Introduction

For patients with localized prostate cancer, external beam radiotherapy (EBRT) is a consolidated treatment option in the curative setting. The constant evolution in technology has led to dose-escalated schedules with a remarkable improvement in terms of biochemical control rates [1, 2]. In the last years, the introduction of image-guided intensity-modulated radiotherapy (IG-IMRT) facilitated the adoption of moderately and extremely hypofractionated schedules. The radiobiological rationale for the use of > 2 Gy per fraction lies on the low α/β ratio of prostate cancer (about 1.5 Gy) compared to the nearby healthy structures [3] (i.e., 3 Gy for rectum and 5–10 Gy for bladder); besides the favorable therapeutic ratio of a tumor more sensitive to higher doses per fraction, hypofractionated schedules may be more attractive in terms of patients’ compliance and cost-effectiveness for the shortening of the overall treatment time [4]. Currently, mature data from several phase III randomized trials confirmed that moderately hypofractionated schedules (2.2–4.0 Gy per fraction) reported similar tumor control and toxicity rates compared to conventional fractionation [5], and recent AUA/ASTRO guidelines recommend their routine use [6].

Herein, we report the results of our retrospective study evaluating 170 patients with localized prostate cancer treated with moderate hypofractionation in simultaneous integrated boost (SIB) using helical tomotherapy (HT, Accuray, Inc., Sunnyvale, CA, USA).

Materials and methods

This is a retrospective analysis of 170 patients with biopsy-proven diagnosis of prostate adenocarcinoma who were treated at our center with moderately hypofractionated radiotherapy.

Primary endpoints of the present study were acute and late genitourinary and gastrointestinal toxicities. Secondary endpoints were quality of life and biochemical relapse-free survival and overall survival. Patients’ characteristics are summarized in Table 1.

Table 1 Patients’ characteristics
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Pre-treatment evaluation consisted of physical examination including digital rectal examination, blood tests including PSA levels, bone scan and abdominal CT or MRI, if needed for staging. Inclusion criteria were: histologically confirmed diagnosis of prostate cancer, Karnofsky performance status ≥ 60, no history of prior pelvic radiotherapy and absence of active chronic inflammatory bowel disease. Patients with a follow-up less than 12 months were excluded from the current analysis.

According to D’Amico classification, patients were stratified in: low risk (T1c or T2a and Gleason score ≤ 6 and PSA < 10 ng/ml), intermediate risk (cT2b and/or Gleason score = 7 and/or PSA = 10–20 ng/ml) and high risk (T2c–T3 and/or Gleason score ≥ 8 and/or PSA > 20 ng/ml). Androgen deprivation therapy was prescribed according to NCCN guidelines for all intermediate- and high-risk patients, respectively, for 6 months and 2–3 years.

For radiotherapy treatment planning, a 2.5-mm-slice-thick CT scan, from the fourth lumbar vertebra to 2 cm below the femoral neck, was acquired with the patient in supine position with flexed legs and knee–ankle immobilization devices. To obtain a reproducible rectal emptying and bladder filling, patients were required to perform a fleet enema 2 hours prior to the examination and to drink 500 ml of water 30 min before the scan. The same protocol was applied during treatment for each fraction.

Regarding target volume delineation, for low-risk patients only a CTV1 consisting of the prostate gland was contoured. Then, PTV1 was generated by adding a 0.8-cm margin in all directions except posteriorly where a 0.6-cm margin was applied. For intermediate-risk cases, a CTV2 consisting of seminal vesicles was delineated; the same margin of PTV1 was applied for generating PTV2. Only for high-risk patients, pelvic lymph nodes (CTV3) were contoured and subsequently a 0.5-cm margin for PTV3 was added.

We adopted a moderately hypofractionated regimen in order to deliver, using a SIB technique, a total dose of 70, 61.6 and 50.4 Gy to prostate, seminal vesicles and pelvic lymph nodes, respectively. For all the target volumes, the prescription dose was 95% of PTV covered by at least 95% of the prescribed dose.

Rectum, bladder, femoral heads and intestinal loops were delineated as organs at risk (OARs), and the following constraints were applied: V65 < 15% for rectum and V55 < 50% and V60 < 30%; V56 < 35%, V60 < 25% for bladder; Dmax < 50 Gy and V46.2 < 5% for femoral heads; for intestinal loops, the prescription was to reduce the dose as low as reasonably achievable. Treatment planning was performed using the tomotherapy planning system. Radiotherapy was delivered with helical tomotherapy; the image-guided system was based on the daily execution of a MegaVoltage CT scan (MVCT) prior to each fraction in order to verify setup accuracy and rectal and bladder preparation. During the treatment course, a weekly evaluation of the patients was carried out; after RT, follow-up visits were scheduled every three months for the first year and then at biannual intervals.

