Phase II Multi-institutional Clinical Trial on a New Mixed Beam RT Scheme of IMRT on Pelvis Combined with a Carbon Ion Boost for High-risk Prostate Cancer Patients

Introduction

Radiotherapy (RT) is one of the first-line curative treatment options for prostate carcinoma (PCa). For high-risk PCa patients, according to the stratification of D'Amico et al (1) (clinical stage ≥T2c or a prostate-specific antigen [PSA] >20 ng/mL or Gleason Score [GS] ≥8), the prognosis is still poor. Biochemical control probability after conventional photon irradiation is 47% at 5 years. When androgen deprivation therapy (ADT) is administrated as adjuvant therapy, biochemical control at 10 years reaches 55% (2, 3). In the last decade, the potential benefit of dose escalation for disease-free survival has become a milestone in the use of curative RT for PCa (4, 5). Recent randomized trials proved that dose escalation up to 79 Gy to the prostate is advantageous in terms of clinical disease control (3). Further dose escalation to 81 Gy delivered in a phase II study using intensity-modulated radiotherapy (IMRT) resulted in excellent 8- to 10-year tumor control and acceptable late toxicity (6, 7).

According to the 2016 National Comprehensive Cancer Network (NCCN) category, the optimal treatment schedule for high-risk prostate cancer is external beam radiation therapy (EBRT) and ADT (8). In the series analyzed by Zelefsky et al (2), where prostate cancer prescription doses ranged from 64.8 to 86.4 Gy, radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels <70.2 Gy and in the range of 70.2-79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Among patients who showed acute adverse effects, the incidence of late genitourinary (GU) and gastrointestinal (GI) toxicity at 10 years was 42% compared to the 9% who did not have acute symptoms. The late GU toxicity (grade >2) incidence at 10 years was 15%. Patients treated with IMRT with a total dose up to 81 Gy experienced a late GU toxicity of 20% at 10 years, compared to the 12% of patients treated with lower doses (p = 0.01).

Despite the results on dose escalation, PCa is considered to be relatively radioresistant to conventional photon RT: the low α/β ratio (range 1.5-3 Gy) implies that the use of fewer large dose fractions might be an alternative to dose escalation using daily fractions of 2 Gy (9). From a radiobiological point of view, larger dose fraction increases tumor control probability without increasing toxicity because fraction size sensitivity is significantly higher for PCa than for nearby dose-limiting normal tissues.

Particle beams with high linear energy transfer (LET), like carbon ions, theoretically offer biological advantages (in terms of radiobiological effectiveness) in tumors with a low a/β ratio such as prostate cancer (10). In addition, heavy charged particles have advantageous intrinsic physical characteristics in terms of dose deposition that provide steep dose gradients with a resulting better sparing of organs at risk (OARs) close to the target. Furthermore, they have a high relative biological effectiveness (RBE), resulting from high LET similar to neutron beams, with a cytocidal effect estimated to be approximately threefold higher than those of photons and protons.

The aim of the present clinical trial is to test the feasibility in terms of safety and efficacy of a new treatment schedule for high-risk PCa patients that allows dose escalation to the prostate tumor with a mixed beam approach of carbon ion boost followed by pelvic IMRT.

We aim to fully exploit the advantageous physical and biological characteristics of a carbon ion boost as compared to the existing data on proton or photon brachytherapy or external beam RT approaches, already used in clinical practice. Furthermore, in the present trial the carbon ion boost will be anticipated in order to exploit the tumoricidal effect of carbon ion on the tumor prostate hypoxic cells (11), thus fostering the cytotoxicity of the following IMRT treatment phase.

In silico studies have been undertaken to assess the impact of contouring and planning variability between the different institutions involved in the study and to standardize a procedure for enrollment and evaluation of the combination of carbon ion boost and photon IMRT.

Methods

Discussion

The management of locally advanced and high-risk PCa is one of the most challenging contemporary issues. In the absence of a randomized trial, it is difficult to compare the real benefit of surgery, RT, ADT, or combinations of these. However, in this scenario it is also difficult to refer patients to the optimal treatment. Taking into account the Japanese experience with carbon ions with hadrons, this phase II study could be useful to address the issue about the opportunity to use a carbon ion boost for PCa patients. In the light of improved outcome in patients with high-risk PCa, RT strategies should be planned correlating treatment intensity to disease aggressiveness and expected prognosis.

Many recent studies support the use of modern RT modalities, such as IMRT and charged particle RT that can provide a well-localized dose to the target, minimizing toxicity to the OARs, even when a hypofractionated regimen is applied.

Hypofractionated radiotherapy potentially may improve the biochemical control of PCa without increasing toxicities associated with late-responding tissue (20). Recently, hypofractionated stereotactic body radiotherapy (SBRT) boost after whole pelvic EBRT has demonstrated excellent efficacy and toxicity profiles (21, 22). The SBRT boost is an attractive option for dose escalation with noninvasive procedure, compared to high-dose-rate brachytherapy. Several studies have been published with the use of EBRT and SBRT boost with promising results; for example, Lin et al (23) reported a biochemical failure-free survival of 91.9% at 4 years.

At the National Institute of Radiological Sciences (NIRS) in Japan, approximately 1,384 patients with localized PCa have been treated with carbon ions alone using passive beam shaping since 1995. The prescribed doses were 54-72 Gy (RBE) in a clinical phase I/II trial and were fixed to 66 Gy (RBE) over 20 fractions in the following clinical phase II trial. Looking at this experience, among the 490 patients classified as high risk (according to the 3 major risk factors of PCa: T stage, initial PSA value, and GS of the tumor), the 5-year cause-specific survival rate was 97.9%. The 5-year biological relapse-free rate was 88.4%. These clinical outcomes were compared with data from other trials, and the 5-year biological relapse-free rate of carbon-ion RT for patients with T3 tumor (T3a and T3b) was superior to those of a combination therapy of RT using photon beams with ADT (10). As far as toxicity is concerned, no acute or late GI or GU ≥ grade 2 reactions were observed.

Centro Nazionale di Adroterapia Oncologica is the first facility in Italy and among 4 others worldwide treating cancer patients with active scanning hadron therapy with a dual beam of both protons and carbon ions. Since 2011, more than 700 patients have been treated, two-thirds of them with carbon ions. Patients with high-risk PCa are currently treated in CNAO within a phase II clinical trial up to 66.64 Gy (RBE) total dose in 16 fractions based on the technical and clinical experience of NIRS in Japan (17).

As for the role of elective pelvic IMRT, despite no consensus even in high-risk localized PCa patients (24), it is possible to assume that the available studies have underestimated its real benefit. The published data concern retrospective or prospective studies, where patients with low and intermediate risk disease were included; this might explain the failure to demonstrate advantages in adding pelvic nodal RT. In our study, selection of patients for RT will include only the high-risk stage, thus allowing for a correct evaluation of the prognostic relevance of pelvic nodal RT.

Our results will provide useful information on the application of a charged-particle RT boost for PCa, in particular for the definition of the optimal carbon ion beam boost dose. The concept of integration of a carbon ion boost, delivered with a hypofractionation scheme to the prostate, with pelvic IMRT, shifts technology-driven research to a more patient-centered approach, allowing for safe dose escalation exploiting the availability of high precision technologies for dose delivery and for continuous patient monitoring during treatment for each given clinical scenario.

Although carbon ions offer a theoretical advantage to photons in delivering higher radiation doses to the prostate while sparing surrounding normal tissue, their cost is substantial and they cannot replace conventional IMRT/image-guided radiotherapy techniques until a large clinical benefit is proven.