Feasibility of Same-Day Prostate Fiducial Markers,Perirectal Hydrogel Spacer Placement,and Computed Tomography and Magnetic Resonance Imaging Simulation for External Beam Radiation Therapy for Low-Risk and Intermediate-Risk Prostate Cancer

PurposeThe use of prostate fiducial markers and perirectal hydrogel spacers can reduce the acute and late toxic effects associated with prostate radiation therapy. These procedures are usually performed days to weeks before simulation during a separate clinic visit to ensure resolution of procedure-related inflammation. The purpose of this study was to assess whether same-day intraprostatic fiducial marker placement, perirectal hydrogel injection, and computed tomography (CT) and magnetic resonance imaging (MRI) simulation were feasible without adversely affecting hydrogel volume, perirectal spacing, or rectal dose. If feasible, performing these procedures on the same day as simulation would expedite the start of radiation therapy, improve patient convenience, and reduce costs.Methods and MaterialsTwenty-one patients with clinically localized prostate cancer who were enrolled on a prospective clinical trial (NCT01617161) underwent same-day marker placement, hydrogel injection, and CT and MRI simulation, then underwent T2 MRI verification scans 3 to 4 weeks later. The MRI scans were fused to the CT planning scans by clinical target volumes (CTVs) to generate comparison treatment plans (70 Gy in 28 fractions). Hydrogel volume and symmetry, perirectal spacing, CTV dose, and organ-at-risk dose were evaluated.ResultsVerification scans occurred a mean of 24.9 ± 4.6 days after simulation and 9.3 ± 4.9 days after treatment start. Prostate volume did not change between scans (median, 67.3 ± 22.1 cm³ vs 64.1 ± 21.8 cm³; P = .64). The median hydrogel change between simulation and verification was ⁻1.8% ± 4.5% (P = .27). No significant differences in perirectal spacing (midgland: 1.33 ± 0.45 cm vs 1.3 ± 0.7 cm; 1 cm superior: 1.25 ± 0.95 cm vs 1.43 ± 0.91 cm; 1 cm inferior: 1.16 ± 0.28 cm vs 1.41 ± 0.49 cm) were identified. No significant differences in rectal V66 (median 2.3 ± 2.18% vs 2.3 ± 2.28%; P = .99), V35 (median 14.79 ± 7.61 vs 14.67 ± 8.4; P = .73), or D1cc (65.7 ± 9.2 Gy vs 68.2 ± 9.0 Gy; P = .80) were found. All plans met CTV and organ-at-risk constraints.ConclusionSame-day placement of intraprostatic fiducial markers, perirectal hydrogel, and simulation scans was feasible and did not significantly affect hydrogel volume, position, CTV coverage, or rectal dose.     

Addition of Iodinated Contrast to Rectal Hydrogel Spacer to Facilitate MRI-Independent Target Delineation and Treatment Planning for Prostate Cancer

PurposeHydrogel spacers reduce rectal dose toxicity during prostate cancer radiation therapy. Current products require magnetic resonance imaging (MRI) for visualization during treatment planning, but MRI incompatibility and cost have prompted alternatives using computed tomography (CT). This case series evaluates the addition of iodinated contrast to hydrogel as such an alternative.Methods and materialsThree patients underwent rectal hydrogel spacer placement with iodinated contrast modification. CT was performed within 1 hour of injection and again 1 week later. MRI was obtained at the time of the second CT. Hydrogel delineation was compared between CT and MRI and between paired CT scans.ResultsSpacer enhancement was visible on CT immediately after hydrogel placement (mean Hounsfield units, 122; range, 52-193) but not at the second CT 1 week later (mean Hounsfield units, 8; range, −8 to 29). Delineated spacer volume did not significantly differ between immediate postprocedure CT and MRI ≥1 week later in 2 patients (patient 1: 16.6 vs 15.5 cm³; patient 2: 12.6 vs 14.7 cm³; paired t-test, P = .81).ConclusionsCT visualization of rectal hydrogel admixed with contrast is feasible and allows delineation of interface with rectum/prostate.     