Acute and late toxicities were prospectively collected and assessed using Common Terminology Criteria for Adverse Events (CTCAE) V4.0, defining acute events as any RT-related symptom occurring within 90 days from the start of treatment. For late adverse events, we considered all the side effects occurring after 90 days. Health-related quality of life (HRQOL) in particular for bladder and gastrointestinal function was assessed with Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire at baseline, at 3-month follow-up and then at annual intervals.

Concerning clinical outcomes, biochemical failure was defined following Phoenix criteria as the identification of the nadir value of PSA + 2 ng/ml after radiotherapy with/without androgen deprivation therapy.

Medians and ranges were calculated for continuous variables. The potential association between toxicity rates and clinical or dosimetric parameters was investigated with a Chi-squared test assuming p ≤ 0.05 as statistically significant. The following clinical parameters were evaluated: age ≥ 75 years, comorbidities (hypertension, diabetes, inflammatory bowel disease, previous abdominal surgery, TURP) and pelvic RT administration; for dosimetric parameters, we investigated: rectal Dmax, V56 Gy, V60 Gy and V65 Gy; bladder Dmax, V55 Gy, V60 Gy, V70 Gy and for PTVs mean, maximum and minimum dose. Using the Wilcoxon signed rank test, we compared the baseline EPIC-26 with the follow-up scores. Time-to-event data were analyzed with the Kaplan–Meier method and log-rank test. All statistical analyses were performed using MedCalc statistical software package v.18.11.3 (Mariakerke, Belgium).

Results

From December 2012 to May 2018, 170 patients with median age 75 years (range 56–88) were treated with definitive hypofractionated helical tomotherapy for prostate cancer. Thirty-four percent were low risk (LR), 30% intermediate risk (IR) and 36% high risk (HR). The median iPSA was 8.79 ng/ml (1.3–170). All patients completed the treatment without any interruption: Acute toxicity was as follows: G1 and G2 in 27.6% and 19.4% of cases for GI; 53% and 24% for GU. No G ≥ 3 event was observed (Table 2 for acute and late toxicity in details).

Table 2 Specific (a) acute and (b) late symptoms according to CTCAE V4.0
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With a median follow-up of 36 months (range 12–78), 3- and 4-year G ≥ 2 late GI and GU adverse events rates were, respectively, 12.4% and 14.3% and 11.8% and 17.1%. Our late G ≥ 3 GI and GU toxicity rates were, respectively, 3% and 2.4% at 3 years and 3% and 4.8% at 4 years (Figs. 1, 2). The highest peak of G3 late adverse events was at 2 years with four GI and three GU cases of G3 toxicity. No G4 event was observed. No statistical correlation between late G3 incidence and clinical or dosimetric parameters was found. Particularly, the addiction of whole pelvis irradiation did not have an impact on GI or GU G ≥ 3 rates (p = 0.30 and p = 0.87). Concerning HRQOL, the EPIC-26 scores reported no statistical differences in terms of urinary or bowel dysfunction between baseline and 4-year data (p = 0.93 and p = 0.45) with a progressive trend to resolution (Fig. 3).

Fig. 1
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Late GI and GU G ≥ 2 toxicity-free survival

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Fig. 2
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Late GI and GU G ≥ 3 toxicity-free survival

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Fig. 3
figure 3

EPIC 26 scores

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At the time of final assessment, in 12 patients (two low risk, five intermediate risk and five high risk, respectively) a biochemical relapse occurred, resulting in 3- and 4-year biochemical relapse-free survival (bRFS) rates of 88.5% and 87.2%, for the entire population. More specifically, for low-risk patients 3- and 4-year bRFS rates were 96.4% and 93.2%, respectively, for intermediate-risk patients were both 88.1% and for high-risk patients were both 81.8% (Fig. 4).

Fig. 4
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Biochemical control for the entire population and according to risk groups

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The log-rank test revealed no difference between the risk groups in terms of biochemical control (p = 0.16). Among these 12 cases, five subjects (one low risk, two intermediate risk and two high risk) developed distant metastases, consisting of three nodal recurrences, successfully treated with stereotactic body radiotherapy, and two bone metastases who underwent palliative treatment. Concerning overall survival (OS), 3- and 4-year OS rates were 88.3% and 82.7%, with only two patients who died by disease progression, respectively, after 16 and 24 months from the end of treatment.

