No impairment of quality of life 18 months after high-dose intensity-modulated radiotherapy for localized prostate cancer: a prospective study. Int J Radiat Oncol Biol Phys 2010;77(4):1053–1059. Ghadjar P, Vock J, Vetterli D, et al. Acute and late toxicity in prostate cancer patients treated by dose escalated intensity modulated radiation therapy and organ tracking. Radiat Oncol 2008;20(3):35. Jackson A, Skwarchuk M, Zelefsky M, et al. Late rectal bleeding after conformal radiotherapy of prostate cancer. II. Volume effects and dose-volume histograms. Int J Radiat Oncol Biol Phys 2001;49(3):685–698. Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: analysis of a large group of patients pooled from three institutions. Radiother Oncol 2002;64(1):1–12. Wachter S, Gerstner N, Goldner G, et al. Rectal sequelae after conformal radiotherapy of prostate cancer: dose-volume histograms as predictive factors. Radiother Oncol 2001;59(1):65– 70. Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose-volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys 2003;57(4):953–962. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys 2000;47(1):103–113. Heemsbergen WD, Hoogeman MS, Hart GA, et al. Gastrointestinal toxicity and its relation to dose distributions in the anorectal region of prostate cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 2005;61(4):1011–1018. Peeters ST, Lebesque JV, Heemsbergen WD, et al. Localized volume effects for late rectal and anal toxicity after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2006;64(4):1151–1161. Munbodh R1, Jackson A, Bauer J, et al. Dosimetric and anatomic indicators of late rectal toxicity after high-dose intensity modulated radiation therapy for prostate cancer. Med Phys 2008;35(5):2137–2150. Falco MD, D’Andrea M, Fedele D, et al. Preliminary experience of a predictive model to define rectal volume and rectal dose during the treatment of prostate cancer. Br J Radiol 2011;84(1005):819–825. Carosi A, Ingrosso G, Ponti E, et al. Dosimetric effect of Elekta Beam Modulator micromultileaf in three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer. Med Dosim 2014 (in press). Fiorino C, Valdagni R, Rancati T, et al. Dose-volume effects for normal tissues in external radiotherapy: Pelvis. Radiother Oncol 2009;93(2):153–167. Herold DM, Hanlon AL, Hanks GE. Diabetes mellitus: a predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys 1999;43(3):475–479. Vargas C, Martinez A, Kestin LL, et al. Dose-volume analysis of predictors for chronic rectal toxicity after treatment of prostate cancer with adaptive image-guided radiotherapy. Int J Radiat Oncol Biol Phys 2005;62(5):1297–1308. 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(4):1019–1034. Schultheiss TE, Lee WR, Hunt MA, et al. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37(1):3–11. Liu M, Pickles T, Berthelet E, et al. Urinary incontinence in prostate cancer patients treated with external beam radiotherapy. Radiother Oncol 2005;74(2):197–201.
G. Ingrosso et al. 45. Takeda K, Takai Y, Narazaki K, et al. Treatment outcome of high-dose image-guided intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer at a single institute in Japan. Radiat Oncol 2012;6(7): 105. 46. Sveistrup J, Af Rosensch¨old PM, Deasy JO, et al. Improvement in toxicity in high risk prostate cancer patients treated with imageguided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance. Radiat Oncol 2014;49(1):44.
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42. Sandhu AS, Zelefsky MJ, Lee HJ, et al. Long-term urinary toxicity after 3-dimensional conformal radiotherapy for prostate cancer in patients with prior history of transurethral resection. Int J Radiat Oncol Biol Phys 2000;48(3):643–647. 43. Al-Mamgani A, van Putten WL, Heemsbergen WD, et al. Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2008;72(4):980–988. 44. Gill S, Thomas J, Fox C, et al. Acute toxicity in prostate cancer patients treated with and without image-guided radiotherapy. Radiat Oncol 2011;28(6):145.
