
==== Front
Adv Radiat Oncol
Adv Radiat Oncol
Advances in Radiation Oncology
2452-1094
Elsevier

S2452-1094(24)00175-1
10.1016/j.adro.2024.101612
101612
Scientific Article
Clinical and Dosimetric Comparison Between Non-image Guided Radiation Therapy and Fiducial-Based Image Guided Radiation Therapy With or Without Reduced Margin in Intensity Modulated Radiation Therapy for Prostate Cancer
Serizawa Itsuko PhD itsuko.serizawa@jfcr.or.jp
a⁎
Kozuka Takuyo PhD b
Soyano Takashi MD c
Sasamura Kazuma MD d
Kamima Tatsuya Bsc a
Kunogi Hiroaki PhD a
Kurihara Nozomi MPh e
Numao Noboru PhD f
Yamamoto Shinya PhD f
Yonese Junji PhD f
Yoshioka Yasuo PhD a
a Department of Radiation Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
b Department of Radiology, University of Tokyo Hospital, Tokyo, Japan
c Department of Radiation Oncology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
d Department of Radiology, Musashino Red Cross Hospital, Tokyo, Japan
e Department of Clinical Trial Planning and Management, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
f Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
⁎ Corresponding author: Itsuko Serizawa, PhD itsuko.serizawa@jfcr.or.jp
24 8 2024
10 2024
24 8 2024
9 10 10161223 1 2024
12 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Purpose

This study aimed to compare the outcomes and toxicities between patients treated with image guided radiation therapy (IGRT) using fiducial markers and non-IGRT in intensity modulated radiation therapy (IMRT) for prostate cancer.

Methods and Materials

In total, 518 patients with intermediate- and high-risk prostate cancer received IMRT with 78 Gy in 39 fractions after neoadjuvant androgen deprivation therapy for at least 3 months. Of these patients, 371 were in the non-IGRT group and 147 in the IGRT group, including the IGRT-A group using the same margins as the non-IGRT group and the IGRT-B group using reduced margins. The median follow-up periods for the non-IGRT, IGRT-A, and IGRT-B groups were 99 months, 88 months, and 63 months, respectively.

Results

The 5-year biochemical recurrence-free survival rates in the non-IGRT, IGRT-A, and IGRT-B groups were 88%, 95%, and 98% (non-IGRT vs IGRT-A, P = .396; IGRT-A vs IGRT-B, P = .426), respectively. Those for intermediate- and high-risk patients were 94%, 93%, and 96% (non-IGRT vs IGRT-A, P = .916; IGRT-A vs IGRT-B, P = .646), respectively, and 87%, 96%, and 100% (non-IGRT vs IGRT-A, P = .500; IGRT-A vs IGRT-B, P = .483), respectively. For the non-IGRT and IGRT-A groups, the rates of acute grade ≥ 2 gastrointestinal toxicities and late grade ≥ 2 genitourinary toxicities were 17% and 7% (P = .019), respectively, and 28% and 16% (P = .028), respectively. In the IGRT-A and IGRT-B groups, the rates of acute grade ≥ 2 genitourinary toxicities were 45% and 21% (P = .003), respectively. All V60Gy = the volume at least received 60Gy and V70Gy = the volume at least received 70Gy values of the bladder and rectal walls in the IGRT-B group were smaller than those in the IGRT-A group.

Conclusions

IGRT with fiducial markers results in lower acute and late toxicities compared with non-IGRT in IMRT for intermediate- and high-risk prostate cancer. Moreover, the toxicities are further decreased by reducing the margins in the treatment planning under IGRT. These processes do not decrease the biochemical recurrence-free survival rates.
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pmcIntroduction