Discussion

This mono-institutional analysis reports moderate hypofractionation with SIB technique by means of helical tomotherapy as a safe and effective treatment option for localized prostate cancer. Our radiotherapy schedule was adopted from the favorable results of the largest series of moderately hypofractionated radiotherapy [7, 8], and we reported excellent rates of acute and late toxicity, similar to other experiences reported in the literature [9,10,11,12,13,14,15,16,17,18] (Table 3); also in terms of biochemical control, our rates are in agreement with previous studies. These data support the routine use of moderate hypofractionation as a more attractive alternative to conventional schedule, as also recommended by recent AUA/ASTRO guidelines. In a previous report, we analyzed acute toxicity in a cohort of 42 patients with no evidence of G3 acute event [19]. This is also confirmed in the current study with mild acute toxicity rates, and no cases of acute G3. Concerning late adverse events, no G4 toxicity occurred, with 3- and 4-year G3 GI and GU toxicity rates of 3% and 2.4%, and 3% and 4.8%, respectively. No clinical or dosimetric parameters were found to be predictive of late toxicity; more specifically, in our series whole pelvis irradiation did not have an impact on GI adverse events incidence. The potential impact of lymph nodes irradiation on GI toxicity was also investigated by Longobardi et al. [20], observing that larger volume of nodal CTV and increased age were predictive factors of acute bowel toxicity.

Table 3 Moderate hypofractionation series
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This finding is also reported in a recent study by Jorgo et al. [21] concerning a cohort of 162 patients with intermediate- and high-risk prostate cancer treated with the same schedule of the present series. Notably, unlike the abovementioned study, we did not exclude high-risk patients older than 70 years from the pelvic lymph nodes irradiation, nevertheless reporting late GI toxicity rates comparable to patients not treated with whole pelvis RT (p = 0.30). Among the randomized trials of comparison between moderate hypofractionation and conventional fractionation, only the Fox Chase experience included whole pelvis irradiation, reporting similar GI rates with a negligible impact on quality of life [22].

The controversial role of pelvic lymph nodes irradiation in high-risk disease is also confirmed by three randomized trials [23,24,25] that reported no advantages in terms of biochemical control or OS, and one reporting on the contrary a gain in biochemical relapse-free survival by adding pelvic lymph nodes radiotherapy [26]. Recently, preliminary data from the PIVOTAL trial were published: This trial randomizes patients to prostate only radiotherapy versus prostate + pelvic lymph nodes RT with the aim to address the real impact of whole pelvis irradiation on clinical outcomes for locally advanced disease. Currently, keeping in mind that this trial adopts a higher pelvic dose compared to previously published studies (i.e., 60 Gy in 37 fractions, equivalent dose 2 Gy = 55.4 Gy), only data about acute and late toxicity are available and similar rates between the two cohorts are reported [27].

Concerning genitourinary toxicity, in our cohort no acute G3 adverse events were observed, and G2 rates were comparable to other series; only four cases of G3 late events were observed, with the highest peak after 24 months from the end of RT. We could not identify any predictive factor for acute or late GU toxicity. Despite the lack of a cohort of comparison with conventional fractionation, these data report a mild profile of toxicity, in agreement with a meta-analysis conducted by Carvalho et al. [28], where similar acute and late GU toxicity rates are reported for both conventional and hypofractionated schedules, especially for treatment regimens below 3 Gy per fraction.

Jereczek-Fossa et al. [29] recently published data about 179 patients treated with hypo-RT (70.2 Gy/2.6 Gy per fraction) reporting a small but not statistically significant increase in late GU adverse events in comparison with a cohort of 170 patients treated with conventional non-image-guided radiotherapy. The authors underline the role of IGRT for the safe delivery of moderate hypofractionation, also providing a cost-effectiveness advantage in terms of overall treatment time, and a favorable impact on biochemical control. Nowadays, there is weak evidence that hypofractionation may be superior to conventional treatment in terms of biochemical relapse-free survival, but non-inferiority trials [10,11,12] have demonstrated that moderately hypofractionated schedules are not worse than 2 Gy per fraction regimens, providing an iso-effective and iso-tolerable therapeutic option.

This study has several limitations: The retrospective nature limits the statistical power of the present series, despite toxicity being prospectively collected; in a large part of our population, especially for intermediate-risk patients, ADT has been administered following previous guidelines recommendations that now have changed, so this factor might have an impact on our results in terms of biochemical control; furthermore, we have already mentioned the lack of a cohort of comparison with a conventionally fractionated schedule, and our follow-up time is relatively short, although being comparable to other literature series.

Conclusions

The use of moderate hypofractionation with SIB by means of helical tomotherapy reports mild acute and late toxicity. Our favorable toxicity pattern reflects in a negligible impact in terms of quality of life. Also, we reported promising results in terms of biochemical control providing a shortening of the overall treatment time that may also favorably impact in terms of patients’ compliance and cost-effectiveness.