Cancer Investigation
ISSN: 0735-7907 (Print) 1532-4192 (Online) Journal homepage: http://www.tandfonline.com/loi/icnv20
Acute and Late Toxicity after Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Gianluca Ingrosso, Alessandra Carosi, Elisabetta Ponti, Alessandra Murgia, Daniela di Cristino, Rosaria Barbarino, Michaela Benassi, Luana Di Murro, Emilia Giudice, Pierluigi Bove & Riccardo Santoni To cite this article: Gianluca Ingrosso, Alessandra Carosi, Elisabetta Ponti, Alessandra Murgia, Daniela di Cristino, Rosaria Barbarino, Michaela Benassi, Luana Di Murro, Emilia Giudice, Pierluigi Bove & Riccardo Santoni (2014) Acute and Late Toxicity after Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer, Cancer Investigation, 32:10, 526-532, DOI: 10.3109/07357907.2014.970193 To link to this article: http://dx.doi.org/10.3109/07357907.2014.970193
Published online: 27 Oct 2014.
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Date: 06 November 2015, At: 01:07
Cancer Investigation, 32:526–532, 2014 ISSN: 0735-7907 print / 1532-4192 online C 2014 Informa Healthcare USA, Inc. Copyright DOI: 10.3109/07357907.2014.970193
ORIGINAL ARTICLE
Acute and Late Toxicity after Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Gianluca Ingrosso,1 Alessandra Carosi,1 Elisabetta Ponti,1 Alessandra Murgia,1 Daniela di Cristino,1 Rosaria Barbarino,1 Michaela Benassi,1 Luana Di Murro,1 Emilia Giudice,1 Pierluigi Bove,2 and Riccardo Santoni1
Cancer Investigation 2014.32:526-532.
Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University General Hospital, 00133 Rome, Italy1 Department of Urology, Tor Vergata University General Hospital, 00133 Rome, Italy2 computed tomography (CBCT) allows for online set-up corrections and for evaluation of rectal and bladder filling and prostate position. Several retrospective studies reported decreased gastrointestinal (GI) and genitourinary (GU) toxicity with image-guided radiation therapy (IGRT), and improved biochemical tumour control (17, 18). In this study we report the clinical outcome and acute and late toxicity in 142 localized prostate cancer patients treated with 3D conformal image-guided radiotherapy using a high definition micro-multileaf collimator (4 mm leaf width at the isocenter) and a linac-integrated cone-beam computed tomography.
We evaluated the clinical impact of a high definition micro-multileaf collimator and a linac-integrated cone-beam computed tomography in 142 patients treated with conformal radiotherapy for localized prostate cancer to a total dose of 76 Gy. Details on treatment toxicity and tumour control were collected. The 3 years biochemical relapse-free survival was 90%. Acute and late gastrointestinal toxicities were low (3-year actuarial late toxicity of 11.2%). Acute genitourinary toxicity was relatively high, the 3-year actuarial genitourinary late toxicity was 12%. Conformal image-guided radiotherapy for localized prostate cancer leads to low rates of late toxicity with a high rate of tumor control. Keywords: Bladder & prostate cancer, Imaging, Late effects of therapy
MATERIALS AND METHODS Between January 2008 and December 2011 142 patients were treated with conformal (3DCRT) image guided radiation therapy (IGRT) for localized prostate cancer, in our Department. Patient characteristics are summarized in Table 1. The mean and median age of patients are respectively 71 and 69 years (range 46–81 years). The median PSA level is 38.14 ng/ml (range 1.31–164 ng/ml). All patients had pathologically confirmed prostate cancer and were stratified according to the National Comprehensive Cancer Network Criteria (NCCN): 60 patients were in the low risk group, 47 in the intermediate, 30 in the high risk group and 5 patients had locally advanced disease (T3b). At the time of radiotherapy 74 patients (all in the group of intermediate/high risk or locally advanced) were on hormone therapy (23 patients on LH-RH agonist, 19 patients on anti-androgen only and 26 with total androgen blockade). All patients underwent CT under radiotherapy planning R Scanner (GE conditions obtained with a GE LightSpeed Healthcare Diagnostic Imaging, Slough, UK). The scan was to start at the level of the iliac crests and continue down through the perineum, with a 2.5 mm slice thickness. A
