Advances in prostate cancer treatment with moderate and ultra-hypofractionated radiotherapy

Abstract

This article comprehensively reviews research progress in prostate cancer radiation therapy. It provides an overview of fundamental principles, encompassing the disease’s epidemiology, pathological mechanisms, and radiation sensitivity, alongside technological advancements. The clinical application, technological progress, and efficacy evaluation of moderate hypofractionated radiation therapy and ultra hypofractionated radiation therapy are discussed. Diagnostic and monitoring techniques specific to radiation therapy are analyzed, alongside prevailing controversies and challenges. Finally, the review outlines future prospects, including novel radiotherapy techniques, multidisciplinary collaboration trends, and the evolving role of radiation within comprehensive treatment. The findings demonstrate continuous technological and clinical evolution in prostate cancer radiotherapy, yet emphasize the need for further exploration to optimize treatments and improve patient survival and quality of life.

Key Words: Prostate cancer; Moderate; Ultra-hypofractionated; Radiation therapy; Treatment; Multidisciplinary collaboration

Core Tip: Technological advances enabling precise targeting have driven continuous evolution in radiation therapy for prostate cancer. Moderate and ultra-hypofractionated regimens have been shown to be as effective as conventional therapy and offer patients greater convenience. However, optimizing treatment strategies requires overcoming challenges such as managing toxicity, defining the optimal dose/fractionation, integrating advanced diagnostics to enable personalized approaches and clarifying the role of radiation within multimodal management. Future progress hinges on refining novel techniques (e.g., FLASH and proton therapy), fostering multidisciplinary collaboration, and focusing on improving survival and quality of life outcomes for patients.

INTRODUCTION

Prostate cancer is a common male malignancy globally, with incidence and mortality varying by region and ethnicity[1]. Despite better early detection and treatment, it remains a leading cause of cancer-related morbidity and mortality, especially in the elderly. Radiation therapy, a core treatment, has advanced from conventional 2-dimensional techniques to precise modalities [intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), stereotactic body radiation therapy (SBRT)], enabling accurate dose delivery, improved tumor control, and reduced healthy tissue toxicity[2].

Recent years have seen a shift to hypofractionated radiotherapy (higher per-fraction doses, shorter duration). Moderate hypofractionated radiation therapy (MHRT) and ultra hypofractionated radiation therapy (UHRT) are promising, supported by prostate cancer’s low α/β ratio (boosting therapeutic index). Trials show hypofractionation is non-inferior or superior to conventional regimens in oncological outcomes, with more convenience and lower healthcare burdens[3]. Challenges include acute/Late toxicities, optimal patient selection, and integrating advanced imaging/biomarker guidance. Radiotherapy’s role in multimodal treatment [with androgen deprivation therapy (ADT), surgery, new systemic agents] also evolves.

This review synthesizes MHRT/UHRT’s tech advances, clinical use, and efficacy. It covers diagnostics/monitoring, addresses controversies, and explores future directions (novel tech, multidisciplinary collaboration, personalized strategies) to optimize radiotherapy and improve patient outcomes.

BASIC THEORY OF RADIATION THERAPY FOR PROSTATE CANCER

Epidemiologic features of prostate cancer

Prostate cancer is one of the most prevalent malignant neoplasms in males, and there is a demonstrable variation in its incidence and mortality rates across different geographical regions and racial groups worldwide. A global data analysis revealed a 161.66% increase in prostate cancer incidence between 1990 and 2021. However, the age-standardized mortality rate and age-standardized disability-adjusted life year rate have exhibited a downward trend, with annual rates of change of -0.68 and -0.83, respectively[4]. In the United States, prostate cancer incidence rates vary significantly by age and race. Between 1975 and 2020, there was an overall increasing trend in incidence rates among men under 50 years of age, although there was a significant decrease from 2009 to 2014, followed by a gradual decrease[5]. Specific factors have been identified to have a negative impact on prognosis, including age at diagnosis under 30 years, late disease stage, and non-Hispanic black race[5]. In India, the urban areas of Delhi, Kamloops and Mumbai have higher incidence rates, with age-adjusted incidence rates of 11.8, 10.9 and 9.7 cases per 100000, respectively[6]. The risk of developing the disease increases with age, reaching an accelerated increase after the age of 64 years. It is estimated that approximately 43.0% of prostate cancer patients have distant metastasis at the time of diagnosis[6]. In the Nigerian study, the mean age of patients was 68.5 years, and 32.0% had a family history of prostate cancer. However, family history did not have a significant effect on prostate-specific antigen (PSA) levels at diagnosis. Furthermore, the majority of patients were already at an advanced or metastatic stage at the time of diagnosis[7].