Evaluation of a Novel Absorbable Radiopaque Hydrogel in Patients Undergoing Image Guided Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma

PurposeWe assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC).Methods and MaterialsHydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥2 mm change in the median and mean interbleb surface distance with a P value <.05 required to reject the null hypothesis and conclude equivalence. For patients undergoing pancreaticoduodenectomy, hydrogel sites were histologically examined for location and local inflammatory reactions.ResultsHydrogel placement was successful in 6 of the 6 evaluable patients. The average changes in median and mean interbleb distances were −0.43 mm and −0.35 mm, respectively, with P < .05. The average change in volume from sim-CT to post-SBRT CT was −1.0%, with P < .05. One patient experienced grade 3 nausea after fiducial/hydrogel placement, with no other adverse events to date.ConclusionsThese data demonstrate feasibility and safety of injecting a hydrogel marker in the pancreaticoduodenal groove in patients with BR/LAPC and set the stage for a follow-up clinical trial to place hydrogel as a spacer between the pancreatic tumor and dose-limiting, radiosensitive duodenum.     

Impact dosimétrique de la pose d’un espaceur rectal dans le traitement de cancer de la prostate localisé par irradiation en conditions stéréotaxiques

PurposeStereotactic body radiotherapy (SBRT) of prostate cancer is associated with rectal toxicities, which can be reduced by using a hydrogel spacer. The object of this retrospective study was to show the feasibility of spacer placement under local anesthesia and utility of hydrogel spacer to reduce the dose to the rectal wall.Material and methodsWe collected data from all patients with localised prostate cancer treated with SBRT (40 Gy in 5 fractions) between 2018 and 2020. A hydrogel spacer (SpaceOAR®) was placed depending on the availability of the product. We collected dosimetric data for target volumes and organs at risk. We calculated mean values, which were compared using non-parametric tests.ResultsAmong 35 patients, mean age was 75 years. Seventeen had a spacer placed, with a mean space created of 10 mm. No complication was reported during the intervention. High doses to the rectal wall were significantly lower in spacer group (V38: 0.39 cm³ vs. 0.72 cm³; P = 0.02). PTV were better covered in spacer group (P = 0.07). Doses to the bladder wall were similar in both groups.ConclusionSpacer procedure under local anesthesia was well tolerated. Hydrogel spacer allowed to reduce doses to the rectum while improving PTV coverage.     

Multigene targeting of signal transduction pathways for the treatment of breast and prostate tumors

Previous studies have demonstrated that monospecific antisense oligonucleotides (oligos) directed against mRNA encoding proteins associated with tumor growth, death, and survival are efficacious against breast and prostate tumors. Targeted proteins, associated with different signal transduction pathways, have included transforming growth factor-alpha [TGF-α (MR₁)], its binding site the epidermal growth factor receptor [EGFR (MR₂)] sharing sequence homology to the breast cancer prognostic marker Her-2/neu, an apoptosis inhibiting protein [bcl-2 (MR₄)], and the androgen receptor [AR (MR₅)]. In attempts to enhance antisense therapy, recent reports describe how two of the binding sites mentioned above can be sequentially placed within a single complementary (bispecific) strand and administered either in the presence or absence of additional therapeutic agents. When tested against breast and prostate tumor cell lines specific differences were noted: MCF-7 breast cancer cells were more receptive to the inhibitory effects of monospecific oligos, whereas PC-3 and LNCaP prostate cells were particularly responsive to bispecifics. In an effort to identify agents which enhance the activity of oligos and which possess less toxicity than traditionally employed chemotherapeutics, Rapamycin, an immunosuppressive agent known to regulate tumor growth and signal transduction mediated by the mTOR receptor, is compared to paclitaxel in combination therapy employing monospecific or bispecific oligos. Bispecifics were constructed recognizing the binding sites for TGF-α and EGFR mRNA [TGF-α/EGFR (MR₁₂) and EGFR/TGF-α (MR₂₁)]; another pair recognized binding sites for EGFR and bcl-2 [EGFR/bcl-2 (MR₂₄) and bcl-2/EGFR (MR₄₂)]; while a third pair employed only against the LNCaP prostate cell line recognized bcl-2 and the androgen receptor [bcl-2/AR (MR4₄₅) and AR/bcl-2 (MR₅₄)]. Oligo pairs differ in their 5′–3′ linear binding site orientations, and were tested in vitro against MCF-7 breast and PC-3 and LNCaP prostate tumor cell lines. Following cell attachment, incubations were done for 2 days with the agents followed by 2 days in their absence. Five experiments evaluated the effect of monospecific or bispecific antisense oligos in combination with an LD₅₀ dosage of either Rapamycin or paclitaxel and led to the conclusion that although these agents act via different mechanisms, they are comparable in effectiveness.     

