Moderate Hypofractionated Helical Tomotherapy for Localized Prostate Cancer in Older Patients: A Single-Institution Study of Toxicity and Outcomes

Abstract

Introduction

The optimal management of localized prostate cancer (PCa) in the “oldest-old” demographic presents a unique clinical challenge, requiring a careful balance between oncological control and the preservation of quality of life. This study aims to evaluate the safety, toxicity profile, and clinical outcomes of moderately hypofractionated helical tomotherapy (HT) in a cohort of patients aged 75 years and older with localized PCa.

Materials and Methods

In this retrospective cohort study, we analyzed 51 consecutive patients with a median age of 79 years treated between 2016 and 2022. All patients received 69 Gy in 25 fractions (2.76 Gy/fraction) via the HT platform. Risk stratification was performed using the D’Amico classification, revealing that the majority were high-risk (52.9%) or intermediate-risk (43.1%). Clinical outcomes included biochemical relapse-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS). Toxicity grading followed CTCAE v4.0 criteria, and Quality of Life (QoL) was evaluated through the International Prostate Symptom Score (IPSS) and a single-item index.

Results

At a median follow-up of 38 months, the 5-year BRFS, CSS, and OS rates were 83.3%, 80.1%, and 68.8%, respectively. Acute Grade 2 genitourinary and gastrointestinal toxicities occurred in 25.5% and 27.5% of the subjects. Late Grade 3 complications were rare (1 GU, 4 GI). Significant longitudinal improvements in IPSS and QoL were observed within 3 months post-treatment ( $p<0.001$ ).

Conclusion

Moderately hypofractionated HT may be a safe and effective treatment for elderly PCa patients, suggesting potential for excellent oncological control and symptomatic relief.

1. Introduction

Prostate cancer (PCa) is fundamentally a disease associated with the aging process, with its incidence rising sharply in men over the age of 65.^1,2 As the global population experiences a significant demographic transition toward a higher proportion of elderly individuals—often referred to as the “Silver Tsunami”—oncology centers are increasingly encountering patients aged 75 years and older, a group frequently termed the “oldest-old”.^3,4 For this specific demographic, the optimal management of localized PCa remains a subject of intense clinical debate and uncertainty. Historically, chronological age was often utilized as a convenient proxy for frailty or limited life expectancy, leading many clinicians to favor conservative management strategies such as androgen deprivation therapy (ADT) monotherapy or watchful waiting.^5,6 However, these “de-escalated” approaches frequently ignore the potential for local tumor progression, which can severely impair a patient’s quality of life (QoL) through complications such as urinary obstruction, gross hematuria, or the development of painful bony metastases.^3,7

The evolution of external beam radiotherapy (EBRT) has effectively challenged these conservative norms by providing a non-invasive, curative-intent alternative.^8,9 The cornerstone of the modern transition toward shorter radiotherapy schedules is the radiobiological understanding of the $\alpha /\beta$ ratio in PCa tissue.^10,11 Unlike the majority of human epithelial carcinomas, which typically exhibit a high $\alpha /\beta$ ratio of approximately 10 Gy, PCa is widely hypothesized to have an exceptionally low $\alpha /\beta$ ratio, estimated to be between 1.2 and 1.8 Gy.^12,13 This unique biological property implies that PCa is highly sensitive to the dose delivered per fraction. When the $\alpha /\beta$ ratio of a tumor is lower than that of the surrounding dose-limiting normal tissues, such as the rectum and bladder wall, a hypofractionated schedule should theoretically improve the therapeutic ratio.^10,11 By increasing the dose per fraction to a range of 2.4–3.4 Gy, clinicians can achieve greater biological cell kill within the tumor while maintaining equivalent or even lower late-term effects on the adjacent organs at risk (OARs).^9,14 This radiobiological advantage is the primary driver behind the adoption of moderate hypofractionation as a global standard of care.^15,16