The incidence and characterization of prostate cancer vary significantly between different regions. In Northern Tanzania, prostate cancer accounted for 31.4% of cancers in adult males, with an increasing incidence. The mean age of patients was 73.9 years, the majority of these patients were symptomatic, and 51.1% had a PSA > 100 ng/mL, 29.5% and 31.2% had Gleason grades 4 and 5, and 43.6% had metastases at the time of initial diagnosis[8]. A study of the Surveillance, Epidemiology, and End Results database in the United States revealed no significant change in the overall age-adjusted incidence rate from 1975 to 2019. However, a shift in the incidence rate of different tumor grades and stages was observed. For instance, there was a substantial increase in the incidence rate of grade 2 prostate cancer, with an annual average percentage change of 2. The incidence rate of grade 4 prostate cancer decreased significantly, with an annual average percentage change of -10.39. Furthermore, the incidence of localized prostate cancer also decreased significantly, with an annual average percentage change of -1.83. A lower incidence rate was observed among the American Indian, Alaska Native, Asian and Pacific Islander ethnic groups, in comparison to other racial groups[9].

Pathogenesis and radiosensitivity of prostate cancer

Prostate cancer is a complex pathology involving multiple signaling pathways and molecular mechanisms, and its radiosensitivity is affected by a variety of factors. Research has indicated that the DNA damage repair pathway, hypoxia, angiogenesis, androgen receptor signaling, and immune escape are all significant factors in the development of radio resistance in prostate cancer. For instance, in a study of prostate cancer cell lines, it was found that some cells exhibited radio resistance by enhancing the DNA damage repair pathway to repair radiation-induced DNA damage[10]. In addition, a hypoxic environment has been demonstrated to result in a state of insensitivity to radiotherapy in tumor cells. This is attributable to the fact that hypoxia exerts an effect on the capacity of radiation-generated free radicals to kill cancer cells.

In recent years, there has been an increase in the number of studies that have been conducted in order to enhance radiosensitivity in prostate cancer. In one study, the combination of ribociclib and 2-(morpholin-4-yl)-benzo[h]chomen-4-one enhanced the radiosensitivity of prostate cancer cells by inhibiting DNA repair[11]. The experimental findings demonstrated that, in comparison with the control group, the combination of X-ray irradiation and ribociclib or 2-(morpholin-4-yl)-benzo[h]chomen-4-one led to a substantial reduction in the proliferation of PC3 and DU145 cells, a decrease in colony formation, and an enhancement in phosphorylated histone H2AX focus formation. Concurrently, the expression levels of cell cycle-associated proteins cyclin-dependent kinase 4, phosphorylated retinoblastoma protein, and cyclin D1, together with the DNA repair proteins radiation-sensitive protein 51 and DNA- dependent protein kinase catalytic subunit, were significantly diminished. Conversely, the expression of the pro-apoptotic protein Bax was augmented[11]. Moreover, pretreatment of prostate cancer cells with 7-coumaroyloxycoumarin has been shown to enhance the toxic effects of radiation by increasing the number of apoptotic cells and decreasing the survival fraction. This pretreatment has also been demonstrated to significantly induce the expression of P53 and Bax and to downregulate the expression of B-cell lymphoma 2, GATA binding protein 6, and cyclin D1. Consequently, this pretreatment improves the radiosensitivity of cells[12].

Basic principles and technological evolution of radiotherapy

The fundamental principle of radiation therapy for prostate cancer entails the utilization of high-energy rays to induce damage to the DNA of cancer cells, thereby impeding their proliferation and division and consequently achieving the objective of eradicating cancer cells. In the context of technological advancement, radiation therapy has undergone a series of significant evolutions. Initially confined to two-dimensional radiotherapy, the field has progressed to encompass three-dimensional conformal radiotherapy, IMRT, VMAT, and SBRT, among other advanced modalities[13]. Conventional two-dimensional radiotherapy techniques have been shown to be less accurate and to cause more damage to surrounding normal tissues. Three-dimensional conformal radiotherapy is able to better focus the radiation dose on the tumor area and reduce irradiation of surrounding normal tissues using computed tomography (CT) images for treatment planning[13].

The advent of IMRT and VMAT technologies has further enhanced the precision of radiotherapy. IMRT has the capacity to adjust the dose intensity in the field, thereby ensuring a more consistent dose distribution that corresponds to the shape of the tumor. This, in turn, results in improved protection of the surrounding normal tissues. In contrast, the VMAT technique involves the dynamic adjustment of both the multileaf collimator and the dose rate while the rack is rotating. This results in a reduction of the treatment time, thus enhancing the efficiency of the process. SBRT is capable of delivering a high dose to the tumor in a short period of time. This is due to the fact that tumor cells and normal tissues respond differently to radiation, thus allowing for improved control of the tumor while simultaneously reducing complications in normal tissues (Figure 1).

Figure 1 Key Advances in moderate/hypofractionated and ultra-hypofractionated radiotherapy for prostate cancer: From radiobiological foundations to multimodality integration. MHRT: Moderate hypofractionated radiation therapy; UHRT: Ultra hypofractionated radiation therapy; CONV-RT: Conventional radiotherapy; RT: Radiotherapy; CBCT: Cone beam computed tomography; MRgRT: Magnetic resonance-guided radiotherapy.