Volumetric and dosimetric impact of MRI in delineation of gross tumor volume of non-spinal vertebral metastases treated with stereotactic ablative radiation therapy

PurposeTo investigate the Gross Tumor Volumes (GTV) and its dosimetric impact of magnetic resonance imaging (MRI) assisted contouring for non-spinal metastasis treated with stereotactic ablative body radiotherapy (SABR).Material and methodsFive observer contours on CT (GTV_CT) and CT + MR (GTV_CT+MR) were evaluated against expert team contours (GTV_EC) for 14 selected cases. Dice Similarity Index (DSC) and Geographical Miss Index (GMI) quantify observer variation. We also analyze the maximum dose (D_max) and dose received by 0.35cc (D_0.35cc) of the spinal cord (SC) for GTV_CT and GTV_CT+MR, where optimization parameters and priorities were unchanged. Percent rank function is also evaluated for SC doses.ResultsThe mean DSC and GMI scores for the CT-only dataset are 0.6974 and 0.2851 and for CT + MR dataset is 0.7764 and 0.1907 respectively. Statistically, significant results were found for mean GTV volumes between GTV_EC versus GTV_CT and GTV_CT versus GTV_CT+MR (P < 0.001). Dosimetric analysis of D_max and D_0.35cc exceeded 84.2% and 88.5% of times its respective threshold doses for CT-only dataset, whereas for the CT + MR dataset, it exceeded only by 18% and 15.7% times. ‘Percent rank’ function analysis for SC doses also indicates the same.ConclusionThis study supports MRI fusion for GTV and OAR delineation for non-spinal metastasis. Our study showed that the dosimetric analysis is vital for observer variation studies and the addition of the MR data set is significant to improve the confidence of Stereotactic treatments.     

Bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors

Antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-α) (MR₁) and its binding site, the epidermal growth factor receptor (EGFR) (MR₂), are efficacious against PC-3 and LNCaP prostate tumors. To enhance activity and aid in simultaneous delivery, “bispecific” 39-mer oligos were constructed containing portions of both MR₁ and MR₂ sequences. The first pair contained truncated sequences recognizing TGF-α and EGFR mRNA binding sites, about their respective AUG initiation codons. These bispecifics differ in their 5’ to 3’ tandem orientation (TGF-α/EGFR [MR₁2] and EGFR/TGF-α [MR₂₁] sequences). A second pair was constructed having complementary sequences for EGFR and bcl-2 (EGFR/bcl-2 [MR₂₄] and bcl-2/EGFR [MR₄₂]). All bispecifics were tested in vitro against PC-3 and LNCaP prostate tumor cells, and compared to mono-specific oligos from which they were derived. The purpose of this study was: (1) to evaluate bispecific antitumor activity; (2) to identify dominant sequences; (3) to identify effects of binding site orientation; and (4) to determine whether bispecifics are more effective when targeting one versus different growth-dependent pathways. Comparisons were made between oligos tested against either PC-3 or LNCaP cells incubated for 2 d with the agents followed by 2 d in their absence. The first PC-3 cell experiment demonstrated that bispecific MR₁2 and MR₂₁ oligos are at least as effective as their mono-specific counterparts and that the MR₂₁ bispecific orientation is more effective than the MR₁ mono-specific by 64% (p = 0.014). It also suggested that the sequence directed against EGFR contributed most to bispecific activity, particularly in the MR₂₁ orientation. In a second PC-3 study a second bispecific pair of 37-mer oligos was constructed containing bases complementary to mRNA encoding EGFR and the apoptosis-associated protein bcl-2 (MR₄). MR₂₄ was constructed with the EGFR complementary site at the 5’ end (EGFR/bcl-2), and MR₄₂, containing the opposite orientation (bcl-2/EGFR). Each contained the dominant EGFR activity identified previously. MR₁, MR₂, MR₄, MR₁2, MR₂1, MR₂4, and MR₄₂ (1X and 2X in concentration) were cultured with cells and compared to controls. Each oligo significantly inhibited growth of PC-3 cells. MR₄₂ was most effective and significantly better than MR₁ (p = 0.0128), MR₂ (p = 0.021), MR₄ (p = 0.0002), and MR₁2 (p = 0.0032). 2X MR₂4 and 2X MR₄₂ were better than their 1X concentration counterparts, but the differences were not significant. In a similar experiment MR₁, MR₂, MR4, MR₁2, MR₂1, MR₂4, and MR42 were cultured with LNCaP cells and compared to lipofectin-containing controls. Each oligo significantly inhibited the growth of LNCaP cells. Again, MR₄₂ was most effective and significantly better than MR₂ (p = 0.021) and MR₄ (p = 0.038). MR₂4 was significantly better than MR₂ (p = 0.048). Bispecific oligos are a significant advance in antisense technology and could play a role in treating prostate cancer, particularly if combined with traditional chemotherapeutics.     

