Simultaneous integrated boost (SIB) to dominant intra-prostatic lesions during extreme hypofractionation for prostate cancer: the impact of rectal spacers

Hypo-fractionation is an attractive option in the management of prostate cancer not only because it is cost-effective and convenient for patients, but also due to the potential therapeutic benefits. There is mounting evidence suggesting that prostate cancers are highly sensitive to dose per fraction rather than the total dose [1‐3]. Clinical trials of moderate and extreme hypo-fractionation have demonstrated the feasibility and non-inferiority of hypo- vs conventional-fractionation [4‐6].

Local recurrences post-radiotherapy mostly originate from highly radio-resistant sub-volumes within the primary treated volume (dominant intra-prostatic lesions (DILs)) [7‐9]. Boosting DILs to significantly higher doses has the potential to maximize tumour control [10]; however, this is constrained by the increased risk of toxicity. The proximity of the prostate to the rectum and the bladder makes DIL boosting more challenging, as both are radiosensitive organs that are susceptible to movement and/or deformations.

Phase 3 trials examining integrated boosts up to 95 Gy in standard fractionation (77 Gy in 35 fractions to the entire prostate) have shown acceptable toxicity [11] and further phase 3 trials are currently underway in moderately hypo-fractionated treatments [12]. A number of phase 1 and 2 trials of integrated boosts during stereotactic ablative radiotherapy (SABR) have demonstrated acceptable toxicity [13‐17].

In recent years, anatomy modifiers of different types have been introduced to spare the rectum by separating the anterior rectal wall from the prostate. Most widely used techniques include injected hydrogel spacers, hyaluronic acid or saline-filled balloons [18‐21].

As demonstrated in many studies, rectal spacers are well tolerated, cost effective and they reduce rectal dose, leading to reduced RT related acute and late toxicity [18, 21, 22]. However, there is little information available on the combination of rectal spacer devices with SABR DIL boosts.

In a previous study [21], we presented our first clinical experience of treating high-risk prostate cancer patients with SABR-VMAT in combination with rectal spacers. Insertion of a spacer resulted in a clinically and statistically significant reduction in rectal doses for all patients investigated [21].

The aim of this study was to assess the technical feasibility of delivering 5-fraction SABR with a SIB for high-risk prostate cancer patients. The impact of using rectal spacers was evaluated by comparing plans generated using planning CT scans of patients taken before and after spacer insertion. Our hypothesis is that when rectal spacers are used, it is possible to boost all intra-prostatic lesions to 50 Gy without increasing the risk of toxicity. A comparison was made between pre-spacer and post-spacer insertion plans in terms of dose coverage and the dose received by organs at risk (OARs). The effect of the location of the DIL region on the achievable boost dose level was also evaluated.

The median DIL CTVpb volume was 4.4 cm³ (range 1.9–7.6 cm³) and the median PTVpsv volume was 111.1cm³ (range: 73.9–133.0 cm³).

Figure 1 gives an overview of staging information, the location of the DIL volumes within the prostate, and the achieved SIB dose levels for all 12 patients in this study.

In 25% of the patients (3/12), higher DIL boost doses were possible in post-spacer compared to pre-spacer plans. The median achieved dose pre-spacer was 45 Gy and 50 Gy in post-spacer insertion plans.

Using pre-spacer scans, clinically acceptable plans were achieved with a SIB of 50 Gy for 5 patients, 47.5 Gy for one patient and 45 Gy for 5 patients. For patient 1, even when planning with a 45 Gy SIB it was not possible to meet rectal dose constrains (V_29Gy = 21.8%, V_36Gy = 2.6 cc). This was due to the 36.25 Gy dose coverage requirement to the PTV rather than the boost dose, which was not an issue for the post-spacer plans.

For the post-spacer scans, it was possible to generate clinically acceptable plans with 50 Gy SIB to the DILs for 6 patients, 47.5 Gy for 3 patients and SIB of 45 Gy in 3 patients. Therefore, the achievable SIB dose increased from 45 to 47.5 Gy in 2 patients and from 45 to 50 Gy in 1 patient (represented by * in Fig. 1).

In all anterior DIL plans, both with and without spacers, the dose-limiting organ was the urethra_PRV. For posterior DIL plans, without a spacer, the dose limiting-organ was the rectum, while with spacers-in-situ, all rectal the dose-volume constraints were always met (i.e. no minor or major violations observed). In this study, the DIL dose affected the rectum in only one patient (patient 12 with a posterior DIL) and using a spacer allowed boosting of the dose to 50 Gy compared to 45 Gy pre-spacer.