CLINICAL PRACTICE OF MHRT FOR PROSTATE CANCER

Historical development and current status of moderate hypofractionated radiation therapy

The concept of macro-fractionated radiotherapy is rooted in a profound comprehension of the tenets of radiobiology, with the objective of preserving or enhancing tumor control while concurrently reducing treatment duration by diminishing the quantity of fractions and augmenting the dose per irradiation[14]. In the early days, the application of macro-fractionated radiotherapy was more cautious due to technical limitations. The advent of sophisticated radiotherapy technologies, such as IMRT and VMAT, has given rise to a gradual escalation in the utilization of macro-fractionated radiotherapy in the treatment of prostate cancer. In the contemporary medical context, macro-fractionated radiotherapy has emerged as a pivotal modality for the treatment of prostate cancer, particularly among patients exhibiting low to intermediate risk profiles.

A number of clinical trials and studies have been conducted to evaluate the efficacy and safety of moderate hypofractionated radiotherapy. For instance, in some randomized controlled trials, macro-fractionated radiotherapy was compared with conventional fractionated radiotherapy. The results demonstrated that macro-fractionated radiotherapy was comparable to conventional fractionated radiotherapy in terms of disease control and survival. Furthermore, macro-fractionated radiotherapy exhibited certain advantages, including a shortened treatment period and improved patient convenience and adherence. However, moderate hypofractionated radiotherapy also faces some challenges, such as the potential increase in toxicity to normal tissues. Further optimization of treatment protocols and techniques is therefore required to ensure its safety and efficacy. There are also variations in the macro-fractionated radiotherapy protocols employed in disparate studies, including the dose and the number of fractions, which also require further standardization and normalization.

Clinical trial results of moderate hypofractionated radiation therapy for prostate cancer

A plethora of clinical trials have been conducted to evaluate the efficacy of moderate hypofractionated radiation therapy for prostate cancer. In a prospective, single-center, open-label, randomized controlled clinical trial, the safety and efficacy of moderately minimally segmented postoperative radiotherapy was compared with conventionally segmented postoperative radiotherapy in patients with limited prostate cancer[15]. This study, which randomly assigned patients to receive either conventionally fractionated post-prostatectomy radiotherapy (66-74 grays, 2 grays per session) or moderately hypofractionated post-prostatectomy radiotherapy (57.5-65 grays, 2.5 grays per session), with the primary endpoints of radiotherapy-related gastrointestinal and genitourinary adverse events, and secondary endpoints of progression-free survival, quality of life, healthcare costs, and overall survival (OS), is currently ongoing.

A further phase I/II prospective study of patients with low- and intermediate-risk limited prostate cancer was conducted, utilizing 4-session split carbon ion radiation therapy (CIRT)[16]. The results demonstrated that no grade 3 or higher gastrointestinal or genitourinary adverse events occurred, and no dose-limiting toxicity was observed in any of the 60 patients during a median follow-up period of 42 months (range 27-59 months). The incidence of grade 2 genitourinary toxicity within 90 days was found to be significantly higher in the 36-40 grays group compared with the 44 grays group (P < 0.01). In the three-year period under consideration, three patients exhibited biochemical failure. However, no cases of clinical recurrence or death due to prostate cancer were observed, thereby suggesting that 40 grays CIRT divided into four fractions may be an appropriate regimen to balance treatment efficacy and toxicity[16]. See Table 1 for details; Furthermore, studies have been conducted to compare the efficacy of radical prostatectomy (RP) and radiotherapy in the treatment of high-risk prostate cancer. Following a matching process based on the propensity score matching method, the radiotherapy group exhibited a higher disease-free survival rate in comparison to the RP group (79.41% vs 55.88%, P = 0.038), a higher quality-of-life score post-treatment, and a significantly higher disease-control rate in the radiotherapy group when compared to the RP group (94.12% vs 76.47%, P = 0.040)[17].

Table 1 Summary of moderate hypofractionated radiation therapy/ultra hypofractionated radiation therapy schemes.

Ref.	Year	Sample size	Dose/fractionation	ADT	Follow-up (median)	Conclusion
Okonogi et al[16]	2025	60	36-40 grays or 44 grays, 4 fractions	Low-risk patients: No ADT received. Intermediate-risk patients: Received 4-8 months of neoadjuvant ADT	42 months (IQR: 27-59 months)	4-fraction carbon-ion RT is safe and effective for prostate cancer; 40 grays balance efficacy/toxicity, but 44 grays increase GU toxicity
Zelefsky et al[25]	2020	551	37.5-40 grays SBRT, 5 fractions in total. Most patients (85.5%, 471/551) received 40.0 grays in 8 grays fractions	151 patients (27.4%) received ADT. Among patients with available data (n = 133), the median duration of hormone therapy was 5.9 months (IQR: 4.1-6.2 months)	17 months (IQR: 7-29 months)	High-dose SBRT for prostate cancer shows favorable short-term tumor control and low toxicity, especially with hydrogel rectal spacers
Abu-Gheida et al[26]	2019	854	70 grays, 28 fractions (2.5 grays per fraction)	61% of patients used ADT. Of these, most received 1-6 months of ADT, and 18% received > 6 months of ADT	11.3 years (maximum 19 years)	Moderately hypofractionated IMRT (70 grays in 28 fractions) for prostate cancer shows excellent 10-year oncologic outcomes with low toxicity across all risk groups
Fransson et al[36]	2021	1180 (591 vs 589)	Conventional fractionation group: 78.0 grays, 39 fractions, 2.0 grays per fraction. Ultra-hypofractionation group: 42.7 grays, 7 fractions, 6.1 grays per fraction	ADT was not permitted	48 months (IQR 25-72 months)	Ultra-hypofractionated radiotherapy for intermediate-to-high-risk prostate cancer shows similar long-term patient-reported quality of life as conventional fractionation, despite higher acute toxicity
Tree et al[53]	2025	1208 (601 to MHRT, 607 to SBRT)	MHRT group: 60 grays, completed in 20 daily fractions. SBRT group: 36.25 grays, 5 fractions	Mandatory ADT for at least 6 months. ADT continued neoadjuvant, concomitantly, and adjuvant until at least 6 months of therapy was complete. Prolongation of ADT (up to a maximum total duration of 18 months) was permitted	During follow-up	PACE-C trial found SBRT and MHRT have similar early RTOG toxicity for higher-risk prostate cancer, though SBRT led to more temporary bowel side-effects

