Timing of High-Dose Rate Brachytherapy with External Beam Radiotherapy in intermediate and high-risk localised Prostate Cancer (THEPCA): a randomised trial - ScienceDirect

Timing of High-Dose Rate Brachytherapy with External Beam Radiotherapy in intermediate and high-risk localised Prostate Cancer (THEPCA): a randomised trial - ScienceDirect

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Abstract

Background

HDR brachytherapy(HDR-BT) and external beam radiotherapy(EBRT) are effective treatments for prostate cancer(PC) but cause genitourinary(GU) and gastrointestinal(GI) toxicities. There is no consensus on the timing of HDR-BT in relation to EBRT and the effect of sequencing on patients.

Objective

The primary objective was to assess differences, if any, in the incidence of Grade 3 or higher GU toxicities from treatment. We also aimed to explore the incidence of G1-4 GI toxicities, quality of life and patient satisfaction. Suppression of PSA and signals for survival differences were also analysed.

Methodology

A single-centre randomised trial in intermediate and high-risk localised PC patients to receive HDR-BT before (Arm A) or after (Arm B) EBRT. Toxicities were graded using CTCAE. IIEF and FACT-P were used to assess erectile dysfunction and QOL at 0, 3, 9 and 12 months.

Results

50 patients were recruited to each arm, with 48 and 46 patients completing treatment and follow up in each arm. 81.5% had high-risk disease. There were no G3 or G4 GU or GI toxicities. G1 urinary frequency was the most common adverse event experienced in both arms, peaking in incidence 3 months after commencing treatment (45.7 and 42.2% in Arm A and B, respectively). Up to 11 % of patients reported G1 urinary frequency at 12 months. Other G1 GU toxicities experienced by >10% of patients were urinary tract obstruction, tract pain and urgency. These symptoms also peaked in incidence at 3 months. G2 GU toxicities were uncommon and experienced in a maximum of 2 patients within each arm at any time point.

Over 30% of patients had G1 flatulence at baseline and this remained the most frequently occurring G1 GI toxicity throughout the study, peaking at 12months (21.4% and 25.6% in Arm A and Arm B, respectively). Other GI toxicities experienced by more than 10% of patients were GI pain, proctitis and rectal mucositis, most of which demonstrated a peak incidence at 3 or 9 months. G2 GI toxicities were uncommon, except G2 flatulence.

No significant difference was found in CTCAE, IPSS, IIEF, FACT-P and QOL scores between the arms.

Median PSA follow-up was 5 years. 7 patients had treatment failure in each arm. DFRS was 93.3% and 90.7% at 5 years in Arm A and B respectively, with median failure time of 60 and 48 months in Arm A and B respectively. There were no statistically significant difference between arms.

Conclusions

The sequencing of HDR-BT and EBRT did not impact the incidence of G3 or G4 toxicities and no significant differences were seen in other patient reported outcomes. Treatment was well tolerated with maintained QOL scores. Treatment failure was low in both arms in a high-risk cohort, however a larger study with longer follow up is underway to establish whether the difference in median time to failure between the two arms is a signal of superiority.

Introduction

Prostate cancer (PC) is the most common cancer affecting males, accounting for 27% of all new cancer cases in men [1].

Treatment options for the management of localised PC include various Radiotherapy (RT) modalities such as brachytherapy (BT), external beam radiotherapy (EBRT), stereotactic body radiation therapy (SBRT) and proton beam therapy (PBT). The role of SBRT and PBT are still emerging, BT and EBRT are established treatment options for localised PC in the UK[3]. Acute and long term Genitourinary (GU) and Gastrointestinal (GI) toxicities occur irrespective of the modality used.

BT can be delivered as a permanent low-dose rate (LDR) or a temporary high-dose rate (HDR) therapy. BT monotherapy is typically offered to patients with low risk, localised, PC (T1/T2, Gleason score (GS) <6, PSA<10) and intermediate favourable risk PC.

Patients with unfavourable intermediate or high risk localised PC may be offered EBRT with a BT boost [3]. A hypo-fractionated radiation schedule offers optimal tumour control in PC due to its low alpha/beta ratio [4-8]. HDR-BT in combination with EBRT enables significant dose escalation while providing a highly conformal treatment plan, due to rapid dose fall off. Combining EBRT and a BT boost has been shown to provide effective long term biochemical control, with a comparable toxicity profile to EBRT alone [9].

EBRT doses range from 37.5 Gy in 15 fractions (2.5 Gy per fraction) to 45-46 Gy in 25 fractions (1.8-2 Gy per fraction) when given with HDR BT. A biological effective dose (BED) of >268 Gy has been demonstrated to be optimal with a α/β-ratio 1.5-3Gy [10]. HDR-BT can be delivered through a number of fractions, however a single dose of 15 Gy is logistically advantageous and can achieve acceptable tumour control [11-13]. When combined, delivery of each modality is within 21 days of the other.