To assess the effect of spacer on each plan, all patients were finally planned using matching dose levels (Table 1). For example, for patient 1 the boost dose was lowered to 45 Gy in the post-spacer plan to facilitate the comparison with the pre-spacer plan (Fig. 2). Figure 2 shows example transverse slices at the level of the DIL volume (CTVpb) for representative patients (pre- and post-spacer insertion). A similar figure for all the patients in the study is presented in Additional file 1: Figure SF1. All isodose lines shown in Fig. 2 were generated for matched CTVpb dose prescription (pre- and post-spacer). The achieved boost dose level is indicated by the coloured geometrical shapes shown at the bottom left of each scan as described in the figure legend.

With a spacer in-situ, the rectal V_36Gy was always below the optimal constraint of 1 cc (Table 1). As expected, rectal dose constraints were harder to meet for the same patients in pre-spacer plans. This was particularly the case for patients with noticeable overlap of the PTVpsv (prescribed to 36.25 Gy) and the rectum (Fig. 2, SF1). The priority of the treatment plan was to achieve target coverage while meeting all OARs dose constraints (Table 1). Therefore, in pre-spacer plans, only minor variations in OAR constraints were allowed, resulting in more reduction in targets coverage as allowed by planning protocols.

Table 1, Figs. 3 and 4 show comparisons of target coverage and OARs dose when patients were planned with and without rectal spacers. The CTVpb and Tpsv coverage were slightly, but significantly better in post-spacer plans compared to pre-spacer plans. No significant differences were observed in TCP between pre- and post- spacer plans, TCP_Boost = 98.3% versus 98.0%, TCP_Tpsv-Boost = 97.2% versus 97.3%, respectively, Additional file 1: S1 and Additional file 1: Figure SF2.

All rectal dose metrics and the associated NTCP (grade 2 + rectal bleeding) values were significantly lower in post-spacer plans compared to plans generated on pre-spacer scans (NTCP = 0.9% [0–2.7%] vs 4% [1.8–11.5%] (p = 0.00049), respectively). The dose received by the bowel, sigmoid, femoral heads, and penile bulb were minimal in all plans pre- and post-spacer insertion.

In post-spacer plans, the dose limiting structures were the urethras (V_45Gy < 0.01 cc) and the urethra_PRVs (V_45Gy < 0.1 cc). A quantitative analysis of CTVpb overlap with urethra_PRV and the corresponding achieved DIL dose level are presented in Additional file 1: Table ST1.

Two observations from the data presented in Additional file 1: Table ST1 warranted further investigation. Firstly, for patient 7 with frontal DIL (Additional file 1: Figure SF1), there was more overlap between CTVpb and urethra in post-spacer scans. Reviewing the CT scans, (Additional file 1: Figure SF3) it appears that the spacer is causing an anterior translation of the urethra bringing it closer to the CTVpb. Secondly, for patient 12 with the posterior-lateral DIL, there was a relatively large overlap in pre-spacer plan but not post-spacer. Inserting the spacer appears to have pushed the urethra away from the CTVpb. Of particular note for this patient, a SIB dose of 50 Gy was achieved post-spacer but only when lowering the dose to 45 Gy in pre-spacer plans were all dose constraints met. To quantify these effects, we measured the dimensions of the prostate at the centre of the PTVpsv on pre- and post-spacer scans for these patients (Additional file 1: Table ST2). The insertion of the spacer reduced the anterior–posterior dimension from 3.1 to 2.6 cm in patient 7 and 3.8 to 3.3 cm in-patient 12. An increase of the lateral dimensions of the prostate from 4.2 to 4.4 cm (patient 7) and 3.8 to 4.0 cm (patient 12) was observed.

In this planning study, we assessed the feasibility of delivering high dose SIB to DILs in the context of prostate SABR before and after rectal spacer insertion. The aim was to deliver the boost dose while keeping OARs’ doses below the specified SABR dose limits in order to maximize the therapeutic ratio of the treatment without adversely affecting patients’ quality of life.

For all the patients in this study, spacer insertion significantly reduced rectum dose metrics and NTCP values compared with plans generated without rectal spacers as shown in Table 1, Fig. 1, and Additional file 1: Figures SF1 and SF2. Using a rectal spacer also enabled an increase in DIL boost dose in 25% of the patients. In pre-spacer plans, the coverage of the PTV and the Tpsv were also compromised in some cases to meet rectal dose constraints. However, this did not translate to significant differences in the TCP values for either the boost or the Tpsv excluding boost CTV in post- and pre-spacer plans.