MHRT: Moderate hypofractionated radiation therapy; SBRT: Stereotactic body radiation therapy; ADT: Androgen deprivation therapy; IQR: Interquartile range; Gu: Genitourinary; RTOG: Radiation therapy oncology group.

Indications and contraindications for moderate hypofractionated radiation therapy

Macro-fractionated radiotherapy is a suitable treatment option for some prostate cancer patients, but its indications and contraindications must be strictly controlled. It is generally accepted that patients with low-risk or intermediate-risk prostate cancer who have limited symptoms are suitable candidates for moderate hypofractionated radiotherapy. For instance, in cases of early-stage tumors with minimal size and no discernible metastasis, moderate hypofractionated radiotherapy has been shown to reduce treatment time, enhance patients’ quality of life, and maintain treatment efficacy. However, for patients with high-risk prostate cancer, the application of moderate hypofractionated radiotherapy necessitates meticulous evaluation, as it may result in significant damage to surrounding normal tissues and elevate the risk of complications[18].

Furthermore, there are certain contraindications to moderate hypofractionated radiotherapy. For instance, if the patient has a poor physical condition, is unable to tolerate a higher dose of single irradiation, or has serious cardiopulmonary dysfunction, moderate hypofractionated radiotherapy is not suitable. Conversely, in cases where the prostate cancer has undergone extensive metastasis, moderate hypofractionated radiotherapy may not be an effective treatment option and is not recommended[19]. Furthermore, in cases with normal tissues susceptible to radiotherapy, such as the rectum and bladder, if effective protection cannot be ensured during radiotherapy, moderate hypofractionated radiotherapy should be avoided in order to prevent serious complications. In clinical practice, doctors must consider the patient’s condition, physical status, and radiotherapy equipment and technology in order to decide whether to use moderate hypofractionated radiotherapy.

TECHNOLOGICAL ADVANCES IN UHRT FOR PROSTATE CANCER

Technical principles and equipment updates for ultra-hypofractionated radiation therapy

Ultra-hypofractionated radiotherapy is a further exploration on the basis of massively segmented radiotherapy, and its technical principle is based on the relatively low α/β ratio of prostate cancer tissues, which makes the tumor cells more sensitive to a single high dose of radiation, and normal tissues are able to better tolerate this treatment[20]. In terms of equipment, with the development of science and technology, radiotherapy equipment is constantly updated, such as advanced linear gas pedals that can more accurately control the radiation dose and the shape of the field of fire, improving the precision of treatment[13]. In addition, the integration of image-guided technologies, such as cone-beam CT and magnetic resonance-guided radiotherapy (MRgRT), allows for real-time monitoring of the position and morphological changes of the prostate gland during the treatment process, and timely adjustment of the treatment plan, to ensure that the radiation dose is accurately delivered to the tumor site and to reduce irradiation of the surrounding normal tissues.

For example, MRgRT technology, by combining a magnetic resonance imaging (MRI) scanner with a linear gas pedal, is able to provide high-resolution soft-tissue images to help doctors identify the prostate and its surrounding tissues more clearly, thus more accurately outlining the target area and the organs at risk (OARs)[21]. During the treatment process, the treatment plan can also be adjusted online according to the real-time MRI images to realize adaptive radiotherapy, which further improves the therapeutic effect and safety[21]. In addition, new radiotherapy equipment, such as proton therapy equipment, using the unique physical properties of protons, can achieve more precise dose deposition at the tumor site and reduce the damage to surrounding normal tissues, which provides more powerful technical support for ultra-hypofractionated radiotherapy[22].

Evaluation of short- and long-term efficacy of ultra-hypofractionated radiation therapy

In order to assess the efficacy of ultra-hypofractionated radiation therapy for prostate cancer, it is necessary to consider the short-term and long-term observables separately. The primary focus of a short-term efficacy assessment is the acute toxicity response and tumor control after treatment. In a study of prostate cancer patients receiving ultra-hypofractionated radiotherapy, the incidence of acute grade 2 gastrointestinal toxicity was 1.8%, acute grade 2 genitourinary toxicity was 10%, and grade 3 acute genitourinary toxicity was 0.7%, which indicated that the treatment was well tolerated in the short term[23-25].

