Abstract
Background/Aim: Radiotherapy represents an important therapeutic option in the management of prostate cancer (PCa). As helical tomotherapy may improve toxicity outcomes, we aimed to evaluate and report the toxicity and clinical outcomes of localized PCa patients treated with moderately hypofractionated helical tomotherapy. Patients and Methods: We retrospectively analyzed 415 patients affected by localized PCa and treated with moderately hypofractionated helical tomotherapy in our department from January 2008 to December 2020. All patients were stratified according to the D’Amico risk classification: low-risk 21%, favorable intermediate-risk 16%, unfavorable intermediate-risk 30.4%, and high-risk 32.6%. The dose prescription for high-risk patients was 72.8 Gy to the prostate (planning tumor volume-PTV1), 61.6 Gy to the seminal vesicles (PTV2), and 50.4 Gy to the pelvic lymph nodes (PTV3) in 28 fractions; for low- and intermediate-risk patients 70 Gy for PTV1, 56 Gy for PTV2, and 50.4 Gy for PTV3 in 28 fractions. Image-guided radiation therapy was performed daily in all patients by mega-voltage computed tomography. Forty-one percent of patients received androgen deprivation therapy (ADT). Acute and late toxicity was assessed according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v.5.0 (CTCAE). Results: Median follow-up was 82.7 months (range=12-157 months) and the median age of patients at diagnosis was 72.5 years (range=49-84 years). The 3, 5, and 7 yr overall survival (OS) rates were 95%, 90%, and 84%, respectively, while 3, 5, and 7 yr disease-free survival (DFS) were 96%, 90%, and 87%, respectively. Acute toxicity was as follows: genitourinary (GU) G1 and G2 in 35.9% and 24%; gastrointestinal (GI) in 13.7% and 8%, with G3 or more acute toxicities less than 1%. The late GI toxicity G2 and G3 were 5.3% and 1%, respectively, and the late GU toxicity G2 and G3 were 4.8% and 2.1%, respectively, and only three patients had a G4 toxicity. Conclusion: Hypofractionated helical tomotherapy for PCa treatment appeared to be safe and reliable, with favorable acute and late toxicity rates and encouraging results in terms of disease control.
External beam radiotherapy is a milestone in the treatment of men with prostate cancer (PCa) with curative intent and is associated with long-term disease control in most patients (1). Historically, the standard radiotherapy treatment involves conventional fractionation, with doses of 1.8-2 Gy/day, treatment approximately over 7 weeks, with onerous costs and a negative impact on the patient’s quality of life (2, 3). Over the last decade, the constant improvement in radiotherapy techniques, including intensity-modulated radiotherapy (IMRT) and image-guided radiotherapy (IGRT), has led to more personalized treatment, with the possibility of using dose-escalated schedules with significant advantages in terms of biochemical control rates and cost-effectiveness (5, 6). Helical tomotherapy, with a combination of linear accelerator and computed tomography characteristics, should provide better dose distribution and conformation than conventional intensity-modulated radiotherapy, with the opportunity to reduce acute and late toxicity without compromising the oncological outcome (7). In the literature, several retrospective and randomized phase III trials have demonstrated the non-inferiority of hypofractionated schedules compared with conventional fractionation, and moderate hypofractionation has recently been shown to be safe and effective and is considered a reliable treatment option in patients with localized PCa (8-12). These results have a radiobiological rationale. In particular, one of the most important features of PCa that differentiates it from other solid tumors is the low alpha/beta ratio. It represents the dose where the linear as well as the quadratic component cause the same amount of cell killing (13). As a result, tissues with a high alpha/beta ratio (≥10 Gy) are considered early responding or rapidly proliferating, whereas tissues with a low alpha/beta are considered late responding or slowly proliferating, with a typically more pronounced resistance to low single doses. Therefore, as reported in the literature (14-19), PCa behaves like the latter, having an alpha/beta ratio of 1.2-1.5.
In this retrospective study, we aimed to evaluate the long-term outcomes and toxicity of 415 patients affected by localized PCa treated with moderately hypofractionated IMRT-helical tomotherapy.
Patients and Methods
We retrospectively evaluated outcomes and toxicities of patients who underwent radical hypofractionated helical tomotherapy for PCa. Our study received final approval by the Institutional Ethics Committee (protocol code: 1006/2019/OS/IRCCSRE approved on 19/11/2019) and was performed in accordance with the principles of Good Clinical Practice (GCP) in compliance with the ICH GCP guidelines and the ethical principles contained in the Declaration of Helsinki and its subsequent updates. A written consent form was obtained from each patient.
