Baukelien van Triest

A Multi-institutional Clinical Trial of Rectal Dose Reduction via Injected Polyethylene-Glycol Hydrogel During Intensity Modulated Radiation Therapy for Prostate Cancer: Analysis of Dosimetric Outcomes

PURPOSE To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiation therapy for prostate cancer and to assess for factors correlated with rectal dose reduction. METHODS AND MATERIALS Fifty-two patients at 4 institutions were enrolled into a prospective pilot clinical trial. Patients underwent baseline scans and then were injected with perirectal spacing hydrogel and rescanned. Intensity modulated radiation therapy plans were created on both scans for comparison. The objectives were to establish rates of creation of ≥ 7.5 mm of prostate-rectal separation, and decrease in rectal V70 of ≥ 25%. Multiple regression analysis was performed to evaluate the associations between preinjection and postinjection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, planning target volume (PTV), and postinjection midgland separation, gel volume, gel thickness, length of PTV/gel contact, and gel left-to-right symmetry. RESULTS Hydrogel resulted in ≥7.5-mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of ≥ 25%, with a mean reduction of 8.0 Gy. There were no significant differences in preinjection and postinjection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different before versus after injection (P=.02); plans with worse conformity indexes after injection compared with before injection (n=13) still had improvements in rectal V70. In multiple regression analysis, greater postinjection reduction in V70 was associated with decreased relative postinjection plan conformity (P=.01). Reductions in V70 did not significantly vary by institution, despite significant interinstitutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed. CONCLUSIONS Injection of hydrogel into the prostate-rectal interface resulted in dose reductions to rectum for >90% of patients treated. Rectal sparing was statistically significant across a range of 10 to 75 Gy and was demonstrated within the presence of significant interinstitutional variability in plan conformity, target definitions, and injection results.

Novel therapeutics in combination with radiotherapy to improve cancer treatment: rationale, mechanisms of action and clinical perspective.

Our increased understanding of the molecular processes underlying cellular sensitivity to ionizing radiation has led to the identification of novel targets for intervention. New agents have become available for combined use to overcome radioresistance and enhance the clinical efficacy of radiotherapy. This rational selection of potential radiosensitizers contrasts with the empirical approach that has dominated the field of chemo-radiotherapy over the last decades. It allows the identification of those patients who will benefit most from a specific combination by exploiting new predictive biomarkers of response. In this review we present several approaches of targeted radiosensitization and discuss the available in vitro and in vivo results that support their translation into clinical trials. We focus on EGFR-inhibiting, anti-angiogenic, apoptosis-modulating and PARP-interfering strategies.

Low rectal toxicity after dose escalated IMRT treatment of prostate cancer using an absorbable hydrogel for increasing and maintaining space between the rectum and prostate: Results of a multi-institutional phase II trial

PURPOSE To evaluate the safety and efficacy of an absorbable hydrogel when injected between the rectum and prostate to reduce rectal radiation toxicity in adult men undergoing Intensity Modulated Radiotherapy (IMRT) for treatment of low and intermediate risk prostate cancer. METHODS This prospective, non-randomized, multi-center, single arm, open-label study included 52 men with a confirmed diagnosis of prostate cancer. They received transperineal injection of the hydrogel and 3-5 days after injection the simulation scans. All patients received IMRT (78Gy delivered, 2 Gy per fraction). Space stability was evaluated by using MRI or CT. Gastrointestinal (GI) and genitourinary (GU) toxicity was assessed using RTOG/EORTC scoring system and proctoscopy after 12 months. The median follow up time was 12 months. RESULTS Hydrogel application was straight forward using brachytherapy equipment and techniques, with minimal patient discomfort. Six patients (12%) experienced acute GI Grade 2 toxicity, with no patients experiencing Grade 3 or 4 toxicity. In addition, no patients had early late GI toxicity ≥ Grade 2 after 12 months. The gel was stable during the course of radiotherapy and was not detectable in MRI after 9-12 months due to absorption in 42 of 43 patients. CONCLUSION These data demonstrated that the hydrogel is a safe method to displace the rectal wall away from the prostate therefore substantially reducing toxicity to the rectum.