Conversely, the assessment of long-term efficacy utilizes various indicators, including survival rates, the incidence of biochemical recurrence, and the manifestation of late toxicities. For instance, in a long-term follow-up study spanning up to 10 years in patients who received hyperfractionated radiotherapy, the findings indicated that the 10-year biochemical recurrence-free survival rates for low-risk, intermediate-risk, and high-risk patients were 88%, 78%, and 42%, respectively. The 10-year clinical recurrence-free survival rates were 95%, 91%, and 85%, respectively. The 10-year OS rate was 69%, while the 10-year prostate cancer-specific mortality rate was 6%. A low incidence of long-term grade 3 and higher genitourinary and gastrointestinal toxicity of 2% and 1%, respectively, was observed, suggesting that ultra-hypofractionated radiotherapy has better tumor control and lower toxicity in the long term[26]. However, the heterogeneity of patient selection criteria and treatment protocols across studies resulted in inconsistent efficacy assessment outcomes. Further high-quality, large-sample, long-term follow-up studies are necessary to provide more definitive insights into the long-term efficacy and safety of ultra-hypofractionated radiotherapy.

DIAGNOSTIC AND MONITORING TECHNIQUES FOR PROSTATE CANCER RADIATION THERAPY

Evaluation of short-term and long-term efficacy of ultra-hypofractionated radiation therapy: Advances in diagnostic imaging techniques for prostate cancer

Recent years have seen considerable advancement in the field of diagnostic imaging techniques for prostate cancer. A variety of advanced techniques have been developed, providing substantial support for the accurate diagnosis and staging of prostate cancer. Multiparametric magnetic resonance imaging has become a significant diagnostic tool for prostate cancer, exhibiting high sensitivity and negative predictive value for clinically significant prostate cancer[27]. For instance, in a study of 150 male patients, multiparametric MRI detected clinically significant prostate cancer with a sensitivity of 90%, a specificity of 85%, and an area under the curve of 0.92, which was superior to transrectal ultrasound and positron emission tomography (PET)/CT[28].

The advent of PET/CT technology has also precipitated new breakthroughs in the diagnosis of prostate cancer, most notably prostate-specific membrane antigen (PSMA) PET/CT, which has been shown to have high sensitivity and specificity for the detection and staging of prostate cancer[29]. Research has demonstrated the efficacy of PSMA-PET/CT in detecting minute metastases that conventional imaging methods often fail to identify. This enhances the accuracy of disease staging and provides a crucial foundation for the development of treatment strategies[29]. Furthermore, ultrasound technology has undergone consistent innovation, exemplified by micro-ultrasound, which has demonstrated comparable sensitivity and specificity to multiparametric MRI in preliminary studies, thus offering a novel alternative for prostate cancer diagnosis[27]. The employment of innovative molecular probes has also led to significant advancements in the precision of diagnostic imaging, facilitating precise visualization and quantitative detection of prostate cancer through specific binding to tumor-associated molecules[30].

Biomarker monitoring of prostate cancer following radiation therapy

Biomarkers play a pivotal role in the monitoring of radiation therapy for prostate cancer, aiding in the assessment of treatment efficacy and the prediction of disease recurrence. Circulating epithelial tumor cells (CETC/CTC) have been identified as a potential biomarker, with the presence of these cells detected in 96% of prostate cancer patients prior to radiotherapy. Furthermore, alterations in the number of these cells during treatment have been shown to be associated with the risk of recurrence. Specifically, a decrease in the number of CETC/CTC has been linked to a reduced risk of recurrence, while an increase in CETC/CTC has been associated with an elevated risk of recurrence (risk ratio = 8.8; P = 0.002)[31].

Furthermore, PSMA-associated assays are of significant importance. For instance, in a study of patients undergoing PSMA-PET/CT-guided salvage radiotherapy, although statistical significance was not reached, PSMA-PET/CT-guided salvage radiotherapy demonstrated superior disease control outcomes, with biochemical progression-free survival at each time point assessed for ¹⁸F-rhPSMA-7/¹⁸F-flotufolastat-guided salvage radiotherapy survival being higher than that of conventional salvage radiotherapy[32]. Furthermore, a number of genetic markers are garnering attention, including the antioxidant stress protein sulfiredoxin-1, which has been demonstrated to exert a significant influence on the response of prostate cancer cells to radiotherapy. Patients exhibiting low sulfiredoxin-1 expression have been observed to demonstrate enhanced prognoses following radiotherapy, as evidenced by a P-value of 0.0072 for the log-rank test of progression-free survival[33]. The monitoring of these biomarkers provides a foundation for the personalized management of prostate cancer radiation therapy.

Methods of evaluating the efficacy of radiation therapy for prostate cancer

Evaluating the efficacy of radiation therapy for prostate cancer is crucial for guiding treatment decisions and predicting patient prognosis. Commonly used assessment methods include a thorough analysis of patient survival rates, biochemical indices and imaging examinations. Several studies have compared the effects of different treatment modalities on OS and disease-free survival. For instance, a study comparing RP and radiotherapy for high-risk prostate cancer found that the disease-free survival rate was higher in the radiotherapy group than in the RP group (79.41% vs 55.88%, P = 0.038), suggesting that radiotherapy is more effective in these patients[17].