Radiation therapy is one of the most effective treatment modalities for localized prostate cancer, and its clinical outcomes are comparable with those of surgery.1 Intensity modulated radiation therapy (IMRT) has made it possible to deliver a higher dose of radiation to the prostate and reduce the dose to the surrounding normal organs at risk, such as the rectum.2, 3, 4, 5, 6 A previous study reported the long-term outcomes of IMRT using a uniform dose of 78 Gy in 39 fractions, in which the rates of biochemical recurrence-free survival (BRFS) for intermediate- and high-risk patients were 86% and 76% at 8 years, respectively.7 Moreover, in this study, the crude incidence rate of late grade 2 to 3 genitourinary (GU) toxicity was 28%, and that of late grade 3 GU toxicity was 2%. The crude incidence rate of late grade 2 gastrointestinal (GI) toxicity was 5%, and cases of late grade 3 GI toxicity were not observed. This previous study did not adopt image guided radiation therapy (IGRT).

Few studies have compared the outcomes between IGRT and non-IGRT for prostate cancer, in many of which late GU and/or GI toxicities have decreased with the use of IGRT.8, 9, 10, 11, 12, 13, 14, 15, 16, 17 In addition, some authors have reported improved BRFS after IGRT.18, 19, 20, 21, 22 We also initiated IGRT using a fiducial marker inserted into the prostate in February 2013. Subsequently, from January 2016, we reduced the prostate-to-clinical target volume (CTV) margin from 5 to 3 mm and the CTV-to-planning target volume (PTV) margin from 5 to 4 mm. Consequently, we established 3 cohorts, including the following: (1) the non-IGRT cohort, (2) IGRT cohort using the same margin as in (1), and (3) IGRT cohort with a reduced margin. We hypothesized that IGRT with a reduced margin would decrease the rate of late GU and/or GI toxicities while maintaining or improving the BRFS rate because of its accurate irradiation. This study aimed to examine this hypothesis by retrospectively comparing the long-term clinical outcomes among the 3 cohorts and their dosimetry to explain the differences in clinical outcomes.

Methods and Materials

Between January 2007 and March 2018, 1072 patients with T1c-T3bN0M0 prostate cancer were treated with IMRT at our hospital. All patients had biopsy-proven adenocarcinoma, and they were staged using the 2018 Union for International Cancer Control Staging System after bone scintigraphy, pelvic computed tomography (CT), and prostate magnetic resonance imaging (MRI). We classified those with T1c-T2a, prostate-specific antigen (PSA) < 10 ng/mL, and Gleason score (GS) ≤ 6 as low-risk; those with T2b-c, PSA 10 to 20, or GS 7 as intermediate-risk; and those with T3a-b, PSA > 20 ng/mL, or GS ≥ 8 as high-risk patients according to the National Comprehensive Cancer Network guidelines.23 None of the patients received whole pelvic radiation therapy or perirectal spacers. From the 1072 patients, we excluded 227 patients who had received hypofractionated IMRT, 133 patients classified as low-risk or whose radiation dose was <78 Gy, 28 patients with a follow-up period of <2 years, 7 patients who had been diagnosed with castration-resistant prostate cancer at the time of IMRT, 6 patients who had been treated with high-intensity focused ultrasound or holmium enucleation of the prostate before IMRT, 4 patients who could not finish the planned radiation therapy course, 4 patients whose duration of androgen deprivation therapy (ADT) was missing, and 1 patient whose GS was missing.

The remaining 661 patients were all intermediate- or high-risk patients treated with IMRT using 78 Gy/39 fractions and with a minimum follow-up period of 2 years. Among them, we further excluded 143 patients who had received ADT for <3 months and expected the same condition before IMRT as much as possible for a fair comparison. ADT consisted of a luteinizing hormone-releasing hormone agonist and an antiandrogen. In principle, neoadjuvant ADT was administered for 6 months before IMRT, and for high-risk patients only, adjuvant ADT was continued so that the total duration of ADT was 2 years. ADT was discontinued if the patient experienced adverse events associated with its use. The remaining 518 patients were included in this study. Their characteristics are shown in Table 1. This retrospective study was approved by the institutional review board of our hospital.Table 1 Patient characteristics