EVALUATION OF FOUR-DIMENSIONAL COMPUTED TOMOGRAPHY-BASED INTENSITY-MODULATED AND RESPIRATORY-GATED RADIOTHERAPY TECHNIQUES FOR PANCREATIC CARCINOMA

PURPOSE To compare conformal radiotherapy (CRT), intensity-modulated radiotherapy (IMRT), and respiration-gated radiotherapy (RGRT) planning techniques for pancreatic cancer. All target volumes were determined using four-dimensional computed tomography scans (4D CT). METHODS AND MATERIALS The pancreatic tumor and enlarged regional lymph nodes were contoured on all 10 phases of a planning 4D CT scan for 10 patients, and the planning target volumes (PTV(all phases)) were generated. Three consecutive respiratory phases for RGRT delivery in both inspiration and expiration were identified, and the corresponding PTVs (PTV(inspiration) and PTV(expiration)) and organ at risk volumes created. Treatment plans using CRT and IMRT, with and without RGRT, were created for each PTV. RESULTS Compared with the CRT plans, IMRT significantly reduced the mean volume of right kidney exposed to 20 Gy from 27.7% +/- 17.7% to 16.0% +/- 18.2% (standard deviation) (p < 0.01), but this was not achieved for the left kidney (11.1% +/- 14.2% to 5.7% +/- 6.5%; p = 0.1). The IMRT plans also reduced the mean gastric, hepatic, and small bowel doses (p < 0.01). No additional reductions in the dose to the kidneys or other organs at risk were seen when RGRT plans were combined with either CRT or IMRT, and the findings for RGRT in end-expiration and end-inspiration were similar. CONCLUSION 4D CT-based IMRT plans for pancreatic tumors significantly reduced the radiation doses to the right kidney, liver, stomach, and small bowel compared with CRT plans. The additional dosimetric benefits from RGRT appear limited in this setting.

Absorbable hydrogel spacer use in men undergoing prostate cancer radiotherapy: 12 month toxicity and proctoscopy results of a prospective multicenter phase II trial

BackgroundRadiation therapy is one of the recommended treatment options for localized prostate cancer. In randomized trials, dose escalation was correlated with better biochemical control but also with higher rectal toxicity. A prospective multicenter phase II study was carried out to evaluate the safety, clinical and dosimetric effects of the hydrogel prostate-rectum spacer. Here we present the 12 months toxicity results of this trial.MethodsFifty two patients with localized prostate cancer received a transperineal PEG hydrogel injection between the prostate and rectum, and then received IMRT to a dose of 78 Gy. Gastrointestinal and genitourinary toxicity were recorded during treatment and at 3, 6 and 12 months following irradiation by using the RTOG/EORTC criteria. Additionally, proctoscopy was performed 12 months after treatment and the results were scored using the Vienna Rectoscopy Scale (VRS).ResultsOf the patients treated 39.6% and 12.5% experienced acute Grade 1 and Grade 2 GI toxicity, respectively. There was no Grade 3 or Grade 4 acute GI toxicity experienced in the study. Only 4.3% showed late Grade 1 GI toxicity, and there was no late Grade 2 or greater GI toxicity experienced in the study. A total of 41.7%, 35.4% and 2.1% of the men experienced acute Grade 1, Grade 2 and Grade 3 GU toxicity, respectively. There was no Grade 4 acute GU toxicity experienced in the study. Late Grade 1 and Grade 2 GU toxicity was experienced in 17.0% and 2.1% of the patients, respectively. There was no late Grade 3 or greater GU toxicity experienced in the study. Seventy one percent of the patients had a VRS score of 0, and one patient (2%) had Grade 3 teleangiectasia. There was no evidence of ulceration, stricture or necrosis at 12 months.ConclusionThe use of PEG spacer gel is a safe and effective method to spare the rectum from higher dose and toxicity.