INTRODUCTION Prostate cancer is the most common male malignancy in Western countries (1, 2); three-dimensional conformal radiotherapy (3DCRT) is one of the standard therapies for localized prostate cancer (3–9). In 3DCRT steep dose gradients and narrow margins are obtained to spare organs at risk (OAR), thus the precise treatment delivery is required; image-guidance reduces geometrical uncertainties in treatment delivery improving the precision of patient repositioning, sparing organs at risk, and escalating radiation doses. Multileaf collimators (MLCs) and high definition micromultileaf collimators (m-MLCs) are well established devices used in 3DCRT to define the field shape in order to “view” the target volume and to shield OARs (10, 11). In particular, the minor leaf width of m-MLCs affects 3D dose distribution in terms of OARs sparing, planning target volume (PTV) coverage and conformity (12–16). In prostate cancer radiotherapy several image-guidance modalities have been developed. In particular cone-beam
Correspondence to: Gianluca Ingrosso, Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University General Hospital, Viale Oxford 81, 00133 Rome, Italy, email: [email protected]; www.ptvonline.it/dip immagini. asp Received 26 March 2014; revised 23 July 2014; accepted 22 September 2014.
Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Table 1. Patient Characteristics (142 Patients) Mean Median Age (years) PSA (ng/ml) at diagnosis T-stage
Gleason score
Cancer Investigation 2014.32:526-532.
Risk group
Hormonal therapy Pre-RT urinary symptoms
71 12.34
No. of patients
Range
69 46–81 38.14 1.31–164 T1c T2a T2b T2c T3b 5 (3+2) 6 (3+3) 7 (3+4) 7 (4+3) 8 (3+5) 8 (4+4) 8 (5+3) 9 (4+5) 9 (5+4) 10 (5+5) Low Intermediate High Locally advanced Yes No Yes No
101 13 8 15 5 2 76 20 13 2 18 2 3 4 2 60 47 30 5 74 68 66 76
planning MRI was obtained in 67 patients within 20 min after CT scanning with a 3.0 T Philips Achieva Intera (Philips Medical Systems, Reigate, UK); T2 TSE (turbo-spin eco) weighted images were acquired for image registration. CT and MRI scans were obtained in a supine position on a flat couch top with the arms on the chest; ankle stocks were used to prevent rotation of the hips, and localizing tattoos were used to maintain a stable position. Bowel preparation was obtained suggesting a diet in combination with a daily mild laxative to reduce intestinal gas and obtain a reproducible bowel volume during CT acquisition and treatment sessions; patients were also invited to have a comfortably full bladder during CT scan and treatment session. For each patient the clinical target volume (CTV) and organs at risk (OARs) were outlined. CTV1 consisted of the prostate and seminal vesicles, and CTV2 prostate and base of the seminal vesicles. Planning target volumes (PTV1 and PTV2 ) were generated by an asymmetric expansion of CTVs (6 mm in all directions except at the posterior margin, where a 5 mm expansion was used). Low-risk patients were treated on prostate and base of the seminal vesicles only. The rectum was contoured as solid organ from the 8th slice (2 cm) above the anal verge to the rectosigmoid junction; the bladder was contoured in its entirety. The penile bulb was defined as a pear-shaped structure comprising the proximal part of the corpus spongiosum; femurs too were outlined. Conformal treatment plans were obtained on Pinnacle3 version 8.0 m (Philips Medical System, Andover, MA); C 2014 Informa Healthcare USA, Inc. Copyright