With regard to biochemical indicators, PSA is a commonly used assessment indicator, as changes in PSA levels can reflect tumor response to treatment. For example, after radiotherapy, a sustained decrease or maintenance of low PSA levels usually suggests that the treatment is effective, whereas elevated PSA levels may imply disease recurrence or progression[34]. Imaging techniques such as MRI and PET/CT also play an important role in efficacy assessment, as they can visualize tumor size, morphological changes and the presence of metastasis. For instance, PSMA-PET/CT can detect recurrence and metastatic foci of prostate cancer, providing important information for subsequent treatment[29]. Additionally, new assessment methods such as radiomics-based analysis, which involves constructing predictive models by extracting dosimetry features from radiotherapy plans, offer new insights into efficacy assessment[35].

CONTROVERSIES AND CHALLENGES IN PROSTATE CANCER RADIOTHERAPY

Safety controversy of moderate and ultra-hypofractionated radiation therapy

Although moderate and ultra-hypofractionated radiation therapy has shown certain advantages in the treatment of prostate cancer, there are controversies surrounding their safety. On the one hand, the increased single irradiation dose may cause more damage to surrounding normal tissues. For instance, some studies have shown that the probability of acute and late gastrointestinal and genitourinary toxicity increases in patients after moderate hypofractionated radiotherapy[36]. A study comparing hyperfractionated radiotherapy with conventionally fractionated radiotherapy found that the proportion of patients experiencing a clinically relevant worsening of certain intestinal symptoms, such as stool frequency, urinary urgency and flatulence, was significantly higher in the hyperfractionated radiotherapy group than in the conventionally fractionated radiotherapy group at the end of treatment[37].

The results of the present study are inconclusive regarding the potential long-term health risks associated with moderate hypofractionated vs ultra-hypofractionated radiotherapy, such as the risk of developing a second primary tumor. While some studies suggest that modern radiotherapy techniques may reduce this risk, confirmation from long-term follow-up data is needed[38]. Furthermore, tolerance to moderate hypofractionated vs ultra-hypofractionated radiotherapy varies from patient to patient. Developing a safe and effective treatment plan for each patient is still a clinical challenge. Therefore, when applying moderate hypofractionated vs ultra-hypofractionated radiotherapy, it is necessary to weigh up its therapeutic efficacy and safety and to fully assess the risks and benefits for patients.

Individualized protocol design for radiation therapy of prostate cancer

The heterogeneity of prostate cancer makes it important to design individualized treatment plans. Prior to radiotherapy, various factors such as the patient’s condition, physical status and genetic characteristics should to be taken into account. Patients with different risk grades are suitable for different radiotherapy programs, depending on their condition. Low-risk patients may be offered milder regimens, such as low-dose, less-fractionated radiotherapy, to minimize treatment-related adverse effects. In contrast, high-risk patients may require more aggressive treatments, such as high-dose radiotherapy combined with ADT, to improve tumor control[39].

The patient’s physical condition is also a key factor, including age and cardiorespiratory fitness, as these can affect tolerance to radiotherapy. For elderly or frail patients, the radiotherapy dose and fractionation plan must be adjusted to ensure the treatment is safe. In terms of genetic characteristics, some genetic markers can predict how a patient will respond to radiotherapy. For instance, the mutation status of certain genes can influence the radiosensitivity of tumor cells. By identifying these genes, a more suitable radiotherapy regimen can be selected for the patient, or a combination of targeted drugs can be employed to enhance the efficacy of radiotherapy[40]. In addition, advances in imaging technology provide support for designing individualized regimens. Examinations such as multiparametric MRI provide a more accurate understanding of the location, size and morphology of tumors, which is useful when developing radiotherapy plans[41].

FUTURE PERSPECTIVES OF RADIATION THERAPY FOR PROSTATE CANCER

Prospects for novel radiation therapy techniques in prostate cancer

New radiation therapy techniques offer new hope for the treatment of prostate cancer. MRgRT combines MRI with linear gas pedals to acquire real-time soft tissue images of the patient, accurately outline the target area and OARs, and adapt the daily treatment plan as needed[42]. This improves the precision of radiotherapy and reduces irradiation of surrounding normal tissues and the risk of complications. For instance, MRgRT has demonstrated favorable dosimetry benefits in prostate cancer treatment, providing enhanced protection for organs such as the rectum and bladder[43].

Another promising novel technique is CIRT, which has unique physical and biological properties that give it an advantage in prostate cancer treatment. CIRT can achieve more precise energy deposition at the tumor site, resulting in a stronger killing effect on tumor cells while causing less damage to surrounding normal tissues[44]. Clinical studies have shown that CIRT induces less genitourinary and gastrointestinal toxicity during prostate cancer treatment and improves overall and biochemical recurrence-free survival, particularly for patients with high-risk prostate cancer[44]. Additionally, radionuclide therapy, such as ¹⁷⁷Lu-PSMA-617, offers a novel treatment option for patients with advanced prostate cancer by targeting PSMA on prostate cancer cell surfaces, achieving precise tumor cell destruction[45].