In 50% of the patients in this study, the dose limiting organs were the urethra and the urethra_PRV. This was highly influenced by the location of the DIL and its proximity to the urethra [29]. The median boost dose was 45 Gy for anterior tumours, and 50 Gy in posterior tumours. An analysis of the uncropped CTVpb (GTVpb + 3 mm) overlap with urethra_PRV demonstrated that this measure could be indicative of the achievable boost dose level (Additional file 1: Table ST1). It can be seen from this table that an overlap of ≥ 0.1 cc was indicative of the need for a lower boost dose. Even when extending the CTVpb by a 1 mm margins, there was no overlap with the rectum or the bladder in 92% of the patients.

This study shows that the achieved boost dose level is strongly influenced by the location of the boost volume, with anterior DIL volumes being more challenging to boost to doses greater than 45 Gy. Contrary to our hypothesis, even when spacers were used, only in 50% of the study cohort was it possible to generate clinically acceptable plans with a 50 Gy SIB to DIL. Interestingly, for patients with posteriorly located boosts, target and OARs doses were easier to achieve even without a spacer. This could be a result of limiting the boost volume to the Tpsv and consequently ensuring there is no overlap between the CTVpb and the rectum, regardless of the presence of a rectal spacer.

There does not appear to be a consensus on appropriate margins for DIL boost volumes; margins in other SABR studies have ranged from 0 to 5 mm [15, 30]. Urethral constraints and PRV margins currently employed are also variable and the challenges in boosting anterior areas would be eased with less strict urethral constraints. Other clinical trials have used higher maximum doses to the urethra [30], smaller or no urethral PRVs [13, 15] or excluded DILs within 3 mm of the urethra [31]. However, even with the tight constraints used in this study, we were able to achieve at least a planned dose of 45 Gy in all patients (except on one patient on pre-spacer scan). This remains a significant dose escalation: 45 Gy, 47.5 Gy and 50 Gy are the equivalent of 135.0 Gy, 149.3 Gy and 164.3 Gy in 2 Gy fractions respectively when converted using the linear quadratic equation and an (α/β = 1.5).

Other studies have commented on the boost dose limitations imposed by rectal constraints [13, 15]. This study did not find this to the same extent, but 6 of the 12 cases analysed had DILs positioned in the anterior prostate where the benefit of a rectal spacer is likely to be minimal. Despite this, plans following spacer insertion had improved PTVpsv coverage and lower rectal NTCP.

In this study, it was observed that spacer insertion seemed to deform the prostate (i.e. changes in the anterior–posterior and the left–right dimensions). These changes are in-line with our observations of urethral shifts. These observations warrant future investigations of the dosimetric impact of prostate deformations due to rectal spacer insertion in relation to the location of DILs. Furthermore, when outlining the GTVpb, such changes are a reminder that the diagnostic MRI should only be used as a guide to DIL size and position: the most accurate outline will adapt the MRI volume to take into account any change in the overall shape of the prostate (e.g. due to hormone therapy or spacer insertion).

Rectal spacer positioning was symmetrical across the midline for all but one patient, Additional file 1: Figure SF4 (patient 8). For this patient, the spacer was predominantly on the same side as the DIL boost volume. However, if the boost volume was on the contralateral side to a posterior DIL, planning would have been much more complicated; suggesting the accuracy of spacer placement plays a key role, particularly for boosts to posterior DILs.

The authors acknowledge that this study has some limitations. Firstly, it can be argued that generous margins were applied for the urethra with strict dose constraints. In this study, fiducial markers-based daily-online-image-guidance with CBCT (pre- each arc delivery and post-treatment) will be employed, however, the urethra is not visible on CT scans. Another option would be to use a urethral catheter with contrast medium although this is an invasive approach. Therefore, the use of PRV was necessary to account for inter- and intra-fraction movements compared to urethral position on planning CT scan. These margins could be revised with the introduction of MR-based-image-guidance and MRI-linacs [32, 33]. To realise the benefit of SABR further, other IGRT strategies that were found effective in monitoring and reducing intra-fraction motion (e.g. gating and real time tracking) may also be adopted to improve the accuracy of the dose delivered to the target and organs at risk [34, 35]. A second limitation is that, despite the variable locations of the DILs volumes investigated in this study, the small number of patients makes it difficult to generalise our conclusions. Yet, this study demonstrates the feasibility delivering 45–50 Gy SIB to DIL without increasing the risk of toxicity in some of the patients. The results of this study will be validated prospectively in future patients. Finally, while comparing radiotherapy plans before and after spacer insertion allowed each patient to be their own matched control, it was not possible to compare clinical outcomes from treatment with and without rectal spacers as all treatments were delivered with the rectal spacer in-situ.

This study shows that boosting dominant intra-prostatic lesions up to 50 Gy without increasing the risk of normal tissue complications is technically feasible for selected patients. The dose-limiting organ in these cases is the urethra. Rectal spacers are favourable for all patients with some patients benefiting more than others. This depends not only on the anatomy of the patients but also on the way rectal spacers are positioned.