An overlap-volume-histogram based method for rectal dose prediction and automated treatment planning in the external beam prostate radiotherapy following hydrogel injection

PURPOSE Hydrogel injected between the rectum and prostate prior to radiotherapy provides a possible means of increased dose sparing to the rectum. Here the authors evaluate the overlap volume histogram (OVH) metric as a means to predict the rectal dose following hydrogel injection. Whether OVH predicted dose can serve as the dose objective or constraint for automated treatment planning was also investigated. METHODS Treatment planning was performed on 21 prostate cancer patients both pre- and posthydrogel injection, with five-field IMRT delivering 78 Gy to the planning target volume (PTV). The authors quantify the geometrical relationship between the rectum and the prostate PTV using an OVH metric which determines the fractional volume of the rectum that is within a specified distance of the PTV. For an OVH distance the authors selected, L(20), the PTV expansion distance at which 20% of the rectum overlaps. The authors calculated the rectal dose, D(20), received by 20% of the rectum volume on the dose volume histogram. Linear regression was used to examine the correlation between the L(20) and D(20), and between ΔL(20) and ΔD(20) (i.e., the change of L(20) and D(20) posthydrogel injection). Additionally, rectal dose D(15), D(25), D(35), D(50), and bladder dose D(15) were predicted from the OVH (L(15), L(25), L(35), L(50), for rectum and L(15) for bladder) by the L(x)-D(x) linear regression. The predicted doses were applied to the objectives for automated treatment planning of ten plans from five patients. Automatically generated plans were compared with plans manually generated on trial-and-error basis. RESULTS The rectal L(20) was increased and dose D(20) decreased due to the enlarged separation of rectum caused by the hydrogel injection. Linear regression showed an inverse linear correlation between L(20) and D(20), and between ΔL(20) and ΔD(20) (r(2) = 0.77, 0.60, respectively; p < 0.0001). The increase in rectal sparing (ΔD(20)) is only weakly correlated with the volume of injected hydrogel (r(2) = 0.17; p = 0.07), indicating OVH is a more predictive indicator of rectal sparing than the volume of hydrogel itself. Application of the predicted rectum and bladder doses to automated planning produced acceptable treatment plans, with rectal dose reduced for eight of ten plans. CONCLUSIONS The OVH metric can predict the rectal dose in the external beam prostate radiotherapy for patients with hydrogel injection. The predicted doses can be applied to the objectives of optimization in automated treatment planning to produce acceptable treatment plans.

Analysis of Carina Position as Surrogate Marker for Delivering Phase-Gated Radiotherapy

PURPOSE Respiratory gating can mitigate the effect of tumor mobility in radiotherapy (RT) for lung cancer. Because the tumor is generally not visualized, external surrogates of tumor position are used to trigger respiration-gated RT. We evaluated the suitability of the carina position as a surrogate in respiration-gated RT. METHODS AND MATERIALS A total of 30 four-dimensional (4D) computed tomography (CT) scans from 14 patients with lung cancer were retrospectively analyzed. Both uncoached (free breathing) and audio-coached 4D-CT scans were acquired from 9 patients, and 12 uncoached 4D-CT scans were acquired from 5 other patients during a 2-4-week period of stereotactic RT. The repeat scans were co-registered. The carina position was identified on the coronal cut planes in all 4D-CT phases. The correlation between the carina position and the total lung volume for each phase was determined, and the reproducibility of the carina position was studied in the 5 patients with repeat uncoached 4D-CT scans. RESULTS The mean extent of carina motion in 21 uncoached scans was 5.3 +/- 1.6 mm in the craniocaudal (CC), 2.3 +/- 1.4 mm in the anteroposterior, and 1.5 +/- 0.7 mm in the mediolateral direction. Audio coaching resulted in a twofold increase in carina mobility in all directions. The CC carina position correlated with changes in the total lung volume (R = 0.89 +/- 0.14), but the correlation was better for the audio-coached than for the uncoached 4D-CT scans (R = 0.93 +/- 0.08 vs. R = 0.85 +/- 0.17; paired t test, p = 0.034). Preliminary data from the 5 patients indicated that the CC carina motion correlated better with tumor motion than did the motion of the diaphragm. CONCLUSIONS The CC position of the carina correlated well with the total lung volume, indicating that the carina is a good surrogate for verifying the total lung volume during respiration-gated RT.