Table 1Characteristic	Non-IGRT, n (%)*	IGRT-A, n (%)*	IGRT-B, n (%)*	P value	
No. of patients	371	86	61		
Age (y)					
 Median	71	73	73	.284	
 Range	49-84	58-82	56-83	-	
T classification					
 T1	70 (18.9)	14 (16.3)	9 (14.8)	.014	
 T2	136 (36.7)	49 (57.0)	40 (66)	-	
 T3	165 (44.5)	23 (26.7)	12 (19.7)	-	
Gleason score					
 ≤6	11 (3.0)	2 (2.3)	0 (0)	.443	
 7	151 (40.7)	30 (34.9)	23 (37.7)	-	
 ≥8	209 (56.3)	54 (62.8)	38 (62.3)	-	
Pretreatment PSA (ng/mL)	
 <10	141 (38.0)	44 (51.2)	27 (44.2)	.001	
 10-20	110 (29.6)	27 (31.4)	24 (39.3)	-	
 >20	120 (32.3)	15 (17.4)	10 (16.3)	-	
 Median	12.8	9.95	10.71	-	
 Range	1.9-499.0	2.5-230.9	4.4-168.2	-	
Risk group					
 Intermediate	92 (24.8)	28 (32.6)	23 (37.7)	.060	
 High	279 (75.2)	58 (67.4)	38 (62.3)	-	
Androgen deprivation therapy	
 6 mo (<9 mo)	116 (31.2)	18 (20.9)	15 (24.6)	<.001	
 12 mo (9-20 mo)	160 (43.1)	25 (29.1)	13 (21.3)	-	
 ≥2 y (>20 mo)	95 (25.6)	43 (50)	33 (54.1)	-	
Follow-up (mo)					
 Median	99.1	87.7	63.0	<.001	
 Range	24.4-155.4	26.3-115.9	24.4-82.3	-	
Abbreviations: IGRT = image guided radiation therapy; PSA = prostate-specific antigen.

⁎ Unless otherwise specified.

Treatment planning

Radiation therapy planning was performed using the Eclipse Treatment Planning System (Varian Medical Systems). A glycerin enema was administered 1 hour before the treatment planning using CT acquisition, and CT and MRI were performed after 1 hour of urine storage on the same day. For patients with non-T3b cancer, the CTV was defined as the prostate gland (and any extracapsular lesion) plus a margin. The proximal seminal vesicles were added, and the rectal and bladder volumes were eliminated from the CTV. For patients with T3b cancer, the CTV included all seminal vesicles. The PTV was defined as the CTV plus margin. The modified PTV was defined as the PTV minus the rectal area.

The prostate-to-CTV margin was defined as 5 mm until December 2015 and then changed to 3 mm after January 2016. A CTV-to-PTV margin of 5 mm was added until December 2015 and then 4 mm after January 2016. A prescribed dose of 78 Gy was administered to 95% of the modified PTV until December 2015, after which it was administered to 98% of the CTV in January 2016.

Methods of IGRT

Until February 2013, we did not use fiducial markers. We did daily bone matching using orthogonal radiographs with on-board imaging before each irradiation. This cohort of patients was named the non-IGRT group (n = 371).

After that, we started IGRT with fiducial gold markers. One or 2 fiducial gold markers were inserted into the prostate under local anesthesia under transrectal ultrasonography guidance. Insertion was performed approximately 7 to 10 days before the treatment planning using CT and MRI. On-board imaging was used to match the fiducial markers before each irradiation, and cone beam CT (CBCT) imaging was used to confirm the spatial location relationship between the prostate and the markers once a week, excluding unexpected displacement of the markers.

This cohort was named the IGRT group and was subdivided into the IGRT-A group (n = 86), whose margins were the same as those of the non-IGRT group, and the IGRT-B group (n = 61), whose margins were reduced, as mentioned above. Patient characteristics of the non-IGRT, IGRT-A, and IGRT-B groups are shown in Table 1.