Technological precision is the mandatory prerequisite for the safe delivery of such biologically potent, high-dose-per-fraction radiation. ¹⁷ Helical Tomotherapy (HT) represents a unique and highly sophisticated platform that fuses a computed tomography (CT) gantry with a 6-MV linear accelerator. While modern conventional C-arm gantry systems widely utilize volumetric modulated arc therapy (VMAT), HT delivers radiation in a continuous helical pattern via a 360-degree rotating fan beam.^18,19 This geometry, combined with a 64-leaf binary multileaf collimator (MLC), facilitates superior dose conformity and an exceptionally focused dose fall-off at the critical interface between the prostate and the anterior rectal wall. ¹⁹ Furthermore, HT’s integrated MegaVoltage CT (MVCT) system allows for daily volumetric imaging prior to every treatment session.^17,20 This ensures that the steep dose gradient is precisely aligned with the moving target, accounting for inter-fractional variations in bladder and rectal filling. ²¹ While previous studies have explored hypofractionation for prostate cancer, the “oldest-old” demographic is often underrepresented or grouped with younger seniors. The novelty of this current work lies in its exclusive focus on patients aged 75 years and older with significant multi-system comorbidities, providing a detailed assessment of both long-term late toxicity and longitudinal patient-reported QoL. This study aims to provide a comprehensive evaluation of a moderately hypofractionated HT regimen, specifically 69 Gy delivered in 25 fractions, in a cohort of 51 elderly patients.

2. Materials and Methods

2.1. Patient Selection and Ethical Considerations

This study is an analysis of a specific elderly cohort derived from a registered clinical trial (ChiCTR-ONC-13004037) and is designed as a retrospective cohort study. The reporting of this study conforms to the STROBE guidelines for observational studies. ²² The study protocol was rigorously reviewed and approved by the Institutional Review Board (IRB) of the Chinese PLA General Hospital (Approval Number: S2013-109-02; Date of approval: December 17, 2013). The study was conducted in full compliance with the Helsinki Declaration of 1975, as revised in 2024. Written informed consent was obtained from all participating patients prior to the initiation of treatment. Furthermore, all patient details have been strictly de-identified such that the identity of any person may not be ascertained in any way.

Fifty-one consecutive patients aged 75 years and older, who underwent radical radiotherapy utilizing the specific moderately hypofractionated regimen (69 Gy in 25 fractions) via the HT platform, were analyzed. Staging was achieved through physical examination, digital rectal examination, serum PSA testing, and advanced imaging modalities including multi-parametric MRI (mpMRI), according to established consensus guidelines. For inclusion in the study, patients were required to have localized disease categorized as T1-T3bN0M0 based on pre-treatment staging. Any patients with a prior history of pelvic irradiation or active inflammatory bowel disease were excluded to ensure the accuracy of toxicity reporting. While standardized geriatric screening tools (e.g., Comprehensive Geriatric Assessment) were not routinely employed, patients were carefully selected for curative-intent treatment based on a multidisciplinary clinical consensus. This process informally evaluated the patients’ biological age and functional reserve, assuring an estimated life expectancy of greater than 5-10 years based on their overall performance status and manageable comorbidities. Risk stratification was standardized using the D’Amico classification system to guide the intensity of systemic therapy.

2.2. Simulation and Volume Delineation

Standardized simulation procedures were utilized to minimize internal motion and ensure the reproducibility of the target volumes. Patients were instructed to follow a strict bowel and bladder protocol, which included emptying the rectum using a fleet enema two hours prior to simulation and drinking 500 mL of water 30 minutes before the scan. Patients were immobilized in the supine position using specialized knee and ankle fixation devices. Simulation CT slices were acquired at 2.5-mm intervals from the level of the L1 vertebra down to 2 cm below the femoral neck. The Gross Tumor Volume (GTV) was delineated as the prostate gland visualized on the fused mpMRI and CT images. The Clinical Target Volume (CTV) included the GTV for all patients, with the addition of the proximal or entire seminal vesicles for intermediate and high-risk patients depending on their clinical profile. It is important to note that clinical nodal status (cN0) was strictly determined using preoperative mpMRI and bone scans. For high-risk patients in this cohort, prophylactic whole-pelvic nodal irradiation was deliberately omitted from this protocol. This decision was driven by the advanced age of the cohort (≥75 years) and the specific intent to minimize severe gastrointestinal toxicities, balancing oncological control with the preservation of QoL. To account for uncertainties, a precise PTV margin was applied, typically including a 5-mm posterior margin to spare the anterior rectal wall and 7–8 mm in other directions.^14,23

