Daily Versus Weekly Prostate Cancer Image Guided Radiation Therapy: Phase 3 Multicenter Randomized Trial

doi:10.1016/j.ijrobp.2018.07.2006

International Journal of Radiation OncologyBiologyPhysics

Volume 102, Issue 5, 1 December 2018, Pages 1420-1429

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https://doi.org/10.1016/j.ijrobp.2018.07.2006 Get rights and content

Purpose

The optimal frequency of prostate cancer image guided radiation therapy (IGRT) has not yet been clearly identified. This study sought to compare the safety and efficacy of daily versus weekly IGRT.

Materials and Methods

This phase 3 randomized trial recruited patients with N0 localized prostate cancer. The total IGRT doses in the prostate ranged from 70 Gy to 80 Gy, sparing the lymph nodes. Patients were randomly assigned (1:1) to 2 prostate IGRT frequency groups: daily and weekly (ie, on days 1, 2, and 3 and then weekly). The primary outcome was 5-year recurrence-free survival. Secondary outcomes included overall survival and toxicity. Post hoc analyses included biochemical progression-free interval, clinical progression-free interval, and other cancer-free interval.

Results

Between June 2007 and November 2012, 470 men from 21 centers were randomized into the 2 groups. Median follow-up was 4.1 years. There was no statistically significant difference in recurrence-free survival between the groups (hazard ratio [HR] = 0.81; P = .330). Overall survival was worse in the daily group than in the weekly group (HR = 2.12 [95% confidence interval (CI), 1.03-4.37]; P = .042). Acute rectal bleeding (grade ≥1) was significantly lower in the daily group (6%) (n = 14) than in the weekly group (11%) (n = 26) (P = .014). Late rectal toxicity (grade ≥1) was significantly lower in the daily group (HR = 0.71 [95% CI, 0.53-0.96]; P = .027). Biochemical progression-free interval (HR = 0.45 [95% CI, 0.25 – 0.80]; P = .007) and clinical progression-free interval (HR = 0.50 [95% CI, 0.24-1.02]; P = .057) were better in the daily group, whereas other cancer-free interval was worse in the daily group (HR = 2.21 [95% CI, 1.10-4.44]; P = .026).

Conclusions

Compared with weekly control, daily IGRT control in prostate cancer significantly improves biochemical progression-free and clinical progression-free interval, and rectal toxicity.

Introduction

Prostate intrapelvic interfraction displacement can be as large as 2 cm, typically in the anteroposterior direction, exposing the patient to an increased risk of both recurrence and toxicity if not corrected using bone anatomy alignment.1, 2 Image guided radiation therapy (IGRT) includes various recently developed techniques, allowing direct or indirect prostate visualization at treatment fractions. The most commonly used IGRT modalities are intraprostatic fiducials visualized on 2 orthogonal planes (kV or portal imaging) and cone beam computed tomography (CBCT).³ The clinical benefit of prostate IGRT has been demonstrated primarily by nonrandomized studies retrospectively comparing non-IGRT and IGRT techniques.4, 5, 6, 7, 8, 9, 10, 11 IGRT has been found to decrease the risk of genitourinary and gastrointestinal (GI) toxicities. However, the role of IGRT in decreasing the risk of recurrence has not been demonstrated because of the short follow-up in these studies.4, 5, 6, 7, 8, 9 Moreover, the optimal frequency of prostate cancer IGRT has not been identified.

Whereas daily control corrects both systematic and random prostate displacement, weekly control solely corrects systematic displacement, with the advantage of being faster and less expensive.¹² Systematic errors occur if the mean irradiation geometry in the fractionated treatment differs from the geometry of the treatment plan. Fraction-to-fraction variations around the mean deviation are called random errors.¹³ The dosimetric consequences of systematic and random geometrical uncertainties differ, with significantly less deleterious effects (increased local failure and toxicity) caused by random deviations.¹⁴

This study sought to assess the benefit of daily prostate control compared with weekly control in a prospective multicenter randomized study.

Section snippets

Inclusion criteria and pretreatment workup

In this phase 3 multicenter open randomized trial, we included patients with localized histologically proven prostate adenocarcinoma—N0 or pN-stage—without metastasis. Pretreatment workup imaging included systematic abdominopelvic computed tomography (CT) and bone scans. Prostate magnetic resonance imaging was not required for all patients and was performed in 62% of patients. Patients with hip prostheses, pacemakers, or target volume including the pelvic lymph nodes were excluded.