Trends in multidisciplinary collaboration in radiation therapy for prostate cancer

Treatment for prostate cancer is increasingly emphasizing a multidisciplinary, collaborative approach. This approach typically involves urologists, radiotherapists, medical oncologists, pathologists and imaging physicians, among others. These professionals work together to formulate personalized treatment plans for patients. During the diagnostic stage, imaging physicians use advanced imaging techniques such as multiparametric MRI and PSMA-PET/CT to provide accurate information for tumor localization and staging. Pathologists analyze biopsy tissue to determine the pathological type and grade of the tumor, providing the basis for subsequent treatment.

During treatment, urologists decide whether to perform surgery and which method to use according to the patient’s condition. Radiotherapists develop precise radiotherapy plans and medical oncologists choose appropriate drug therapies such as ADT, chemotherapeutic agents, or novel targeted drugs. They also consider the timing and protocol for combining drugs and radiotherapy[39]. For instance, when treating some high-risk prostate cancer patients, the multidisciplinary team will consider using a comprehensive treatment program combining radiotherapy with ADT and novel anti-androgen drugs to improve the treatment effect[46]. Multidisciplinary collaboration is also evident in the post-treatment follow-up and rehabilitation phase, where doctors from various disciplines work together to support patients’ recovery, address any complications or adverse reactions promptly, and enhance their quality of life.

Evolving role of radiation therapy in the comprehensive management of prostate cancer

The role of radiation therapy in the comprehensive treatment of prostate cancer is constantly evolving. Historically, it was primarily employed in patients with locally advanced or inoperable prostate cancer as a palliative treatment to alleviate symptoms. However, with technological advances and a better understanding of the biological characteristics of prostate cancer, radiation therapy has also become an important treatment for early-stage prostate cancer. It is often used alongside surgery and endocrine therapy to improve survival rates and quality of life[41].

For locally confined prostate cancer, radiotherapy can be used as a radical treatment with similar efficacy to RP. For patients who are unsuitable for surgery, radiotherapy is an important alternative[47]. In the treatment of metastatic prostate cancer, the role of radiotherapy is also expanding. As well as traditional palliative radiotherapy to relieve symptoms such as bone metastases, recent studies have shown that, for oligometastatic prostate cancer, local radiotherapy combined with systemic therapy (such as combined with ADT or novel targeted drugs) can prolong survival and improve prognosis[48]. Furthermore, radiotherapy can be combined with emerging therapies, such as immunotherapy, to enhance its effects by regulating the tumor microenvironment and opening up new avenues for prostate cancer treatment[49]. Deep learning shows great promise in the MRI-based diagnosis, segmentation, radiotherapy planning and prognostic prediction of prostate cancer. By optimizing models, expanding data and fusing modalities, deep learning is set to become a core technology in precision medicine for prostate cancer, enhancing diagnostic efficiency and treatment accuracy[50].

Toxicity management in hypofractionated radiotherapy for prostate cancer

Hypofractionated radiotherapy for prostate cancer, while enhancing tumor control rates, also elevates the risk of normal tissue toxicity due to higher doses per fraction. Therefore, diligent toxicity management is crucial.

Precise dose optimization and advanced image guidance are fundamental to protecting normal organs. Techniques such as IMRT and VMAT are employed to meticulously limit radiation doses to OARs, including the rectum, bladder, and urethra. State-of-the-art approaches like MRgRT, which leverages daily MRI for real-time plan adjustments, have demonstrated significant advantages. For instance, a study highlighted that online adaptation in MRgRT notably improved target coverage (planning target volume -star dose covering 95% of the volume increased by 2.7%) while also contributing to OAR sparing, with accumulated bladder dose 0.2cc decreasing by 0.4% and urethra + 2 mm dose 0.2cc by 0.8%. This adaptive strategy effectively compensates for anatomical variations, ensuring highly accurate dose delivery and minimizing cumulative dose to critical structures[51].

The strategic application of rectal spacers offers a highly effective means of mitigating rectal toxicity. By injecting an absorbable hydrogel (e.g., SpaceOAR) between the prostate and rectum, the physical separation between these two structures is increased, consequently reducing the radiation dose absorbed by the rectum. Large-scale real-world evidence indicated that a 100-percentage-point increase in rectal spacer use at the county level was associated with a 7.1%-55.1% reduction in the prevalence of bowel, urinary, or sexual dysfunction diagnoses over a 1-5 year period, with the most pronounced association observed for bowel dysfunction[52]. Randomized clinical trials have consistently corroborated this benefit, showing that spacers significantly decrease the incidence of late grade ≥ 2 rectal toxicities.

Continuous image guidance and conformal techniques are indispensable for ensuring treatment precision and reliably maintaining target coverage while safeguarding OARs. MR-guided adaptive radiotherapy employs daily scanning and plan modifications to address inter-fractional anatomical changes, such as prostate swelling or rectal gas, thereby enhancing dose conformity. While some studies, such as the PACE-C trial reported a higher incidence of temporary bowel side-effects with SBRT compared to MHRT during the early period, these effects typically resolve, and no significant difference in clinician-reported bladder side-effects was observed[53]. The ongoing evolution of image-guided techniques facilitates the reduction of planning target volume margins, further optimizing OAR protection without compromising tumor coverage.