2.3. Planning and Helical Tomotherapy Delivery

Radiotherapy plans were developed using the Helical Tomotherapy Planning System. The prescription dose was set at 69 Gy delivered in 25 fractions, with a fraction size of 2.76 Gy. This regimen was selected to provide a total Biological Effective Dose (BED) equivalent to roughly 78–80 Gy in conventional fractions.^8,24 Dose-volume histogram (DVH) constraints were strictly applied to ensure OAR sparing, especially for the rectum and bladder where V60 was kept below 25% and V65 below 15%, respectively.^8,20 Furthermore, hotspots within the Planning Target Volume (PTV) were strictly limited to ≤ 105% of the prescription dose, and maximum dose constraints were applied to the urethra and penile bulb. Radiotherapy was delivered five days per week over a total period of five weeks. Each fraction was preceded by an MVCT scan to verify the position of the prostate. Given that intraprostatic fiducial markers were not routinely implanted in this elderly cohort to avoid invasive procedure-related complications, daily image guidance relied on soft-tissue alignment. Coregistration of the MVCT with the planning CT was performed by prioritizing the interface of the prostate capsule, the anterior rectal wall, and the posterior bladder wall, supported by pelvic bony anatomy. The soft-tissue contrast of daily MVCT was deemed clinically robust enough to track these structures and account for inter-fractional prostate rotations or internal deformations caused by physiological variations in rectal or bladder filling. This setup accuracy allowed for real-time translational and rotational shifts, ensuring high geometrical precision throughout the treatment course.^17,20 The typical beam-on treatment time for HT delivery ranged from 5 to 7 minutes, which significantly minimized the potential for intra-fractional patient movement and alleviated lying discomfort in this vulnerable elderly cohort.

2.4. Systemic Treatment and Combined Therapy

Androgen deprivation therapy (ADT) was integrated into the treatment paradigm for intermediate- and high-risk patients in accordance with NCCN recommendations.^18,25 High-risk patients typically received long-course ADT, consisting of neoadjuvant, concurrent, and adjuvant phases for a total duration of 18 to 36 months, which has been shown to improve oncological outcomes and metastasis-free survival.^5,26 Intermediate-risk patients were generally prescribed short-course ADT for a period of 4 to 6 months. ADT typically utilized LHRH agonists or antagonists. For the two low-risk patients in the cohort, ADT was omitted, and radical radiotherapy was performed as monotherapy.

2.5. Outcomes, Toxicity, and Longitudinal HRQoL

The primary oncological endpoint was biochemical relapse-free survival (BRFS) defined by the Phoenix criteria. Secondary endpoints included overall survival (OS), cancer-specific survival (CSS), and toxicity grading according to the CTCAE v4.0. Clinical toxicity was evaluated weekly during treatment and at intervals of 3 to 6 months during follow-up. Furthermore, patient-reported health-related quality of life (HRQoL) was monitored longitudinally using the IPSS and a single-item QoL index.^27,28

2.6. Statistical Analysis

Survival rates were estimated using the Kaplan-Meier method. To statistically analyze these longitudinal trends while accounting for missing data and inter-patient variability, a Linear Mixed-Effects Model (LMM) was employed. All statistical tests were two-sided, and a $p$ -value of less than 0.05 was considered statistically significant.