Study design

The study

Results

Between June 20, 2007, and November 16, 2012, 470 patients were included in the randomized stage: 236 patients in the daily IGRT group and 234 patients in the weekly IGRT group. Two patients (1 from each group) withdrew consent, although both patients allowed their data to be used (Fig. E1; available online at https://dx.doi.org/10.1016/j.ijrobp.2018.07.2006). The baseline patient and tumor characteristics are presented in Table 1. Table E1 (available online at //dx.doi.org/10.1016/j.ijrobp.2018.07.2006

Discussion

We believe that this is the first randomized phase 3 trial evaluating the benefits of IGRT in prostate cancer for toxicity and recurrence. By improving prostate targeting, daily control outperforms weekly control, significantly decreasing the risk of biochemical and clinical recurrences and rectal toxicity.

The combination of IMRT and daily IGRT has become the standard of care for external-beam radiation treatment (EBRT) in prostate cancer, particularly when delivering a high dose or using a

Conclusions

Compared with weekly control, daily control in prostate-cancer IGRT decreases the risks of biochemical and clinical recurrences and rectal toxicity. However, longer follow-up is needed to confirm the results.

Acknowledgment

We thank the reviewers for enhancing the quality of the article.

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Citation Excerpt :
However, the heterogeneity of both analyses was large, with I2 = 71 % and I2 = 73 %, respectively. Among them, de Crevoisier et al. [23] showed that daily IGRT significantly reduced the 5-year OS of patients and potentially increased the SCM. However, Kuo et al. [51] believed that daily IGRT had no effect on 5-year OS and SCM.
Image-guided radiotherapy (IGRT) has gradually been widely promoted in clinical procedure. However, there has been no consensus on the effects of IGRT on toxicity and survival, and no clear level 1 evidence has even been promulgated.
Medline, EMBASE, PubMed, Cochrane databases and ClinicalTrials.gov were searched for studies comparing IGRT vs non-IGRT or higher frequency IGRT vs lower frequency IGRT during prostate radiotherapy, indexed from database inception to April 2022.
The review included 18 studies (3 randomized clinical trial and 15 cohort studies) involving 6521 men, with a median duration of patient follow-up of 46.2 months in the IGRT group vs 52.7 months in the control group. The meta-analysis demonstrated that IGRT significantly reduced acute GU (risk ratio [RR], 0.78; 95 % confidence interval [CI], 0.69–0.88; P < 0.001 [9 studies]) and GI toxicity (RR, 0.49; 95 % CI, 0.35–0.68; P < 0.001 [4 studies]) and late GI toxicity (HR, 0.25; 95 % CI, 0.07–0.87; P = 0.03 [3 studies]) compared with non-IGRT. Meanwhile, compared with prospective studies, retrospective studies showed that IGRT had a more significant effect in reducing the late GI toxicity. Compared with non-daily IGRT, daily IGRT significantly improved 3-year PRFS (HR, 0.45; 95 % CI, 0.28–0.72; P = 0.001 [2 studies]) and BFFS (HR, 0.57; 95 % CI, 0.39–0.83; P = 0.003 [3 studies]). Furthermore, high-frequency daily IGRT could lead to greater 3-year BFFS benefit in prostate cancer patients than weekly IGRT. However, no significant effects of IGRT on acute rectal toxicity, late GU toxicity, 5-year OS and SCM were found.
For men receiving prostate radiotherapy, IGRT was associated with an improvement in biochemical tumor control and a reduction in GI and acute GU toxicity, but did not significantly improve 5-year OS or increase 5-year SCM.
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: Conflict of interest: none.

: This study was funded by the French National Cancer Institute. The financers had no role in study design, data collection, analysis, or interpretation, nor in the writing of the report.

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Clinical InvestigationDaily Versus Weekly Prostate Cancer Image Guided Radiation Therapy: Phase 3 Multicenter Randomized Trial

Purpose

Materials and Methods

Results

Conclusions

Introduction

Section snippets

Inclusion criteria and pretreatment workup

Study design

Results

Discussion

Conclusions

Acknowledgment

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Rep Pract Oncol Radiother

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Control Clin Trials

Lancet Oncol

Clinical Investigation
Daily Versus Weekly Prostate Cancer Image Guided Radiation Therapy: Phase 3 Multicenter Randomized Trial