Inclusion criteria: Age more than 18 years; proven histological diagnosis of PCa; patients who underwent radical moderately hypofractionated IMRT performed with helical tomotherapy; locally advanced PCa; concurrent/adjuvant ADT was allowed; performance status ECOG 0-2; signed informed consent.
Exclusion criteria: Performance status ECOG 3 or worse; any psychological condition that affects the possibility of signing the informed consent; patients treated with systemic therapy (chemotherapy or abiraterone or enzalutamide); presence of extra-regional metastasis at recurrence time; stage IV patients.
Aims: To evaluate acute and late gastrointestinal (GI) and genitourinary (GU) toxicity in patients with PCa treated with curative intent using hypofractionated tomotherapy, identifying any related risk factors. To evaluate local control of the disease, disease-free survival, overall survival, and the cancer-related mortality rate, identifying any risk factors related to them.
Radiotherapy treatment. For all patients, computed tomography (CT) simulation with 3 mm slice thickness was performed in supine position using a knee-fix immobilization system. In the case of patients with high disease risk, where pelvic lymph node irradiation was planned, simulation CT was performed using iodinated contrast medium. Contrast-enhanced axial plane images were obtained from the lower level of L2 to proximal femurs. The target volumes and organs at risk (OARs) were contoured by specialized radiation oncologists. Before planning, a second radiation oncologist evaluated and approved the contours or requested a revision in the event of disagreement. The clinical target volume (CTV) was defined as the entire prostate in the case of low-risk disease, and proximal seminal vesicles were included in the intermediate-risk CTV2, while all the vesicles were included in the case of high-risk or in the case of seminal vesicle invasion. An additional CTV3 was designed to identify pelvic lymph nodes. The planning target volume (PTV) included CTV1, 2, and 3 with a 5-6 mm margin that were used to create PTV1, 2, and 3. Normal structures including the rectum, bladder, femoral head, penile bulb, and bowel were considered to be OARs. Normal structures were constrained on an individual basis using maximum and dose-volume histogram dose constraints without compromising PTV1 coverage. The prescribed doses were as follows: for high-risk patients 72.8 Gy for PTV1, 61.6 Gy for PTV2 and 50.4 Gy for PTV3 in 28 fractions; for low- and intermediate-risk patients 70 Gy for PTV1, 56 Gy for PTV2 and 50.4 Gy for PTV3 in 28 fractions. A total of 332 patients (80%) were low-risk and did not receive pelvic irradiation. IGRT was performed daily in all patients. Acquired CT images using mega-voltage CT (MVCT) were superimposed onto the treatment plans. The median treatment time (beam on) was 340 s (range=190-913 s). The patient’s position was adjusted according to prostate matching before each treatment. The dose constraints used are as follows: rectum: V50<45%, V60<30%, V65<20%; bladder: V60<35 Gy and femurs: Dmax<40 Gy (Figure 1).
Case example of a prostate helical tomotherapy treatment in the three spatial planes, showing the dose distribution.
Hormonal therapy (ADT). The androgen blockade consisted of a luteinizing hormone-releasing hormone (LHRH), and anti-androgen therapy was performed as neoadjuvant, concurrent and adjuvant for all intermediate and high-risk patients. Androgen deprivation therapy duration was modulated in relation to risk classification: 6 months for intermediate and 2-3 years for high risk. A preliminary cardiological evaluation was performed on patients with cardiac co-pathologies to evaluate contraindications to the use of ADT.
Follow-up. The follow-up schedule consisted of clinical examination and prostate specific antigen (PSA) detection every 3 months for the first year after the irradiation, then every 6 months. Restaging with CT scan plus bone scan or functional imaging (11C-choline-PET/CT or 68Ga-PSMA PET/CT) was performed in patients with increasing PSA (with a focus on the PSA doubling time) and/or new onset symptoms (urinary retention, hematuria, or bone pain refractory to pain relief). Biochemical recurrence of disease was defined in accordance with the Phoenix criteria (PSA ≥ PSA nadir +2 ng/ml) (20, 21).
Acute and late toxicity was evaluated and graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events v.5.0 (CTCAE).