66 Gy were prescribed to PTV1 and 76 Gy to PTV2 ; a criterion of 95% of the target volume receiving the 95% of prescribed dose was satisfied for all plans. Daily fractions of 2 Gy (5 days a week) were delivered with 6 conformal shaped treatment fields (15 MV) using the micro-multi-leaf collimator (m-MLC Beam ModulatorTM ; 4 mm leaf width at the isocenter) of an Elekta Synergy linear accelerator (Elekta Synergy S) equipped with a kilovolt (kV) imaging system capable of acquiring 3D X-ray volume images based on kV cone-beam computed tomography (CBCT). All the images were stored and processed on a control work station (XVI). For every patient, planning CT images, with OARs, PTV and marker isocenter were transferred from Pinnacle to XVI. Daily CBCT scans were acquired for every patient before each treatment session, during the first 5 days of radiotherapy; planning CT images were matched online with the daily CBCT images using bone-matching algorithm for 3D image registration (chamfer matching); an alignment clip-box for volumes matching was defined by the physicians. The registration was evaluated by a physician using a “cut” display modality and rectal and bladder volumes were checked, in order to define prostate and OARs position and to perform on-line corrections before the treatment session; set-up errors greater than 3 mm were corrected. Thereafter CBCT was practiced 2 times a week; in patients with problems in obtaining an empty rectum CBCT was performed 3 or 4 times a week. Acute (within 90 days from the start of radiotherapy) and late genitourinary (GU) and gastrointestinal (GI) toxicities were scored by the radiation oncologist, according to the RTOG/EORTC toxicity scale. For biochemical failure definition we referred to the Phoenix definition, revised by ASTRO and RTOG in Phoenix, as a rise in PSA by 2 ng/ml or more above the nadir PSA (defined as the lowest PSA achieved) (19). Follow-up visits with PSA measurement were scheduled every 3 months during the first 2 years and every 6 months thereafter. The follow-up started from the date of the end of radiotherapy. Dose-Volume-Histograms (DVHs) were used to provide a quantitative analysis. Maximum, mean, minimum doses and a set of appropriate Vx (percent of OAR volume receiving the x dose) were evaluated for rectum and bladder; in particular we recorded V50 , V60 , V66 and V70 for the rectum and V50 , V60 and V70 for the bladder (20, 21). Statistical analysis was carried out using a commercial statistical software package (SPSS 9.0; SPSS Inc, Chicago, IL). Correlation between dose volume parameters considered as continuous variables and grade ≥ 2 toxicities were assessed by Student’s t-test for independent samples in case of normal distribution, otherwise by non-parametric Mann-Whitney test. Data were tested for normality with the KolmogorovSmirnov test. Correlation between grade ≥ 2 late toxicities and clinical parameters was performed using the χ 2 -test for categorial variables. The survival analysis was performed with Kaplan-Meier method.
G. Ingrosso et al.
Table 2. Mean values and Range of Variability of Dose-Volume-Histogram Parameters (142 Conformal Plans) Organ volume (cc) Rectum V76 V70 V66 V60 V50 Bladder V70 V60 V50 PTV1 PTV2
Volume (%)
Maximum dose (Gy)
Mean dose (Gy)
Minimum dose (Gy)
76.3 (66.0–84.9)
42.5 (23.9–54.2)
7.5 (1.6–25.4)
78.3 (66.4–84.6)
40.1 (8.6–66.8)
4.2 (1.3–24.8)
40.6 (19.4–45.0) 1.8 (0–20) 14.0 (0–30) 20.0 (3–38) 26.8 (8–48) 36.2 (12–60) 170.5 (82.4–559) 23.1 (7–55) 33.8 (11–70) 42.0 (16–73) 150.5 (92.3–258.9) 107.6 (57.2–212.0)
Cancer Investigation 2014.32:526-532.
