Early toxicity and patient reported quality-of-life in patients receiving proton therapy for localized prostate cancer: a single institutional review of prospectively recorded outcomes

Numerous treatment options exist for localized prostate cancer. External beam radiation therapy is a non-invasive option that has shown similar disease control rates compared to other approaches such as radical prostatectomy and brachytherapy [1‐5], and treatment modality choice is generally a consideration of side effect profile and shared decision making.

Dose escalation has been shown to improve cancer control in prostate cancer [6]. Delivering the high radiotherapy doses to the prostate necessary to improve outcomes can be challenging due to tolerance of surrounding organs at risk, in particular rectum and bladder. Higher radiation doses using conventional external beam techniques have been shown in several retrospective studies to increase the risk of late treatment related toxicity [7, 8]. Proton beam therapy (PBT) has emerged as an external beam radiotherapy treatment option. The unique dosimetric characteristics of PBT allow for dose escalation while reducing dose to surrounding structures, especially in the low-dose bath [7].

While numerous studies have demonstrated this reduction in low dose bath to surrounding normal tissues such as rectum and bladder, the clinical advantage remains unclear [8]. Only a few centers have reported clinical outcomes of patients treated with PBT for prostate cancer [9‐18]. Existing proton literature in prostate cancer is mostly based on passive scattering proton technology, while pencil beam scanning (PBS) has some dosimetric advantages [19]. We present our 2-year outcomes regarding toxicity and patient reported quality of life (QOL) for patients receiving PBT at our institution. To our knowledge, this is the largest reported series of patients treated mostly with PBS proton technology.

Statistical computations were performed with R version 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria). Cumulative incidence of toxicity was estimated using the Kaplan-Meier product limit estimator. Univariate Cox proportional hazards regression was used to assess associations of grade 2 or higher (GR2+) toxicity with potential clinical, treatment-related, and dosimetry variables (listed in Tables 1 and 2). The univariate analysis was considered exploratory and hypothesis-generating, so the P-values were not adjusted to account for the number of comparisons. Changes in QOL scores from before and after treatment were analyzed using generalized estimating equation-based linear regression to account for the repeated measurements per patient. Patients who did not have baseline and at least one follow up QOL responses were excluded from that analysis. Throughout the data analysis, two-sided P values < 0.05 were considered statistically significant.

This is one of few contemporary studies that evaluates outcomes and toxicity of PBT for localized prostate cancer with prospectively collected data, including patient reported outcomes. This is the largest series to our knowledge that includes patients treated mostly with PBS, which has dosimetric advantages over older passive scattering proton technology in some scenarios [19]. Although PBT offers known dosimetric advantages over photon radiation, especially in the low to intermediate-dose region (such as volume receiving up to 50 Gy), the clinical impact of this is unclear [7, 20].

In our study population, with median follow up of 1.7 years, we found that rates of GR2+ toxicity outcomes were comparable to other reported data. The low rate of GR3 GU toxicity in this study (5/192 patients) is comparable to other evaluations of PBT, with rates generally < 3% [9]. In the largest prospectively captured data of PBT outcomes for prostate cancer to date, Bryant et al. at the University of Florida found a late GR3 GU actuarial 5-year toxicity rate at of 2.9% [9]. Prior retrospective studies from this group found 1.0% GR3 GU toxicity [13], while other groups have reported a range of 0–2% [15, 17].