Stereotactic Pelvic Reirradiation for Locoregional Cancer Relapse

AimsUp to 40% of patients who have received radiation for a pelvic malignancy will develop locoregional recurrence in the previously irradiated volume. Stereotactic body radiotherapy (SBRT) has been used in the oligometastatic setting, and provides an ablative approach ideal for reirradiation. The purpose of this study was to evaluate the outcomes after SBRT reirradiation of extraosseous recurrences in the pelvis.Materials and methodsThis single institution retrospective study evaluated patients treated with SBRT reirradiation in the pelvis from January 2011 to February 2018. Patients with more than five oligometastatic lesions, >7 cm in size, and recurrence within the prostate were excluded.ResultsIn total, 30 patients were treated with SBRT with a median follow-up of 29.4 months. The primary tumour sites were most commonly rectum (30.8%) and prostate (30.8%). The median time interval between irradiation for the primary and SBRT reirradiation was 48 months (3–245). The typical reirradiation treatment was 35 Gy in five fractions, the median gross tumour volume size was 10.2 (0.3–110.5) ml and the most common target was the iliac nodes (40%). There were three (10%) acute grade 3 toxicities and no late grade 3 or more toxicities. At 12/24 months, local relapse-free survival, metastasis-free survival, progression-free survival and overall survival were 67.7%/50.7%, 67%/41.7%, 34.8%/14.9% and 83.2%/62.5%, respectively. On univariate analysis, improved local control was associated with low gross tumour volume (<10 ml) (P = 0.003) and prostate primary (P = 0.02), but was no longer significant on multivariate analysis. The proximity of organ at risk to the target did not significantly correlate with worse toxicity (P = 0.14) or tumour coverage (gross tumour volume: P = 0.8, planning target volume: P = 0.4).ConclusionSBRT pelvic reirradiation in oligometastatic patients is a safe and effective treatment modality. Careful consideration should be taken with larger tumour size, as it may be associated with worse oncological and toxicity outcome.     

Safety of Prostate Stereotactic Body Radiation Therapy after Transurethral Resection of Prostate (TURP): A Propensity Score Matched Pair Analysis

PurposeTo determine the genitourinary (GU) toxicity outcomes in prostate cancer patients treated with stereotactic body radiation therapy (SBRT) who have undergone a prior transurethral resection of prostate (TURP) and compare it to a similar non-TURP cohort.Materials and MethodsFifty prostate cancer patients who had undergone a single TURP, had a good baseline urinary function, and had been subsequently treated with SBRT were chosen from a prospectively maintained database. These were propensity score matched to a similar non-TURP cohort treated during the same period. Matching was done for diabetes mellitus and volume of radiation therapy. Acute GU and late GU toxicity were scored using the Radiation Therapy Oncology Group (RTOG) criteria. Stricture and incontinence were scored using Common Terminology for Common Adverse Events version 4.0.ResultsMedian follow-up for the entire cohort was 26 months (non-TURP vs TURP, 30 months vs 22 months, P = .34). The median duration between TURP and start of SBRT was 10 months. There was no significant difference between non-TURP versus TURP cohort in terms of RTOG acute GU toxicities grade ≥2 (8% vs 6%, P = .45), RTOG late GU toxicities grade ≥2 (8% vs 12%, P = .10), stricture rates (4% vs 6%, P = .64), and incontinence rates (0% vs 4%, P = .15). The median duration of time to late toxicity was 16 months vs 10 months (P = .12) in non-TURP and TURP cohort, respectively.ConclusionsAlthough modestly increased as compared with non-TURP patients, GU toxicities remains low with SBRT in post-TURP patients. SBRT can be safely performed in carefully selected post-TURP prostate cancer patients.     