3. Results

3.1. Baseline Characteristics

The comprehensive baseline characteristics of the 51 elderly patients included in this study are summarized in Table 1. The median age of the cohort was 79.0 years, representing a significantly older population than those typically enrolled in large-scale clinical trials. ²⁹ Comorbidities were highly prevalent in this group, as 62.7% of surgical candidates had hypertension and 33.3% had a documented history of cardiovascular or cerebrovascular disease. In terms of disease severity, 52.9% were categorized as high-risk and 43.1% as intermediate-risk, while only 3.9% presented with low-risk features. The median pre-treatment PSA was 13.9 ng/ml, and a majority of patients presented with T2 stage disease at diagnosis as detailed in Table 1.

Table 1.

Baseline Characteristics

Characteristics	Total (n = 51)
Age(years)
Median (IQR)	79.0 (77.0, 82.5)
PSA before treatment(ng/ml)
Median (IQR)	13.9 (8.7, 22.0)
Diabetes, n (%)
No	37 (72.5)
Yes	14 (27.5)
Hypertension, n (%)
No	19 (37.3)
Yes	32 (62.7)
Prior.malignancy, n (%)
No	42 (82.4)
Yes	9 (17.6)
CVD.CBD, n (%)
No	34 (66.7)
Yes	17 (33.3)
D’Amico risk group classification
Low risk	2 (3.9)
Intermediate risk	22 (43.1)
High risk	27 (52.9)
Tstage, n (%)
T1	2 (3.9)
T2	39 (76.5)
T3	10 (19.6)
Gleason score, n (%)
≤6	34 (66.7)
7-8	10 (19.6)
≥9	7 (13.7)

3.2. Survival Outcomes

The median follow-up period for the entire cohort was 38 months, with an observational range extending from 28 to 74 months. Overall, the oncological efficacy achieved via the moderately hypofractionated HT regimen was robust and consistent as illustrated in Figure 1. As demonstrated in Figure 1A, the BRFS rate reached 100% at the three-year milestone and remained as high as 83.3% at the five-year interval. Biochemical failures recorded during the follow-up period were infrequent and occurred predominantly within the high-risk subgroup. Similarly, the CSS reached an impressive 80.1% at five years as depicted in Figure 1B, indicating that the vast majority of patients did not succumb to disease progression during the study period. ³⁰

Figure 1.

Kaplan-Meier survival analysis for the elderly cohort. The X-axis represents time in months.

In contrast, the OS rate was 68.8% at the five-year mark as shown in Figure 1C. A progressive and statistically notable divergence between the CSS and OS curves was observed as the follow-up duration increased. This phenomenon underscores the significant impact of the “competing risk of death” that is inherently prevalent in an elderly population. Mortality within this cohort was primarily driven by non-malignant causes, including heart failure and cerebrovascular accidents, rather than a failure of the radiotherapy regimen to curb the primary malignancy.

3.3. Toxicity Analysis

All 51 patients completed the prescribed 25 fractions of radiotherapy without any dose modifications. The acute toxicity profile is detailed in Table 2. Acute Grade 1 and Grade 2 genitourinary toxicities occurred in 49.0% and 13.7% of patients, respectively. Similarly, acute gastrointestinal events were frequent but mild, with 21.6% experiencing Grade 2 GI toxicity. No Grade 3 or higher acute events were recorded, indicating that the fraction size was well-tolerated in the short term.^31,32 The late toxicity outcomes are provided in Table 3. Late GU toxicity was remarkably low, with only a single patient (1.9%) developing Grade 3 urinary obstruction that required surgical correction. In contrast, 4 patients (7.8%) experienced Grade 3 rectal bleeding. It is important to consider that these patients were concurrently on anticoagulant therapy for cardiovascular conditions, a factor that likely contributed to the bleeding severity as shown across the cohort. As illustrated in Figure 2, the cumulative incidence of late complications primarily stabilized within 24 months post-treatment.^8,29

Table 2.