Statistical analysis. Disease-free survival (DFS), overall survival (OS), and toxicity outcomes were investigated. DFS was defined as the time between the first day hypofractionated helical tomotherapy (HT) to the detection of clinical disease outside the PTV after further biochemical progression. OS was defined as the time between the end of primary treatment and patient’s death from any cause. Univariate analysis was performed to assess factors influencing outcome in both categories. Survival analysis was performed using the Kaplan–Meier method; univariate and multivariate analyses were undertaken using log rank test and Cox’s regression model, respectively. A p-value <0.05 was considered statistically significant.
Results
From January 2008 to December 2020, 415 patients affected by localized and locally advanced PCa were treated with moderately hypofractionated helical tomotherapy in our department. The median age at diagnosis was 72.5 years (range=49-84 years) and the median prostate-specific antigen (iPSA) value was 8.6 ng/ml (range=4.1-149 ng/ml). Table I reports the patients’ baseline and tumor characteristics. The patients’ risk stratification according to the D’Amico classification was: low-risk 87 (21%), favorable intermediate-risk 67 (16%), unfavorable intermediate-risk 126 (30.4%) and high-risk 135 (32.6%). In 91.3% of cases, the tumor was limited within the prostate (T1: 44.3%, T2: 47%), whereas in the remaining patients the tumor had already infiltrated and passed the capsule (T3: 7%, T4: 1.7%). Lymph node metastases were detected in 28 patients (6.7%). One, 2,3,4 and 5 International Society of Urological Pathology Grade Group (ISUP GG) were 142 (34.3%), 76 (18.3%), 119 (28.6%), 52 (12.5%), and 26 (6.3), respectively. Neoadjuvant/concurrent and adjuvant ADT was administered in 170 patients (41%), and 332 patients (80%) did not receive pelvic irradiation.
Patient baseline and tumor characteristics.
Outcomes. The median follow-up was 82.7 months (range=12-157 months); 3, 5, and 7y OS were 95%, 90% and 84%, respectively, while 3, 5, and 7y DFS were 96%, 90%, and 87%, respectively. At the time of writing, 316 patients were alive with no evidence of disease, 39 were alive with disease, 52, 4, and 21 patients had biochemical, intraprostatic, and lymph node recurrence, respectively, while 31 developed metastatic spread. Sixty patients died, 8 of which due to cancer-related death.
The univariate analysis relating to OS and DFS is summarized in Table II. ADT duration and pelvic irradiation did not affect survival, while age, T stage, N1 stage, high-risk profile, and high ISUS GG statistically correlated with OS, and with the exception of age also with DFS. It should be noted that the increase in the duration of radiotherapy treatment showed a correlation trend with both OS and DFS though not significant (p=0.094 and p=0.093, respectively). These data were also confirmed in a multivariate analysis. A comparison between high-grade PCa and any-grade PCa treatment with reference to OS and DFS according to d’Amico class risk are shown in Figure 2. The 3-5-7y OS in the high-risk group were 92%-84%-77% compared to 3-5-7y OS of intermediate- and low-risk of 97%-89%-89% and 98%-97%-90%, respectively, whereas the 3-5-7y DFS in the high-risk group was 92%-88%-84% compared to 3-5-7y DFS of intermediate- and low-risk of 99%-85%-84% and 99%-96%-93%, respectively.
Results of univariate analysis concerning overall survival (OS) and disease-free survival (DFS).
Overall survival (A) and disease-free survival (B) probability stratified according to D’Amico risk class.
Toxicity. The radiation treatment was well tolerated by all patients, and none discontinued treatment. Acute and late GI and GU toxicities were recorded and are summarized in Table III. Most patients did not experience acute or late GI and GU toxicity ≥ G2. Moderate G1-2 toxicity was reported, the main symptoms being pollakiuria, stranguria, and nocturia. Severe acute toxicity was found in 2 patients, one patient had acute rectal bleeding and one patient (0.3%) had urethral obstruction (0.3%). Regarding late toxicity, three patients developed G4 urethral stricture requiring unblocking surgery and temporary bladder catheter placement, while nine patients developed GU G3 toxicity characterized by hemorrhagic cystitis, bleeding, and incontinence. Regarding GI toxicity, four patients developed actinic proctitis with hemorrhage, which required endoscopic cauterization of the rectal mucosa vessels.
Summary of acute and late genitourinary (GU) and gastrointestinal (GI) toxicity recorded.