Characterization of an Iodinated Rectal Spacer for Prostate Photon and Proton Radiation Therapy

PurposeConventional rectal spacers (nonI-SPs) are low-contrast on computed tomography (CT), often necessitating magnetic resonance imaging for accurate delineation. A new formulation of spacers (I-SPs) incorporates iodine to improve radiopacity and CT visualization. We characterized placement, stability, and plan quality of I-SPs compared to nonI-SPs.Methods and MaterialsPatients with intact prostate cancer (n = 50) treated with I-SPs and photons were compared to randomly selected patients (n = 50) with nonI-SPs (photon or proton therapy). The I-SP was contoured on the planning CT and cone beam CTs at 3 timepoints: first, middle, and final treatment (n = 200 scans). I-SPs Hounsfield units (HU), volume, surface area (SA), centroid position relative to prostate centroid, and distance between prostate/rectum centroids were compared on the planning CTs between each cohort. I-SP changes were evaluated on cone beam CTs over courses of treatment. Dosimetric evaluations of plan quality and robustness were performed. I-SP was tested in a phantom to characterize its relative linear stopping power for protons.ResultsI-SPs yielded a distinct visible contrast on planning CTs compared to nonI-SPs (HU 138 vs 12, P < .001), allowing delineation on CT alone. The delineated volume and SA of I-SPs were smaller than nonI-SPs (volume 8.9 vs 10.6 mL, P < .001; SA 28 vs 35 cm², P < .001), yet relative spacer position and prostate-rectal separation were similar (P = .79). No significant change in HU, volume, SA, or relative position of the I-SPs hydrogel occurred over courses of treatment (all P > .1). Dosimetric analysis concluded there were no significant changes in plan quality or robustness for I-SPs compared to nonI-SPs. The I-SP relative linear stopping power was 1.018, necessitating HU override for proton planning.ConclusionsI-SPs provide a manifest CT contrast, allowing for delineation on planning CT alone with no magnetic resonance imaging necessary. I-SPs radiopacity, size, and relative position remained stable over courses of treatment from 28 to 44 fractions. No changes in plan quality or robustness were seen comparing I-SPs and nonI-SPs.     

Separation Effect and Development of Implantation Technique of Hydrogel Spacer for Prostate Cancers

PurposeThe purpose of this study is to improve the placement of a hydrogel spacer in patients with prostate cancer receiving radiation therapy.Methods and MaterialsA total of 160 patients with prostate cancer were classified into 3 groups: No spacer (group 1; n = 30), spacer placed using conventional technique (group 2; n = 100), and spacer placed using new technique (group 3; n = 30). When placing the spacer, the tip of the needle is placed at the middle of the prostate gland (group 2), or at a level corresponding to a cranial:caudal ratio of 6:4 and as close to the prostate gland as possible (group 3). The separation effect was examined and compared among the groups.ResultsThe separation in group 2 was larger than that in group 1 from the base to the apex level of the prostate (4 mm), but the separation in group 3 was larger than that in group 2 from the middle to the apex level of the prostate (4 mm). The separation values for the middle to the apex, the spacer thickness from the apex level to the apex (10 mm), the rectal exclusion from the middle to the apex, and the laterality were correlated with the 50 and 60 Gy relative biologic effectiveness (Gy[RBE]) rectal dose (P = 4.1 × 10⁻⁹ – .046). The separation vales were strongly correlated with the spacer thickness at the apex (10 mm) and the apex (4 mm; P = 1.1 × 10⁻¹⁸ – 1.8 × 10⁻¹⁷). The rectal volumes at 10 to 60 Gy(RBE) differed among the groups (P = 5.1 × 10⁻¹⁹ – 5.4 × 10⁻³). The rectal volumes in group 2 were smaller than those in group 1 at all dose levels, but those in group 3 were smaller than those in group 2 at dose levels of 30 to 50 Gy(RBE).ConclusionsThe separation, spacer thickness, and rectal exclusion from the middle to the apex of the prostate and the laterality of the hydrogel spacer affected the reduction in the rectal dose. The rectal dose can be further reduced by implanting a spacer on the caudal and prostate side.     

Combination chemotherapy employing bispecific antisense oligonucleotides having binding sites directed against an autocrine regulated growth pathway and bcl-2 for the treatment of prostate tumors