Acute Toxicity and Specific Symptoms According to CTCAEv4.0

Toxicity categories/Symptoms	G1	G2
Genitourinary
Obstruction	1	1
Urinary	10	5
Urinary tract pain	14	7
Gastrointestinal
Diarrhea	6	3
Rectal tenesmus	13	10
Stipsis	0	0
Hemorrhoids	0	1

Table 3.

Late Toxicity and Specific Symptoms According to CTCAEv4.0

Symptoms	G1	G2	G3
Genitourinary
Urinary tract pain	6	1	0
Urinary frequency	6	3	0
Urinary obstruction	1	0	1
Gastrointestinal
Diarrhea	1	2	0
Rectal bleeding	2	3	4
Proctitis	4	1	0

Figure 2.

Cumulative incidence of late-term toxicities according to the CTCAE v4.0 criteria.

3.4. IPSS and QoL Trajectories

The results of the longitudinal analysis for patient-reported outcomes are displayed in Figure 3. There was a significant and clinically meaningful positive trajectory observed in both urinary symptoms and general well-being. According to the data summarized in Figure 3A, the median IPSS score decreased significantly from a baseline of 12.5 to approximately 4.2 at the 3-month follow-up ( $p<0.001$ ). This reflects a rapid transition for the majority of patients from a symptomatic state to one that is mild or asymptomatic. ²⁷ Furthermore, as shown in Figure 3B, the single-item QoL score also improved from a mean of 3.6 to 1.8. These results suggest that for the elderly population, radical radiotherapy via the HT platform acting as both an oncological and functional intervention helps in alleviating symptoms caused by the primary lesion. ³³

Figure 3.

Longitudinal assessment of symptomatic changes and patient-reported outcomes.

4. Discussion

4.1. Comparison With Clinical Trials and Prior HT Experiences

The safety of moderate hypofractionation for PCa has been substantiated by high-level evidence from landmark trials including CHHiP, HYPRO, and PROFIT.^15,16,29 Although these trials yielded excellent outcomes, their median ages were generally in the late 60s or early 70s, leaving a significant evidence gap for the “very elderly” aged 75 and older. Our study specifically addresses this demographic, with a median age of 79 years. Our toxicity results are highly consistent with other moderately hypofractionated HT experiences, such as the study by Cuccia et al., ³⁴ who analyzed 170 localized prostate cancer patients treated with 70 Gy in 28 fractions. They similarly reported excellent tolerability with no acute grade ≥ 3 events and very low rates of severe late gastrointestinal (3%) and genitourinary (4.8%) toxicities at 4 years. Furthermore, our findings corroborate and expand upon the related work by Cuccia et al., ⁷ who evaluated a similar HT regimen specifically in a cohort of 95 older patients. While Cuccia et al firmly established the oncological safety and low toxicity profile of HT, our study provides further granularity by incorporating longitudinal trajectories of patient-reported QoL and symptom relief, reinforcing its functional value specifically for the “oldest-old” subpopulation.

Despite the high-risk nature of our cohort compared to many trial participants, our 5-year BRFS of 83.3% is competitive with the outcomes reported in the CHHiP trial. ³² Furthermore, while modern conventional C-arm linear accelerators utilizing VMAT have also demonstrated excellent outcomes and are widely used for delivering moderate hypofractionation, the unique 360-degree helical delivery and binary MLC of the HT platform continue to offer highly competitive dose conformality and strict OAR sparing. This feature is particularly advantageous in minimizing severe gastrointestinal and genitourinary toxicity in frail patients who inherently carry a higher burden of baseline comorbidities. This indicates that the radiobiological sensitivity of PCa to larger fraction sizes remains a robust clinical advantage in the elderly population regardless of chronological age.