Enhanced future perspectives: Towards an actionable clinical workflow in prostate cancer radiotherapy

As radiotherapy for prostate cancer continues to evolve with advanced MHRT/UHRT, it becomes imperative to outline a prospective, actionable clinical workflow that integrates current evidence, risk-stratified guidance, and judicious combination strategies. This will significantly enhance the translational value of these advancements and guide future clinical implementation. A conceptual workflow for MHRT/UHRT would encompass comprehensive pre-treatment assessment and risk stratification using advanced diagnostics like multiparametric MRI and PSMA-PET/CT, alongside emerging biomarkers (e.g., circulating tumor cells, genetic markers like sulfiredoxin 1 expression)[33]. This robust stratification is paramount for identifying patient and tumor characteristics crucial for treatment choice and toxicity prediction. Precise treatment planning, leveraging state-of-the-art techniques such as IMRT, VMAT, SBRT, and MRgRT, along with particle therapy like CIRT, is key to achieving highly conformal dose delivery, with meticulous target delineation and rigorous OAR (rectum, bladder, urethra) dose optimization. Adaptive treatment delivery, utilizing real-time image guidance (e.g., daily MR imaging in MRgRT) to monitor prostate position and anatomical changes, enables adaptive planning and delivery, ensuring accurate dose to the target while minimizing cumulative OAR exposure[51]. Integrated toxicity management, including the routine use of rectal spacers (e.g., hydrogel) to physically separate the prostate from the rectum, is crucial[52]. Continuous monitoring for acute and late gastrointestinal and genitourinary toxicities is essential, with predefined protocols for intervention. Finally, long-term post-treatment surveillance with PSA monitoring, advanced imaging (e.g., PSMA-PET/CT for biochemical recurrence)[32,34], and emerging biomarkers will assess oncological outcomes and late toxicities.

Risk-stratified guidance for MHRT/UHRT is crucial for optimizing patient selection. For low to intermediate-risk localized prostate cancer, MHRT/UHRT regimens are increasingly becoming the standard of care due to their demonstrated non-inferior oncologic outcomes, improved convenience, and favorable toxicity profiles in these cohorts. Individualized patient factors and shared decision-making remain key. For high-risk localized prostate cancer, MHRT/UHRT may be considered, but generally requires careful individualized assessment. The integration of advanced techniques like CIRT may offer enhanced therapeutic ratios for these patients[16,34], necessitating close scrutiny of OAR doses and patient-specific risk factors for toxicity. Future guidance will increasingly incorporate genetic and molecular subtypes, utilizing genetic biomarkers (e.g., sulfiredoxin 1)[33] to predict radiosensitivity and inform the aggressiveness or suitability of hypofractionated regimens, thereby moving towards truly personalized radiation oncology.

Combination strategies, particularly involving ADT and additional radiation, are vital for comprehensive prostate cancer management. For high-risk localized prostate cancer, the combination of ADT with MHRT/UHRT remains a cornerstone of treatment, leveraging ADT’s synergistic benefits as a radiosensitizer[34,39,46]. The duration and timing of ADT should be carefully considered within multidisciplinary discussions, tailored to risk stratification and patient tolerance. Beyond primary treatment, MHRT/UHRT holds significant promise in salvage settings for radio-recurrent prostate cancer (e.g., after prostatectomy or prior radiation). PSMA-PET/CT-guided salvage radiotherapy exemplifies a precise approach to re-irradiation[32], where the high dose per fraction and steep dose gradients of UHRT can be advantageous in targeting recurrent disease while sparing previously irradiated normal tissues. In the adjuvant setting (e.g., post-prostatectomy for high-risk features), MHRT/UHRT may be employed to target microscopic residual disease, aiming for equivalent oncologic control with reduced treatment burden and potentially lower long-term toxicity compared to conventional adjuvant regimens, although further dedicated trials are needed. Furthermore, for oligometastatic hormone-sensitive prostate cancer, local MHRT/UHRT to metastatic sites combined with systemic therapy offers a strategy to delay progression and potentially improve survival, expanding the role of radiotherapy beyond primary tumor treatment[48]. This forward-looking perspective, grounded in current evidence and anticipating future developments, underscores the dynamic evolution of prostate cancer radiotherapy and its increasing integration into a personalized, multidisciplinary care paradigm.

CONCLUSION

Prostate cancer radiotherapy has evolved significantly through technological advances, enabling precise hypofractionated regimens (MHRT/UHRT). These shorter-course treatments demonstrate non-inferior oncologic outcomes compared to conventional radiotherapy while improving patient convenience. However, challenges remain in optimizing doses, managing toxicity, and personalizing treatment through advanced imaging (e.g., multiparametric MRI, PSMA-PET/CT) and biomarker integration. Future progress hinges on novel techniques like magnetic resonance-guided and carbon ion radiotherapy, which may further improve precision and reduce side effects. Multidisciplinary collaboration is essential to integrate radiotherapy effectively with systemic and emerging therapies. The ultimate goal remains enhancing both survival and quality of life for prostate cancer patients.