RESULTS With a median and mean follow-up periods of 35.8 months and 35.05 months, respectively, (range 10–61.1 months) 88.73% (126/142) of patients were free from biochemical relapse, 2 patients were dead for other diseases and 9.8% (14/142) had active prostate cancer disease (5 with biochemical relapse; 7 with pelvic or lumbar-aortic lymphatic metastases and 2 with bony metastases). The 3 years biochemical relapse-free survival was 90% (Figure 1). Dose–volume histograms parameters of 142 treatment plans are reported in Table 2. All patients completed the prescribed radiation treatment, with no interruption. Table 3 reports acute and late toxicity rates. Acute GI toxicity was observed only in 34 patients: G1 in 2.1% (3/142), G2 in 20.4% (29/142), and G3 in 1.4% (2/142); acute GU toxicity was observed in 100 patients: G1 in 3.5% (5/142), G2 in 63.38% (90/142), and G3 in 3.5% (5/142). No RTOG grade 4–5 late toxicity was recorded; 5 patients (3.5%) had late G3 gastrointestinal toxicity and 1 of these presented heavy bleeding managed with laser photocoagulation; 8 pts (5.6%) had late G2 gastrointestinal toxicity. Five patients (3.5%) showed late G3 genitourinary toxicity consisting in urethral stricture (in 3 patients) and in hematuria (in 2 pa-
tients); 9 patients (6.3%) had late G2 genitourinary toxicity. Table 4 summarizes toxicity rates from different studies using IGRT. In our series the 3-year actuarial late grade ≥ 2 GI and GU toxicity rates were 11.2% and 12%, respectively (Figure 2). Table 5 summarizes the correlation analysis between dose volume parameters and grade ≥ 2 late GU and GI toxicity; while there was no correlation between DVH parameters and late GU toxicity, for late GI toxicity the mean rectal dose (D mean ) and V 50 rectal dose parameter were statistically significant (p = .03 and p = .02, respectively). Finally, we found a correlation between acute and late GI toxicity (p = .03) while no other clinical variable was statistically significant (Table 6). DISCUSSION To our knowledge this is one of the few studies demonstrating the clinical effect of 3D conformal image-guided radiotherapy using a high definition micro-multileaf collimator and a linac-integrated cone-beam computed tomography; the total dose of 76 Gy (2 Gy per fraction) can be safely delivered obtaining a 90% 3-year biochemical-free survival with a 3-year actuarial rate of late GI and GU toxicity of 11.2% and 12%, respectively. Acute grade ≥ 2 GI toxicity was observed in 21.8% of the patients (G2 in 20.4 and G3 in 1.4%). Data in literature show that a transient moderate-severe acute GI toxicity may occur in about 25% of patients (Table 4). Martin et al. (22) reported a lower acute GI toxicity rate, with a G2 toxicity of 10.1% in 259 men treated with IGRT to a total dose of 79.8 Gy (1.9 Gy per fraction). Guckenberger et al. (18) analyzed 100
Table 3. Radiation Therapy Oncology Group (RTOG) Toxicity in 142 Patients G1 GI GU
Figure 1. Biochemical relapse-free survival curve.
GI GU
G2
Acute toxicity 20.4% (29/142) 63.3% (90/142) Late toxicity 1.4% (2/142) 5.6% (8/142) 9.1% (13/142) 6.3% (9/142) 2.1% (3/142) 3.5% (5/142)
G3 1.4% (2/142) 3.5% (5/142) 3.5% (5/142) 3.5% (5/142)
Cancer Investigation
Three-Dimensional Conformal Image-Guided Radiotherapy for Localized Prostate Cancer Table 4. Toxicity Rate from Different Studies Using IGRT G ≥ 2 acute toxicity
G ≥ 2 late toxicity
Patients
RT
Total
Fractions
Toxicity
Author
(n)
technique
dose (Gy)
(n)
scoring
GI (%)
GU (%)
GI (%)
GU (%)
Ghadjar [25] 2008 Lips [23] 2008 Martin [22] 2009
39 331 259
80 76 79.8
40 35 42
CTCAE v3.0 CTC/RTOG RTOG
3 30 10.1
64 51 33
8 10.3 4.3
31 25.3 8.6
Guckenberger [18] 2010 Gill [44] 2011 Takeda [45] 2012 Present series
75 249 141 142
IMRT IMRT 3DCRT/ IMRT IMRT IMRT IMRT 3DCRT
76.31 78 76/80 76
33 39 38/40 38
CTCAE v3.0 CTCAE v3.0 CTCAE v4.0 RTOG
12 9 1.4 21.8
41 63 9 66.8
— — 5.7 9.1
— — 6.4 9.8
Table 5. Correlation Between DVH Parameters and Late Toxicity. (Student’s t test /Mann-Whitney test)
Cancer Investigation 2014.32:526-532.