As shown in Table 4, reports including the present study consistently show that the risk of grade 3+ GU and GI toxicity is generally low after both PBT and IMRT [9, 13, 15, 17, 21‐24]. However, wide variations can be seen in GR2+ toxicity rates with both IMRT and PBT. For example, in two IMRT studies, GU and GI GR2+ toxicity rates reported by Vora et al. were 24.4% and 10.9% respectively, while Spratt et al. reported rates of 8.5% and 2.0% [22, 23]. Multiple factors illustrated in Table 4 may explain this variability and also make true comparison across standalone studies difficult. First, using RTOG versus CTCAE scoring criteria can significantly impact physician-reported toxicity rates, since RTOG criteria depend on subjective assessments of what qualifies as mild (grade 1) versus moderate (grade 2) toxicity, whereas CTCAE criteria require medical or procedural intervention to qualify as grade 2. Second, many studies report observed toxicity rates (numbers of patients experiencing toxicity) with varying lengths of median follow-up [22‐24]. This can be addressed by comparing actuarial toxicity rates at specific time intervals, such as 5-years, but these are only inconsistently reported, and at varying time-points themselves [9, 13, 15, 17, 21]. Third, the dose to which patients are treated often varies from study to study. Fourth and finally, treatment planning and patient setup vary from institution to institution.

There is a clear need for studies that can compare PBT and IMRT in a standardized fashion. Although level one evidence comparing IMRT and PBT in patients with prostate cancer is currently being collected in the PARTIQoL and COMPPARE trials (NCT01617161, NCT03561220), results will not be available for years. Thus far, there is conflicting evidence regarding comparative toxicities. In a case-matched comparison of intensity-modulated radiotherapy (IMRT) or PBT based treatment matched for age, GI and GU co-morbidity, and risk group, Fang et al. report that at 2 years there were no differences in GR2 or higher GU or GI toxicities [24]. A Medicare-based comparative study found lower GU toxicity for PBT at 6 months, but no difference at 12 months [18]. Gray et al. compared three dimensional conformal radiotherapy (3D CRT), IMRT, and PBT and found worse acute patient-reported QOL for urinary symptoms for patients treated with 3D CRT but there were no differences by 2 years [12]. A comparison of patient-reported QOL after PBT with patient-reported QOL from the Prostate Cancer Outcomes and Satisfaction (PROSTQA) treatment assessment study of men treated with high-dose photon radiation, showed no differences in any toxicity domain at 2 years [25]. However, a more recent study using private commercial insurance claims reported that PBT was associated with significant reductions in urinary toxicity but increased bowel toxicity three years after treatment [26].

The dosimetric improvement with PBT over IMRT lies in reductions to low and moderate-dose range exposures of normal tissue and not high dose range (70–80 Gy), therefore it is important to qualify the differences that one might expect from PBT in comparison to IMRT [20]. Some of these benefits may be recognized as a decrease in long term toxicity and changes, including the risk of secondary malignancy, and will require much longer follow up with large patient numbers to fully realize [25]. We found no association of toxicity incidence with PBS versus UNS technique in our patient cohort. This is consistent with a previous study that also showed no associations in a cohort treated with mostly passive scatter, and some pencil beam technique [15]. Thus, PBS treatment technique may not clinically affect toxicity rates in prostate cancer treatment, despite potential dosimetric advantages.

Previous retrospective studies have reported excellent biochemical outcomes with PBT [9, 17]. At this time, we did not have enough patient events or follow up time to comment on control rates in this group. We plan to report updated outcomes in the future as patients accrue to the registry and follow up data matures.

Limitations of this study include the patient selection bias for those treated at a single institution. There could also be a selection bias for those patients who sought access to PBT. The follow up period is short, and radiation toxicity is known to develop years after radiotherapy [27]. However, we believe the present study is an important addition to the literature, to assess early outcomes with modern treatment techniques including daily image guidance with intraprostatic fiducials and PBS approach. Strengths include the rigor of prospectively collected toxicity and outcome data, and data that is both patient and physician reported. Future analysis will include continued patient accrual with longer median follow up. The larger patient numbers will allow us to better assess late treatment toxicities and PSA trends amongst patients treated with PBT for prostate cancer at our institution.

We report toxicity rates in patients treated with contemporary PBT techniques (mostly PBS) at our institution with median 1.7 years of follow up. Grade 3+ toxicities were rare. Patient reported quality-of-life are excellent, with no change in urinary function post-radiation, and small declines in erectile function and bowel QOL by 1-year post-treatment. Larger patient numbers and longer follow up are anticipated to add robustness to our data.