In previous studies we demonstrated that antisense oligonucleotides (oligos) against transforming growth factor-alpha (TGF-α [MR₁]), its binding site the epidermal growth factor receptor (EGFR [MR₂]), and the anti-apoptosis protein bcl-2 (MR₄) are efficacious against prostate tumors. In recent reports we also describe how two of these mRNA directed binding sites can be synthesized sequentially within a single linear complementary strand and administered either in the presence or absence of additional therapeutic agents. In these continuing experiments “bispecific” oligo pairs were further evaluated in the presence or absence of Cytoxan, Taxol, or DES. One oligo pair recognized the binding sites for TGF-α and EGFR mRNA (TGF-α/EGFR [MR₁₂] and EGFR/TGF-α [MR₂₁]); another pair recognized binding sites for EGFR and bcl-2 (EGFR/bcl-2 [MR₂₄] and bcl-2/EGFR [MR₄₂]). Oligo pairs differ in their linear 5′ to 3′ binding site orientations, and were tested in vitro against PC-3 and LNCaP prostate tumor cell lines. Following cell attachment, incubations were for 2 days with the agents followed by 2 days in their absence. When tested against PC-3 cells and combined with LD₅₀ Cytoxan, MR₂, MR₄, MR₂₄, MR₄₂ significantly inhibited 47.3, 45.7, 68.3, and 64.9%; with LD₅₀ Taxol MR₂, MR₄, MR₂₄, MR₄₂ significantly inhibited 49.8, 45.8, 64.1, and 59.2%; and with LD₅₀ DES MR₂, MR₄, MR₂₄, MR₄₂ significantly inhibited 66.6, 67.6, 64.3, and 67.2% respectively. Each agent significantly increased the inhibition produced by either oligo alone. LNCaP cells were also incubated with mono- and bispecific oligos in either the presence or absence of chemotherapeutics. MR₂, MR₄, MR₂₄, MR₄₂ produced significant inhibitions of 57.4, 58.4, 69.4, and 68.6% with LD₅₀ Cytoxan; 70.4, 70.1, 73.6, and 74.0% with LD₅₀ Taxol; and 49.8, 50.1, 59.6, and 53.9%, respectively with LD₅₀ DES. A complete PC-3 experiment compared MR₁, MR₂, MR₄, MR₁₂, MR₂₁, MR₂₄ and MR₄₂, in the presence of LD₅₀ Cytoxan. Each oligo combined with Cytoxan significantly inhibited: MR₁ by 51.0, MR₂ by 55.0, MR₄ by 58.0; MR₁₂ by 56.0; MR₂₁ by 61.1, MR₂₄ by 65.5 and MR₄₂ by 66.0%. Bispecifics directed against two different pathways, MR_24, and MR₄₂ were the most effective. A complete LNCaP experiment compared the same series of oligos also in the presence of LD₅₀ Cytoxan. Each oligo combined with Cytoxan significantly inhibited: MR₁ by 49.0, MR₂ by 50.0, MR₄ by 53.0; MR₁₂ by 52.0; MR₂₁ by 58.6, MR₂₄ by 53.9 and MR₄₂ by 58.0%.     

Early Outcomes and Decision Regret Using PSMA/MRI-Guided Focal Boost for Prostate Cancer SBRT

PurposeStereotactic body radiation therapy (SBRT) is a recognized treatment for low- and intermediate-risk prostate cancer, with 36.25 Gy in 5 fractions the most commonly used regimen. We explored the preliminary efficacy, patient recorded toxicity, and decision regret in intermediate- and high-risk prostate cancer receiving SBRT with prostate-specific membrane antigen (PSMA)/magnetic resonance imaging (MRI) guided focal gross tumor volume boost to 45 Gy.Methods and MaterialsBetween July 2015 and June 2019, 120 patients received SBRT across 2 institutions with a uniform protocol. All patients had fiducial markers and hydrogel, MRI and PSMA positron emission tomography (PET) scan. All patients received a questionnaire asking the degree of urinary, bowel, and sexual bother experienced at set time points, including questions about treatment choice and decision regret.ResultsOne hundred twelve of 120 patients consented. Their median age was 72 years and median follow-up was 2.3 years. As per National Comprehensive Cancer Network guidelines, 78% had intermediate risk and 20% high risk. Androgen deprivation was combined with radiation in 6 patients. Most patients (74%) reported that receiving SBRT significantly influenced their choice of treatment. Five men (4%) expressed “quite a lot” (n = 4) or “very much” regret (n = 1) regarding their choice of treatment, while 89% expressed “no regret.” Similar to pretreatment levels, “quite a lot” or “very much” urinary or bowel bother was expressed in 8% and 6% of patients, respectively. Two patients experienced nadir +2 biochemical failure, both found to have bone metastases. A third patient underwent PSMA PET at nadir +1.7 and had disease at the penile bulb, which was out of field. Three year estimated freedom from biochemical failure was 99% for intermediate and 85% for high-risk groups.ConclusionsWe have demonstrated promising efficacy and low toxicity with PSMA/MRI-guided SBRT focal boost. Less than 5% of patients expressed significant decision regret for their choice of treatment.     