A randomised phase three trial in which EBRT (55 Gy in 20 fractions) mono therapy was compared with EBRT (37.5 Gy in 13 fractions) delivered before HDR-BT (2 × 8.5 Gy within 24 hours) reported a 5-year incidence of any severe GU (26%) and GI(7%) symptoms in the combination arm using an adapted Dische scale [9]. With 12 years of follow-up, severe GU symptoms persisted in 11% and 13% at 6 and 12 years, respectively. Severe GI symptoms were reported in 7% and 8% of patients at 6 and 12 years, respectively. Importantly, there were no significant differences in the toxicities in both groups and the ten year relapse free survival favoured combination treatment [15].

Martell et al. treated 500 patients with 15 Gy HDR-BT before EBRT (37.5 GY in 15 fractions). After a median follow up of 5.2 years, 20% of patients had a maximum Common Terminology Criteria for Adverse Events (CTCAE) GU toxicity grade of 3 (G3). No grade 4 (G4) or 5 (G5) GU toxicities were reported [12]. There were no G3,4 or 5 GI events reported over the follow up period [12].

The use of HDR-BT before EBRT may allow early identification of patients that are not suitable for BT. The procedure may be easier to perform, more comfortable for patients and may have a lower risk of rectal bleeding, rectal pain or skin inflammation than EBRT. It is often feared that a pre-treated prostate could make BT challenging and increase the risk of tissue damage. Additionally, high dose of radiation with BT early on in treatment, may confer a tumour control advantage, with the alpa/beta ratio of PC being low, particularly in unfavourable intermediate or high-risk disease.

Conversely, in resource constrained departments it may be more straightforward to commence planning and deliver EBRT first, scheduling BT thereafter. During BT, a urethral catheter is inserted. The procedure carries a small increased risk of infection, bleeding and damage to surrounding tissue when inserting needles. Complications may delay further treatment and negatively impact patient outcomes. Moreover, if significant urinary disturbance occurs following BT, patients may require an indwelling long term urinary catheter to complete their treatment, increasing the risk of urinary tract infections.

There is no consensus on whether EBRT should be administered before or after a HDR boost. The radiation dose, sequence, and the timing of HDR-BT and EBRT varies between centres. Based upon the existing literature, with a lack of head-to-head comparison and short term toxicity data in addition to the variations in routine practice and lack of consensus on sequencing of therapy, we can reasonably posit a hypothesis of no significant differences in the incidence and severity of toxicities, irrespective of sequencing.

Our study aimed to prospectively assess if there is a difference in GU and GI toxicities experienced by patients when BT is given before or after EBRT. Our primary endpoint was to establish if there was a statistically significant difference in G3 GU toxicity. Secondary, exploratory, outcomes included assessing differences in G1 and G2 GU toxicities, G1-4 GI toxicities, quality of life, long term PSA control and survival. We also aimed to establish if the sequencing of RT caused challenges with planning by evaluating if there were differences in participants’ ability to complete their assigned treatment without interruptions or deviations in radiation schedule, dose or delivery.

Section snippets

Method

This was a single centre randomised, two arm (Arm A and Arm B) parallel group study, in patients with intermediate and high-risk PC. The study obtained ethical approval through the local NHS research ethics committee (IRAS project ID: 140231).

Eligible participants were all aged 18 or over with a newly diagnosed, histologically confirmed, prostate adenocarcinoma (stages T1b-T3bN0M0) with no evidence of metastatic disease on computed tomography (CT), magnetic resonance (MRI) or Positron Emission

Results

100 patients were recruited between January 2015 and August 2017, with 50 patients randomised into each arm. After randomisation, one participant withdrew consent and another was excluded for a prior TURP in Arm A. Two participants withdrew consent and one participant was excluded for a prior TURP in Arm B. A further two participants in Arm B were deemed ineligible secondary to a previous TURP and acute kidney injury prior to treatment commencing. One participant withdrew consent after

Discussion

To our knowledge, this is the first head to head randomised trial assessing the sequencing of EBRT in relation to BT and the impact of this on GU and GI toxicities in addition to other patient reported quality of life outcomes. There were no technical difficulties experienced in either arm. Treatment did not deviate in dose or schedule and was well tolerated in an elderly population. There was good engagement throughout the study by patients with only one patient lost to follow up in each

References

  • 2.

    Lifetime risk estimates calculated by the Statistical Information Team at Cancer Research UK. Based on Office for National Statistics (ONS) 2016-based Life expectancies

© 2023 Published by Elsevier Inc.

 

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