Analysis

Biochemical failure was defined as the nadir value of PSA plus 2 ng/mL in accordance with the Phoenix Consensus.24 Overall survival and BRFS were estimated using the Kaplan-Meier method. The log-rank test was used to examine statistically significant differences among the groups. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Acute toxicity was defined as symptoms of toxicity observed during or after treatment that had completely resolved by 3 months after treatment. Treatment-related toxicity that persisted or occurred >3 months after treatment completion was considered late toxicity.

Because the median follow-up period differed among the 3 groups, late adverse events were counted only within 6 years after the first day of IMRT. We used the Kruskal-Wallis test to compare the patient characteristics between the 3 groups, the Fisher's exact test to compare the occurrence rates of adverse events, and the t test to compare the parameters of the dose-volume histograms (DVHs) between different pairs of 2 groups (non-IGRT vs IGRT-A and IGRT-A vs IGRT-B). P < .05 was considered statistically significant, and .05 ≤ P value < .1 was considered to have a tendency. All statistical analyses were performed using IBM SPSS Statistics version 24.0.

Results

Patient characteristics of the 3 groups are shown in Table 1, in which some characteristics were significantly different between the groups. Patients with T3 tumors and those with PSA > 20 ng/mL were more frequently observed in the non-IGRT group than in the IGRT group (both P < .001), which led to a higher proportion of the high-risk group patients in the non-IGRT group than in the IGRT group (P = .029). On the other hand, the duration of ADT was longer in the IGRT group (P < .001), which might be attributed to the physicians’ stricter adherence to the clinical practice guidelines for the more recent patients. The median follow-up periods for the non-IGRT, IGRT-A, and IGRT-B groups were 99, 88, and 63 months, respectively (P < .001).

The 5-year actuarial rates of BRFS for each group were 88.4% (95% CI, 85.1-91.7), 94.9% (95% CI, 90.0-99.8), and 98.2% (95% CI, 94.9-102), respectively (statistically not significantly different). For the intermediate-risk patients, the 5-year BRFS rates in the non-IGRT, IGRT-A, and IGRT-B groups were 94.3%, 92.6%, and 95.5%, respectively. For the high-risk patients, they were 86.5%, 96.1%, and 100%, respectively. Survival curves are shown in Fig. 1.Figure 1 Comparison of biochemical recurrence-free survival rates between the nonimage guided radiation therapy (IGRT), IGRT-A, and IGRT-B groups for (a) all, (b) intermediate-risk, and (c) high-risk patients.

Figure 1

Figure 2 shows the occurrence rates of acute and late adverse events in the non-IGRT, IGRT-A, and IGRT-B groups. Compared with the non-IGRT group, the IGRT-A group showed a significantly lower occurrence rate of acute grade ≥ 2 GI (7% vs 17%, P = .019) and late grade ≥ 2 GU toxicities (16% vs 28%, P = .028) and a lower tendency of the rate for acute grade ≥ 1 GI toxicity (44% vs 55%, P = .072). Next, compared with the IGRT-A group, the IGRT-B group had significantly lower rates of acute grade ≥ 2 GU (21% vs 45%, P = .003) and acute grade ≥ 1 GI toxicities (18% vs 44%, P = .001).Figure 2 The occurrence rates of acute and late adverse events in the nonimage guided radiation therapy (IGRT), IGRT-A, and IGRT-B groups. Note that the late adverse events were counted only within 6 years after the first day of radiation therapy.

Abbreviations: GI = gastrointestinal; GU = genitourinary.