Stereotactic Radiosurgery for Postoperative Spine Malignancy: A Systematic Review and International Stereotactic Radiosurgery Society Practice Guidelines

PurposeTo determine safety and efficacy of postoperative spine stereotactic body radiation therapy (SBRT) in the published literature, and to present practice recommendations on behalf of the International Stereotactic Radiosurgery Society.Methods and MaterialsA systematic review of the literature was performed, specific to postoperative spine SBRT, using PubMed and Embase databases. A meta-analysis for 1-year local control (LC), overall survival (OS), and vertebral compression fracture probability was conducted.ResultsThe literature search revealed 251 potentially relevant articles after duplicates were removed. Of these 56 were reviewed in-depth for eligibility and 12 met all the inclusion criteria for analysis. 7 studies were retrospective, 2 prospective observational and 3 were prospective phase 1 and 2 clinical trials. Outcomes for a total of 461 patients and 499 spinal segments were reported. Ten studies used a magnetic resonance imaging (MRI) scan fused to computed tomography (CT) simulation for treatment planning, and 2 investigations reported on all patients receiving a CT-myelogram at the time of planning. Meta-analysis for 1 year LC and OS was 88.9% and 57%, respectively. The crude reported vertebral compression fracture rate was 5.6%. One case of myelopathy was described in a patient with a previously irradiated spinal segment. One patient developed an esophageal fistula requiring surgical repair.ConclusionsPostoperative spine SBRT delivers a high 1-year LC with acceptably low toxicity. Patients who may benefit from this include those with oligometastatic disease, radioresistant histology, paraspinal masses, or those with a history of prior irradiation to the affected spinal segment. The International Stereotactic Radiosurgery Society recommends a minimum interval of 8 to 14 days after invasive surgery before simulation for SBRT, with initiation of radiation therapy within 4 weeks of surgery. An MRI fused to the planning CT, or the use of a CT-myelogram, are necessary for target and organ-at-risk delineation. A planning organ-at-risk volume (PRV) of 1.5 to 2 mm for the spinal cord is advised.     

Concomitant Chemotherapy and Radiotherapy with SBRT Boost for Unresectable Stage III Non–Small Cell Lung Cancer: A Phase I Study

ObjectivesStereotactic body radiation therapy (SBRT) is now the standard of care in medically inoperable stage I NSCLC, yielding high rates of local control. It is unknown whether SBRT can be safely utilized in the locally advanced NSCLC setting. This multi-institution phase I study evaluated the safety of 44 Gy of conventionally fractionated thoracic radiation with concurrent chemotherapy plus dose-escalated SBRT boost to both the primary tumor and involved mediastinal lymph nodes. The primary end point of this study was to establish the maximum tolerated dose (MTD) of the SBRT boost.MethodsInclusion criteria included unresectable stage IIIA or IIIB disease, primary tumor 8 cm or smaller, and N1 or N2 lymph nodes 5 cm or smaller. Tumors were staged with positron emission tomography/computed tomography (CT), and four-dimensional CT simulation was used for radiation planning. The treatment schema was 44 Gy of thoracic radiation (2 Gy/d) with weekly carboplatin and paclitaxel chemotherapy. A second CT simulation was obtained after 40 Gy had been delivered, and a SBRT boost was planned to the remaining gross disease at the primary site and involved mediastinal lymph nodes. Consolidation chemotherapy was given at the discretion of the treating medical oncologist. Four SBRT boost dose cohorts were tested: cohort 1 (9 Gy × 2), cohort 2 (10 Gy × 5), cohort 3 (6 Gy × 5), and cohort 4 (7 Gy × 5). Patients were treated in cohorts of three patients, and the Bayesian escalation with overdose control method was used to determine the MTD of the SBRT boost. Dose-limiting toxicities (DLTs) were defined as any grade 3 or higher toxicities within 30 days of treatment attributed to treatment, not including hematologic toxicity, or any grade 5 toxicity attributed to treatment.ResultsThe study enrolled 19 patients from November 2012 to December 2016. There were four screen failures, and 15 patients were treated on study. There were no DLTs in dose cohort 1 (n = 3) and 2 (n = 6). DLT developed in one patient in dose cohort 3 (n = 3) and in 2 patients in dose cohort 4 (n = 3). The calculated MTD was 6 Gy × 5. The DLT observed at this dose level was a tracheoesophageal fistula; given this substantial toxicity, there was investigator reluctance to enroll further patients at this dose level. Thus, the calculated MTD was 6 Gy × 5; however, 10 Gy × 2 is thought to be a reasonable dose as well, given that no grade 5 toxicities occurred with that dose.ConclusionsThe MTD of a SBRT boost combined with 44 Gy of thoracic chemoradiation was 6 Gy × 5. A SBRT boost dose of 10 Gy × 2 could be considered safer, with no grade 3 or higher toxicities observed at this dose level during the follow-up period in this study.     