GI toxicity
GU toxicity
DVH parameter
G 0-1 (mean + sd)
G ≥ 2 (mean + sd)
p-value
G 0-1 (mean + sd)
G ≥ 2 (mean + sd)
p-value
Dmax (Gy) Dmean (Gy) Dmin (Gy) V(50) (%) V(60) (%) V(66) (%) V(70) (%) CTV (cc)
76.4 ± 2.2 42.3 ± 6.5 7.5 ± 5.0 35.7 ± 10.7 26.5 ± 8.6 19.9 ± 7.3 14.3 ± 6.5 151.0 ± 39.3
75.7 ± 3.1 45.3 ± 3.6 7.7 ± 6.9 42.0 ± 9.0 30.0 ± 7.2 22.3 ± 9.9 16.0 ± 8.6 145.5 ± 34.1
0.47 0.02∗ 0.67 0.03∗ 0.12 0.41 0.50 0.59
78.4 ± 2.3 40.2 ± 13.3 4.3 ± 4.0 42.5 ± 16.2 34.0 ± 15.6 — 23.1 ± 11.9 149.7 ± 38.8
78.3 ± 1.9 39.4 ± 7.6 2.8 ± 1.6 39.5 ± 12.1 32.6 ± 11.0 — 22.7 ± 9.4 157.3 ± 39.8
0.90 0.74 0.21 0.41 0.68 — 0.87 0.51
sd = standard deviation. ∗ p-value ≤ 0.05.
patients treated with simultaneous integrated boost (SIB) IMRT (total dose 76.23 Gy) and IGRT obtained with conebeam computed tomography; acute GI ≥ 2 toxicity was 12%. Lips et al. collected data from 331 patients with localized prostate cancer that received 76 Gy in 35 fractions using IMRT combined with IGRT; acute grade 2 GI toxicity was 30% (23). The late grade ≥ 2 GI toxicity reported in literature for patients treated with IGRT for localized prostate cancer varies from 6% to 12% (18, 23–25). In our study late grade 2 and grade 3 GI toxicity were respectively 5.6% and 3.5%, and the actuarial late grade ≥ 2 toxicity rate at 3 years was 11.2%. We found a statistically significant correlation between the rectal dose-volume parameter V50 and late toxicity and between mean rectal dose and late toxicity (Table 5). In fact, not only high but also intermediate doses delivered to the Table 6. Correlation Analysis Between Late Toxicity and Clinical Variables. (χ 2 -test)
Smoke Hypertension Age ≥ 70 Hormonal therapy Diabetes Acute toxicity Pre-RT urinary symptoms ∗
G ≥ 2 late GI toxicity
G ≥ 2 late GU toxicity
p-value
p-value
0.09 0.54 0.31 0.30
0.07 0.54 0.69
0.53 0.03∗ —
— 0.37 0.39
p-value ≤ .05.
C 2014 Informa Healthcare USA, Inc. Copyright
rectum are correlated with late GI toxicity; data in literature show that a total dose of 40–50 Gy to a large part of the rectal volume increases the incidence of late toxicity (ie rectal bleeding) (26–28) and it is important to respect dose-volume constraints in the V40 - V50 region of the DVH in order to reduce the risk of rectal toxicity. A reproducible empty rectal volume and position during CT acquisition and daily treatment session, achieved suggesting a diet in combination with a daily mild laxative, may reduce the risk of late toxicity; in fact, several studies demonstrate that also the spatial distribution of the dose, depending mainly on rectal volume and position, is important as well (27, 29, 30–33). Munbdoh et al. found that late rectal toxicity is related to the irradiation of the upper part of the rectum and to rectal size on the planning CT (33). In previous reports we reported that a daily bowel preparation is useful to control the physiological changes of the rectum during the radiation treatment (34) and that in empty rectum condition, with the upper tract of the rectum far from the posterior surface of the prostate, the use of mMLC in 3DCRT helps to respect dose-volume constraints in the V60 and V50 DVH region (35); in fact, m-MLC better protect the rectum from radiation by better adapting every beam to the shape of the PTV because of the small leaf width, with evident advantages in the development of 3D conformal treatment plans. Finally, the use of on-board cone-beam CT allows to check rectal volume and position just before the treatment session. Using the χ 2 -test we found no significant correlation between all but one clinical variable and late GI toxicity and data in literature are controversial about this issue (36); some author reports a correlation between diabetes (37) or
Cancer Investigation 2014.32:526-532.