Figure 2

Figure 3 shows box and whisker plots of the prostate volume and V60Gy= the volume at least received 60Gy and V70Gy = the volume at least received 70Gy for the bladder and rectal walls, comparing the non-IGRT, IGRT-A, and IGRT-B groups. Prostate volumes were not significantly different among the 3 groups, with each having an average ± SD of 27.4 ± 12.5, 27.4 ± 11.4, and 27.5 ± 10.8 cm3, respectively. The V60Gy of the bladder wall tended to be larger in the non-IGRT group (27.3 ± 7.8 cm3) than in the IGRT-A group (25.6 ± 7.0 cm3; P = .059), and that of the IGRT-A group was significantly larger than that of the IGRT-B group (16.6 ± 4.3 cm3; P < .001). The V70Gy of the bladder wall was significantly larger in the order of the non-IGRT (22.6 ± 6.33 cm3), IGRT-A (20.9 ± 6.22 cm3; P = .025), and IGRT-B (12.07 ± 3.45 cm3; P < .001) groups. We confirmed similar results for the rectal wall, also with significant differences among the 3 groups for both V60Gy and V70Gy (non-IGRT vs IGRT-A and IGRT-A vs IGRT-B): V60Gy in the order of non-IGRT, IGRT-A, and IGRT-B as 26.3 ± 3.92 cm3, 23.5 ± 3.20 cm3 (P < .001), and 20.62 ± 3.90 cm3 (P < .001), respectively, and V70Gy as 18.4 ± 2.97 cm3, 16.7 ± 3.18 cm3 (P < .001), and 13.9 ± 3.23 cm3 (P < .001), respectively.Figure 3 Box and whisker plots showing (a) prostate volume, (b) V60Gy = the volume at least received 60Gy and V70Gy = the volume at least received 70Gy for the bladder wall, and (c) V60Gy = the volume at least received 60Gy and V70Gy = the volume at least received 70Gy for the rectal wall, comparing the nonimage guided radiation therapy (IGRT), IGRT-A, and IGRT-B groups. The center line and the x-mark of each box represent the median and mean values, respectively. The upper and lower edges represent the 25th and 75th percentiles, respectively.

Figure 3

IGRT-B showed a smaller V60Gy and V70Gy for both the bladder and rectal wall than IGRT-A because the margins had been reduced in the treatment planning. However, it seemed not logical that the non-IGRT and IGRT-A groups revealed a statistically significant difference in V60Gy and V70Gy because they had the same margins and similar prostate volumes. We reviewed the treatment planning and DVHs of the non-IGRT group and found a trend of chronological improvement in the bladder and rectal doses over time. This could be partly due to the influence of the improved skills of treatment planners.25

Discussion

We compared the outcomes of the following 3 groups: non-IGRT, fiducial marker-based IGRT using the same margin settings as non-IGRT, and fiducial marker-based IGRT with reduced margins in IMRT treatment for intermediate- and high-risk prostate cancer. IGRT with fiducial markers using the same margin settings had lower adverse events compared with non-IGRT, specifically acute GI and late GU toxicities. Adverse events were further reduced in acute and late GU and GI toxicities by reducing the margins when using IGRT. These processes did not decrease BRFS rates. To the best of our knowledge, this is the first study to compare 3 groups treated with a uniform prescription dose of IMRT.

There have been several comparative reports on radiation therapy for localized prostate cancer with and without IGRT. However, in most of these reports, other confounding factors, including the prescription dose and margin settings, were modified, which made the simple comparison of the effect of IGRT difficult.26, 27, 28 Singh et al17 compared 128 patients not treated with IGRT and 154 patients treated with IGRT who received fiducial marker insertion and MRI fusion using 3-dimensional conformal radiation therapy (3D-CRT). In their study, the IGRT group showed a significant reduction in symptoms related to the rectum but without improvement in symptoms related to urination. Although the IGRT group had higher-stage tumors, received higher prescribed doses, and had larger volumes of rectum receiving high dosages than the non-IGRT group, a significant reduction in bowel dysfunction symptoms was confirmed in men selected for IGRT. Their results on the reduction of GI symptoms in the IGRT group are in line with the findings of our study; however, the present study also showed a reduction in GU toxicity, in contrast to their results. The larger volumes of higher rectal doses in the IGRT group seemed partly paradoxical, although they might enforce the positive effect of IGRT. Finally, they used 3D-CRT, and their follow-up period (8-26 months) was significantly shorter than that of our study (24-155 months), which used IMRT and MRI fusion for all patients.