A moving target: Image guidance for stereotactic body radiation therapy for early-stage non-small cell lung cancer

PurposePrecise patient positioning is critical due to the large fractional doses and small treatment margins employed for thoracic stereotactic body radiation therapy (SBRT). The goals of this study were to evaluate the following: (1) the accuracy of kilovoltage x-ray (kV x-ray) matching to bony anatomy for pretreatment positioning; (2) the magnitude of intrafraction tumor motion; and (3) whether treatment or patient characteristics correlate with intrafraction motion.Methods and MaterialsEighty-seven patients with lung cancer were treated with SBRT. Patients were positioned with orthogonal kV x-rays matched to bony anatomy followed by cone-beam computed tomography (CBCT), with matching of the CBCT-visualized tumor to the internal gross target volume obtained from a 4-dimensional CT simulation data set. Patients underwent a posttreatment CBCT to assess the magnitude of intrafraction motion.ResultsThe mean CBCT-based shifts after initial patient positioning using kV x-rays were 2.2 mm in the vertical axis, 1.8 mm in the longitudinal axis, and 1.6 mm in the lateral axis (n = 335). The percentage of shifts greater than 3 mm and 5 mm represented 39% and 17%, respectively, of all fractions delivered. The mean CBCT-based shifts after treatment were 1.6 mm vertically, 1.5 mm longitudinally, and 1.1 mm laterally (n = 343). Twenty-seven percent and 10% of shifts were greater than 3 mm and 5 mm, respectively. Univariate and multivariable analysis demonstrated a significant association between intrafraction motion with weight and pulmonary function.ConclusionsKilovoltage x-ray matching to bony anatomy is inadequate for accurate positioning when a conventional 3-5 mm margin is employed prior to lung SBRT. Given the treatment techniques used in this study, CBCT image guidance with a 5-mm planning target volume margin is recommended. Further work is required to find determinants of interfraction and intrafraction motion that may help guide the individualized application of planning target volume margins.     

Acute Side Effects After Definitive Stereotactic Body Radiation Therapy (SBRT) for Patients with Clinically Localized Or Locally Advanced Prostate Cancer: a Single Institution Prospective Study

BackgroundThe aim of the study was to evaluate acute side effects after extremely hypofractionated intensity-modulated radiotherapy (IMRT) with stereotactic body radiation therapy (SBRT) for definitive treatment of prostate cancer patients.Patients and methodsBetween February 2018 and August 2019, 205 low-, intermediate- and high-risk prostate cancer patients were treated with SBRT using “CyberKnife M6” linear accelerator. In low-risk patients 7.5–8 Gy was delivered to the prostate gland by each fraction. For intermediate- and high-risk disease a dose of 7.5–8 Gy was delivered to the prostate and 6–6.5 Gy to the seminal vesicles by each fraction with a simultaneous integrated boost (SIB) technique. A total of 5 fractions (total dose 37.5–40 Gy) were given on every second working day. Acute radiotherapy-related genitourinary (GU) and gastrointestinal (GI) side effects were assessed using Radiation Therapy Oncology Group (RTOG) scoring system.ResultsOf the 205 patients (28 low-, 115 intermediate-, 62 high-risk) treated with SBRT, 203 (99%) completed the radiotherapy as planned. The duration of radiation therapy was 1 week and 3 days. The frequencies of acute radiotherapy-related side effects were as follows: GU grade 0 – 17.1%, grade I – 30.7%, grade II – 50.7%, grade III – 1.5%; and GI grade 0 – 62.4%, grade I–31.7%, grade II–5.9%, grade III–0%. None of the patients developed grade ≥ 4 acute toxicity.ConclusionsSBRT with a total dose of 37.5–40 Gy in 5 fractions appears to be a safe and well tolerated treatment option in patients with prostate cancer, associated with slight or moderate early side effects. Longer follow-up is needed to evaluate long-term toxicity and biochemical control.Key words: prostate cancer, stereotactic radiotherapy, CyberKnife, extreme hypofractionation     

Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial

PurposePreviously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit.Methods and MaterialsClinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed.ResultsRectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines.ConclusionsThere was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.