4.2. Technical Performance of Helical Tomotherapy

The successful delivery of a moderately hypofractionated schedule requires high degree of technical precision to ensure a favorable therapeutic ratio. In this study, HT was instrumental in maintaining low toxicity rates despite the high biological dose. HT utilizes a binary MLC and a continuous rotary delivery system, facilitating a highly conformal dose distribution and steep dose gradient between the PTV and the anterior rectal wall.^18,24 Additionally, the daily use of MVCT image guidance proved essential for avoiding unintended high-grade injuries to OARs in an elderly cohort where internal anatomy can vary significantly due to physiological changes. ²³

4.3. Toxicity and Biological Integrity in the Elderly

A common concern in geriatric oncology is whether older tissues possess reduced regenerative capacity leading to higher incidence of late-onset toxicity. However, our findings refute the idea that elderly patients are inherently too fragile for moderate hypofractionation. The low rate of Grade 3 GU events confirms that 2.76 Gy is well-tolerated by the prostatic urethra and bladder neck.^16,35 While we observed a 7.8% incidence of late Grade 3 GI toxicity, this must be interpreted within the context of the patients’ baselines. Significant cardiovascular burden and anticoagulant use likely exacerbated the severity of minor rectal bleeding episodes, suggesting that clinicians should still carefully manage patients on aggressive anti-thrombotic therapy.

4.4. Quality of Life and Logistical Implications

In managing elderly patients, preservation of HRQoL is often prioritized over absolute survival metrics. Our finding that IPSS scores improved significantly post-treatment as shown in Figure 2 is a key finding.^27,33 Radical radiotherapy effectively shrinks the primary tumor and alleviates tumor-induced obstructive symptoms. Furthermore, adopting a shorter 25-fraction schedule has profound social implications. By shortening the duration from 8 to 5 weeks, we significantly reduced travel-related burdens for caregivers, which is particularly relevant in the context of pandemic preparedness and healthcare resource optimization.^25,36

4.5. Study Limitations

This study has several limitations, including the relatively small sample size (n=51) and the post-hoc nature of analyzing this specific elderly subgroup. While the follow-up period is sufficient to assess peak late toxicities, capturing extremely late complications may require longer monitoring periods. Additionally, the heterogeneity of ADT durations within the cohort may have influenced biochemical outcomes. Furthermore, a notable limitation in our patient selection process was the absence of validated geriatric screening tools (such as the Comprehensive Geriatric Assessment) or formal, objective life expectancy calculation metrics. Although a multidisciplinary clinical consensus was utilized to estimate functional fitness and ensure a life expectancy of greater than 5-10 years, this approach relies heavily on subjective clinician judgment rather than standardized scoring systems. Future prospective trials incorporating validated geriatric screening tools are necessary to further refine patient selection, objectively quantify frailty, and optimize management for this vulnerable population.

5. Conclusions

This mono-institutional investigation offers observational evidence suggesting that a moderately hypofractionated regimen delivered via helical tomotherapy may serve as an oncologically resilient and safe curative strategy for localized prostate cancer in patients aged 75 years and older. The findings indicate that this five-week protocol yields durable five-year biochemical control and cancer-specific survival, even among a demographic characterized by highly aggressive disease and a heavy burden of baseline multi-system comorbidities. The intrinsic precision of helical delivery, synergized with daily volumetric image guidance, facilitates a remarkably manageable safety profile. This is evidenced by a minimal incidence of high-grade late-term complications, suggesting that intensive radiotherapy may be successfully navigated by the oldest-old population without compromising biological tolerance.

Beyond its technical efficacy, this treatment paradigm provides significant functional and logistical dividends that resonate with the priorities of geriatric care. The longitudinal improvement in urinary-specific quality of life and symptomatic scores underscores that radical radiotherapy effectively mitigates tumor-induced obstructive voiding symptoms, functioning as both a curative and a functionally restorative intervention. Moreover, by compressing the therapeutic window from the traditional eight weeks to just five, this regimen significantly alleviates the socioeconomic and logistical strain exerted on elderly patients and their support networks. Ultimately, these findings reinforce the clinical mandate that chronological age should not routinely preclude patients from receiving curative-intent therapy; instead, shortened, high-precision helical tomotherapy may be recognized as a viable option to ensure equitable and effective oncological management for the aging population.