Zelefsky et al18 reported for the first time the difference in toxicity and tumor control for localized prostate cancer treated with 86.4 Gy IMRT between the groups with and without IGRT at the same margin settings. A total of 186 patients treated with IGRT and daily correction of the target position based on kilovoltage imaging of implanted prostatic fiducial markers were retrospectively compared with a similar cohort of 190 patients treated without IGRT. A significantly lower late urinary toxicity was observed in patients treated with IGRT compared with those not treated with IGRT. The 3-year likelihood of grade ≥ 2 GU toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (P = .02). The incidence rate of grade ≥ 2 rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; P = .81). Their results were in accordance with the findings of the present study, where the late grade ≥ 2 GU toxicity showed a significant difference (28.0%, 16.3%, and 18.0% for non-IGRT, IGRT-A, and IGRT-B, respectively), but the late grade ≥ 2 GI toxicity did not (4.0%, 1.2%, and 1.6%, respectively). Similar to their explanation, we hypothesized the reason for this to be the incidence rate of late grade ≥ 2 GI toxicity, which was remarkably low to reach statistical significance. In contrast to the findings of our study, the DVH analysis was not mentioned in their report, nor was the effect of a reduced margin examined. Notably, for high-risk patients in their study, a significant improvement in BRFS was observed at 3 years in patients treated with IGRT compared with those treated without IGRT.

Kok et al19 retrospectively compared 311 patients who received 74 Gy without fiducial markers with 243 patients who received 78 Gy with IGRT using fiducial markers (FMIGRT). The hazard ratio (HR) for late grade ≥ 2 GI toxicity moderate/severe in the non-FMIGRT group was 3.66 (95% CI, 1.63-8.23; P = .003) compared with patients in the FMIGRT group. There was no difference in the HR of late grade ≥ 2 GU toxicity between the 2 groups, but patients treated with FMIGRT had a quicker recovery from their GU toxicities (HR, 0.24; 95% CI, 0.10-0.59) than those not treated with FMIGRT. No differences in BRFS were detected between the cohorts. In their study, only 57 (23%) patients in the FMIGRT group and 18 (6%) patients in the non-FMIGRT group received IMRT. However, they did not examine the effects of reducing the margins, and the median follow-up period to evaluate late toxicities was rather short (22 months).

Wang et al29 performed a meta-analysis of the role of IGRT in prostate cancer. This study analyzed 18 studies, including 3 randomized controlled trials, 4 prospective cohort studies, and 11 retrospective cohort studies. In total, 6521 patients were enrolled; 3104 men were included in the IGRT group and 3107 men in the control group, with median durations of patient follow-up of 46.2 months in the IGRT group and 52.7 months in the control group. The meta-analysis demonstrated that IGRT significantly reduced acute GU (risk ratio, 0.78; 95% CI, 0.69-0.88; P < .001), acute GI (risk ratio, 0.49; 95% CI, 0.35-0.68; P < .001), and late GI (HR, 0.25; 95% CI, 0.07-0.87; P = .03) toxicities. The significant reduction reported in acute GU and GI toxicities in the IGRT group was in accordance with the results observed in the present study. However, this study revealed a reduction in late GU toxicity in the IGRT group. This might be attributed to the IGRT method because Wang et al29 hypothesized in their subgroup analysis that an IGRT technique comprising 2-dimensional imaging plus fiducial markers might be more beneficial for late GU than other types of IGRT, which is identical to our IGRT method. Their results showing that late GI toxicity decreased by IGRT were also different from our results, but this could be attributed to the low rate of late GI toxicity using IMRT, as already mentioned above. Our incidence rates of late grade ≥ 2 GI toxicity (4.0%, 1.2%, and 1.6% for the non-IGRT, IGRT-A, and IGRT-B groups, respectively) were significantly lower than those of the 3 studies, which performed the meta-analysis of the late GI toxicity. The 3 studies comprised a significant number of patients treated with 3D-CRT, showing remarkably higher incidence rates of late grade ≥ 2 GI toxicity for patients treated with 3D-CRT at 49% to 57.3%, and for patients treated with IMRT at 5.8% to 29%.15,19,21