G. Ingrosso et al.
Figure 2. (a) Actuarial late grade ≥ 2 gastrointestinal toxicity. (b) Actuarial late grade ≥ 2 genitourinary toxicity.
androgen deprivation (30) and the onset of late rectal toxicity. The only significant correlation we obtained with the χ 2 test is between acute and late GI toxicity (Table 6; p = .03), as reported in literature (38, 39). We observed an acute grade ≥ 2 GU toxicity in 66.8% of the patients (G2 toxicity of 63.38% and a G3 toxicity of 3.5%); however, it is to say that in these patients pre-existing urinary symptoms may influence GU toxicity, misleading to the analysis of urinary tract complications, which may be erroneously registered as acute events related to radiotherapy (40–42). Since 2012 we use the International Prostate Score System (IPSS) in order to score lower urinary tract symptoms prior to radiotherapy and in follow-up. Many authors in literature (Table 4) reported an acute grade ≥ 2 GU toxicity ranging between 30% to 60% after IGRT for localized prostate cancer (18, 23, 25); this wide range of GU side effects across different reports may be due to different target margins, organs at risk definition, plan development (dose constraints and treatment delivery techniques) and toxicity assessment tools.
In our series late grade 2 and grade 3 GU toxicity were respectively 6.3% and 3.5%, and the actuarial late grade ≥ 2 toxicity rate at 3 years was 12%. The late ≥ 2 GU toxicity in patients treated with IGRT for localized prostate cancer varies from 10% to 30% (18, 23–25). We found no correlation between bladder dose-volume parameters and late toxicity (Table 5). Other studies report a little or no correlation between bladder DVH constraints and toxicity (22) and it is also interesting to notice that no dose-escalation trial has shown a significant difference in GU toxicity with higher dose of radiotherapy (43). These results may be due to the fact that urinary toxicities after radiotherapy could be attributed to dose exposure to the urethra and bladder neck. In fact during radiotherapy all of the prostatic urethra receives the full dose; on the other hand, IGRT decrease the volume of the bladder neck region exposed to high doses, reducing the incidence of late toxicity (17). We believe that our low GU late toxicity rate is due to the combination of 3DCRT with a m-MLC, that allows better bladder shielding (35), and of CBCT repositioning, that reduces geometrical uncertainties in treatment delivery. Using the χ 2 -test we obtained no significant correlation between clinical variables and late GU toxicity (Table 6). Many of the issues in the literature investigating the impact of IGRT on clinical outcome refer to patients treated with IMRT (18, 23, 25, 44–45); their comparison is difficult for the different toxicity scoring system, target margins, organs at risk definition and plan development. In spite of the limitations of our study (ie retrospective analysis, short length of follow-up) it is one of few the issues investigating the combination soft tissue image-guidance and m-MLC 3D conformal radiotherapy for localized prostate cancer; we obtained low 3-year toxicity rates, as reported in other works (23, 25, 45), and comparable disease control rates (17, 46). Toxicity is a serious concern in radiotherapy and new technologies are available allowing dose escalation and sparing organs at risk at the same time. Three-dimensional conformal IGRT for localized prostate cancer, using a high definition micro-multileaf collimator and a linac-integrated CBCT, is feasible and leads to low rates of late rectal and urinary toxicity without impairment of tumour control probabilities. DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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