The results of the univariate and multivariate analyses are summarized in Table IV. No dose parameters showed statistically significant correlation with regard to rectal and bladder toxicity for the duration of the treatment. Conversely, the overcoming of all bowel dose constraints found a correlation with the toxicity, also confirmed by the subsequent multivariate analysis.
Results of statistical analysis regarding toxicity.
Discussion
Radiotherapy plays a crucial role in the management of PCa, both with curative intent and in the salvage setting. Emerging data have placed RT as a useful therapeutic option also for oligometastatic and oligorecurrent/oligoprogressive disease (22), rare histologies (23-25), or in combination with new drugs available for hormone-sensitive and castrate-resistant PCa.
Due to the low PCa alpha/beta ratio (i.e., ∼1.5 Gy), hypofractionation may increase the tumor cell control. Several experiences using moderate hypofractionation (i.e., 2.5 Gy to 3 Gy per fractions) for PCa proving the non inferiority in terms of outcomes and stackable site effects compared to conventional fractionation (26-29).
We retrospectively analyzed the outcomes of patients affected by localized or locally advanced PCa undergoing moderately hypofractionated using helical tomotherapy. Our department was one of the first in Italy to use moderate hypofractionation IMRT with tomotherapy for PCa, so we had the opportunity to analyze a long follow-up that allowed us to have reliable results. We obtained a 5y OS and a 5-year PFS rate of 90% with grade 3 (G3) or more acute toxicities less than 1%. The late G2 and G3 gastrointestinal toxicities were 5.3% and 1%, respectively, and the G2 and G3 late urinary toxicities were 4.8% and 2.1%, respectively, with only three patients reporting a G4 toxicity. The hypofractionation efficacy is related to radiobiological aspects as a consequence of the low PCa alpha/beta ratio, as reported above. This method has several significant advantages including a shorter treatment duration with associated better patient compliance and quality of life (30). In the literature, numerous trials have shown the efficacy of hypofractionation regimens in PCa treatment with different toxicity results, probably as a consequence of different treatment techniques, IGRT and different CTV to PTV margins (8-11). One of the most important trials is the CHHiP study, which showed the non-inferiority of hypofractionation compared to conventional fractionation, with slightly higher acute gastrointestinal and similar genitourinary toxicity (10). Another important non-inferiority trial supporting hypofractionation efficacy in terms of biochemical control is the PROFIT study, which reported a better toxicity profile compared to the CHHiP trial, where IGRT was used only in 30% of patients, with a major exposure of OAR to radiation (11).
In our experience, we obtained toxicity rates slightly lower than the aforementioned trials, and this is probably related to some characteristics of helical tomotherapy, where the couch and gantry are continuously moving, describing a helical trajectory, and this delivery modality makes it possible to better conform dose distribution with optimal OAR sparing (31). Furthermore, we had the opportunity to check patient positioning daily by means of the MVCT system integrated in the tomotherapy, allowing us to correct the patient position according to the specific daily individual condition. This led us to use tight margins for CTV to PTV expansion (0.5-0.6 cm), and this could be another reason behind our low toxicity rates, confirming literature data where MVCT use has been associated with no evidence of GI/GU G3 acute toxicities in high-risk PCa patients who underwent hypofractionated HT-IMRT (32).
Our results are in line with previous experiences. Tenti et al. recently retrospectively analyzed 76 patients treated with a total dose of 60 Gy in 20 fractions or 67.5 Gy in 25 fractions for localized PCa. After a median follow-up of 42.46 months, they obtained a 4y OS and MFS of 91% and 89%, respectively, with acute and late G ≥2 GI toxicity reported in 6.5% and 2.6% of patients, respectively, and acute and late G ≥2 GU toxicity in 31.5% and 3.9% (33). The authors also reported an interesting association between acute GI toxicity and statin medication and ADT, the latter not found in our analysis, and a relation of acute GU toxicity and use of anticoagulants and antiaggregants. In 2020, Cuccia et al. published data on 170 patients affected by localized PCa who were treated with hypofractionated helical tomotherapy with a total dose of 70 Gy in 28 fractions to the prostate, 61.6 Gy to the seminal vesicles for intermediate-risk, and 50.4 Gy to pelvic lymph nodes for high-risk patients. There was no evidence of G3 acute events and only late G3 GI and GU toxicity <5% was reported (34). Moderate hypofractionation with helical tomotherapy was also tested in older patients in a phase I-II trial. The authors recently reported the long-term outcomes of their analysis where, after a median follow-up of 8.9 years, the 7y PFS was 71.6% and the 7y-biochemical-free survival, prostate cancer specific survival, and OS for all the patients were 77.6%, 91.9%, and 77.0%, respectively. Moreover, they reported a 7y G ≥2 late GU toxicities 6.2% and 6.3% in Group-1 (normal fraction action) and −2 (hypofractionation group), respectively (35).