The strengths of the present study include the following: (1) all 518 patients received IMRT with a uniform dose of 78 Gy in 39 fractions using an MRI-fused treatment planning; (2) 2-step comparison was used comprising (a) the first step as simply introducing IGRT using the same margin settings (non-IGRT vs IGRT-A) and (b) the second step as reducing margins in IGRT (IGRT-A vs IGRT-B); and (3) DVH analysis was performed in all the patients, and the data well-explained the observed clinical differences between the IGRT-A and IGRT-B groups. However, the major limitation of this study was its retrospective nature. There were statistical differences between the 3 groups in terms of T stage, pretreatment PSA, ADT duration, and length of follow-up. The non-IGRT group had a significantly higher proportion of T3 tumors, PSA > 20 ng/mL, and high-risk patients. We confirmed that the prostate volumes were not statistically different between the 3 groups, which implied that such baseline characteristics of the patients did not affect the results. Patients treated before 2010 were often administered ADT for an inadequately short duration, partly because of poor adherence to the guidelines for intermediate- and high-risk prostate cancer at that time. Therefore, we excluded patients treated with ADT for <3 months. To minimize the effect of the difference in follow-up periods between the 3 groups, we counted late adverse events only within 6 years after the first day of IMRT. However, we cannot exclude some influence by an imbalance between the cohorts.

Long-term patient accrual of >10 years may involve changes in treatment planning quality, including improvements in radiation treatment planning software and the human skills of treatment planners. When we moved from IGRT-A to IGRT-B, we changed both margin settings: the prostate-to-CTV margin from 5 mm to 3 mm and the CTV-to-PTV margin from 5 mm to 4 mm. The reduction of the former margin was not attributed to the IGRT method but was based on the clinicians’ decision at that time. However, we believe what affected the clinical results was the reduction of the total margin from the prostate to PTV (10 mm to 7 mm), so the conclusion of this study will not change. We attempted to eliminate as many biases as possible to examine the pure effects of IGRT; however, our study cohort might have contained inherent biases.

Initially, we inserted 2 1-cm long gold markers. However, considering the cost, we changed it to a combination of one gold marker and cone beam CT imaging once a week. Although there is a possibility that 2 or more gold markers will improve the accuracy, the difference between 0 and 1 marker was considered much larger than that between 1 and 2 or more markers.30,31

Recently, radiation therapy for prostate cancer is moving toward more hypofractionated regimens.32, 33, 34, 35, 36 Since our results were based on a conventional fractionation regimen of 78 Gy in 39 fractions uniformly, one should be cautious when applying our results to other hypofractionated regimens. However, it seems reasonable to hypothesize that in the setting of hypofractionation, the impact of IGRT might be even greater than reported here because of the smaller number of irradiation sessions and larger given dose per session. In support of this, the guideline for hypofractionated radiation therapy made the use of IGRT mandatory.32

Finally, while we note that only the prostate was treated in this series, many radiation oncologists would treat the pelvic nodes in the cases described here.37 If one aligns to fiducials in the prostate while simultaneously treating pelvic nodes without daily plan adaptation, it will bring deleterious dosimetric effects on those nodes. Therefore, it should be noted that the results of the current study are applicable to prostate-only radiation therapy, not to whole pelvic radiation therapy.

Conclusions

In this retrospective study, IGRT with fiducial markers resulted in lower acute and late toxicities compared with non-IGRT in IMRT for intermediate- and high-risk prostate cancer at the same dose and the same CTV and PTV margin settings. The toxicities were further minimized by reducing the margins in the treatment planning under IGRT. Notably, these processes did not decrease the BRFS rates.

Disclosures

The authors have no conflicts of interest to declare. All the authors have approved the submission of the manuscript.

Acknowledgments

Itsuko Serizawa and Nozomi Kurihara performed the statistical analysis.

Research data are not currently available.
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