Repeat CT assessed CTV variation and PTV margins for short- and long-course pre-operative RT of rectal cancer

PURPOSE To quantify the inter-fraction shape variation of the CTV in rectal-cancer patients treated with 5 × 5 (SCRT) and 25 × 2 Gy (LCRT) and derive PTV margins. METHODS AND MATERIALS Thirty-three SCRT with daily repeat CT scans and 30 LCRT patients with daily scans during the first week followed by weekly scans were included. The CTV was delineated on all scans and local shape variation was calculated with respect to the planning CT. Margin estimation was done using the local shape variation to assure 95% minimum dose for at least 90% of patients. RESULTS Using 482 CT scans, systematic and random CTV shape variation was heterogeneous, ranging from 0.2 cm close to bony structures up to 1.0 cm SD at the upper-anterior CTV region. A significant reduction in rectal volume during LCRT resulted in an average 0.5 cm posterior shift of the upper-anterior CTV. Required margins ranged from 0.7 cm close to bony structures up to 3.1 and 2.3 cm in the upper-anterior region for SCRT and LCRT, respectively. CONCLUSIONS Heterogeneous shape variation demands anisotropic PTV margins. Required margins were substantially larger in the anterior direction compared to current clinical margins. These larger margins were, however, based on strict delineated CTVs, resulting in smaller PTVs compared to current practice.

Adaptive radiotherapy for long course neo-adjuvant treatment of rectal cancer.

PURPOSE To quantify the potential margin reduction with adaptive radiotherapy (ART) during neo-adjuvant treatment of locally-advanced rectal cancer. METHODS AND MATERIALS Repeat CT scans were acquired for 28 patients treated with 25×2 Gy, daily during the first week, and followed by weekly scans. The CTV was delineated on all scans, and shape variation was estimated. Five ART strategies were tested, consisting of an average CTV over the planning CT and one to five repeat CTs. Required PTV margins were calculated for adapted and non-adapted treatment. The strategy with the least PTV volume over the whole treatment was selected and bowel area dose reduction was estimated. RESULTS Substantial systematic and random shape variation demanded for a PTV margin up to 2.4 cm at the upper-anterior part of the CTV. Plan adaptation after fraction 4 resulted in a maximum 0.7 cm margin reduction and a significant PTV reduction from 1185 to 1023 cc (p<0.0001). The bowel area volume receiving 15, 45, and 50 Gy was reduced from 436 to 402 cc, 111 to 81 cc, and 49 to 29 cc, respectively (p<0.0001). CONCLUSIONS With adaptive radiotherapy, maximum required PTV margins can be reduced from 2.4 to 1.7 cm, resulting in significantly less dose to the bowel area.

The quality of radiation care: The results of focus group interviews and concept mapping to explore the patient’s perspective

BACKGROUND AND PURPOSE In this study, we explore the quality aspects of radiation care from the patients perspective in order to develop a draft Consumer Quality Index (CQI) Radiation Care instrument. MATERIALS AND METHODS Four focus group discussions with (former) cancer patients were held to explore the aspects determining the quality of radiation care. The list of aspects generated was categorised based on similarity and importance in a concept mapping procedure. RESULTS Four focus group discussions revealed seven main themes related to the quality of radiation care: information provision, a patient-centred approach, professional competence, planning and waiting times, accessibility, cooperation and communication, and follow-up care. Results of concept mapping procedures revealed which items the patients considered to be most important. A radiation oncologist who is up to date about the patients file is of paramount importance for cancer patients receiving radiotherapy. CONCLUSIONS The quality aspects found through focus group discussions provided useful insight into how patients experience radiation care. Furthermore, concept mapping made these results more solid. To evaluate the quality of radiation care from the patients perspective, these quality aspects will be guiding in the development of a CQI Radiation Care.