According to the results of the statistical analysis conducted on our series, compliance with the dose limits on the bowel was fundamental in order to minimize gastrointestinal toxicity, perhaps even at the expense of target coverage. In our series, 20% of patients underwent pelvic irradiation, but at univariate analysis it was not shown to be related to OS and only a correlation trend with DFS was detected. Actually, pelvic irradiation in PCa patients is highly debated in the literature. One of the first randomized controlled trials that addressed this topic, assessing toxicity prospectively in patients receiving prostate-only and prostate plus high-dose pelvic irradiations, was the PIVOTAL trial where, however, pelvic doses were slightly higher compared to our schedule and other published experiences. The authors reported no significance differences in acute and late toxicity between the 2 randomized groups and there was no suggestion of an increasing toxicity profile over time in either group (36). Although this trial showed encouraging safety data, the impact of pelvic irradiation in addition to prostate RT should be better defined, and the RTOG 09-24 (NCT01368588), an ongoing phase 3 trial, should provide us with more information (37).
It should be emphasized that one of the main limitations of treatment with tomotherapy is the duration of the treatment, certainly longer than in modern linear accelerators (LINACs). This is a limit not only for patient compliance, but also for the potential risk of intrafraction prostate motion. In our case, the duration of the treatment was associated with a negative impact on the outcomes with a clearly visible trend, albeit without a statistically significant value. Therefore, optimal bladder and rectal preparation and the use of IGRT are mandatory to reduce the risk of partial target missing, while modern tracking techniques have been developed precisely to minimize this risk. Furthermore, the new generation helical tomotherapy machines have been designed and built to complete the treatment more quickly.
Recently, stereotactic body radiation therapy (SBRT) (38) has been evaluated for effectiveness and side effect risks. Ultra-hypofractionation (less than 5 fractions) is currently the standard of care in low and intermediate risk PCa. The effectiveness of SBRT, in terms of outcomes, secondary side effects, costs and quality of life has been confirmed by several trials (38-43).
Moreover, improvements in imaging, the introduction of automated target segmentation algorithms and treatment delivery techniques, along with the potential for further reduction in the number of treatment, add to the attractiveness of extreme hypofractionated radiotherapy and will greatly enhance its currently unmatched cost-effectiveness profile (44). Despite the promising results, to date, moderate fractionation represents the first option recommended by the guidelines and mandatory in patients with high risk of disease.
Our study has some important strengths, such as the long follow-up and sample size; to our knowledge it is one of the few studies in the literature to analyze more than 400 patients. However, there are also some limitations, including the retrospective nature of the study, which limits the statistical power of our analysis, and the lack of self-reported toxicity by patients, which would have improved the toxicity profile.
Conclusion
This study reports long-term data on patients with locally advanced PCa treated with helicoidal tomotherapy technique. Although retrospective, it is one of the studies with the largest number of patients and the longest follow-up in the literature, and it is the result of our long experience in this setting, being among the first in Italy to use IMRT. In conclusion, we showed the safety and tolerability of moderately hypofractionated helical tomotherapy for PCa treatment, reporting favorable acute and late toxicity rates and encouraging results in terms of disease control.
Footnotes
Authors’ Contributions
Conceptualization: S.C. and R.M.P. Methodology: A.B. and V.T.; Validation: C.I.; Investigation: S.B.G., F.V., M.A., and F.I.; Resources: S.C.; S.F.G., and R.M.P.; Data curation: M.P.R, F.I., S.F.G.; L.G., and S.C; Writing—original draft preparation: S.C. and E.A..; Review and editing: P.C. and C.I.; Project administration: S.C. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This study was partially supported by the Italian Ministry of Health-Ricerca Corrente. Annual program 2022/2023.
- Received January 20, 2023.
- Revision received February 8, 2023.
- Accepted February 10, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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