Aswin L. Hoffmann

Lanreotide Reduces the Volume of Polycystic Liver: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND & AIMS Therapy for polycystic liver is invasive, expensive, and has disappointing long-term results. Treatment with somatostatin analogues slowed kidney growth in patients with polycystic kidney disease (PKD) and reduced liver and kidney volume in a PKD rodent model. We evaluated the effects of lanreotide, a somatostatin analogue, in patients with polycystic liver because of autosomal-dominant (AD) PKD or autosomal-dominant polycystic liver disease (PCLD). METHODS We performed a randomized, double-blind, placebo-controlled trial in 2 tertiary referral centers. Patients with polycystic liver (n = 54) were randomly assigned to groups given lanreotide (120 mg) or placebo, administered every 28 days for 24 weeks. The primary end point was the difference in total liver volume, measured by computerized tomography at weeks 0 and 24. Analyses were performed on an intention-to-treat basis. RESULTS Baseline characteristics were comparable for both groups, except that more patients with ADPKD were assigned to the placebo group (P = .03). The mean liver volume decreased 2.9%, from 4606 mL (95% confidence interval (CI): 547-8665) to 4471 mL (95% CI: 542-8401 mL), in patients given lanreotide. In the placebo group, the mean liver volume increased 1.6%, from 4689 mL (95% CI: 613-8765 mL) to 4895 mL (95% CI: 739-9053 mL) (P < .01). Post hoc stratification for patients with ADPKD or PCLD revealed similar changes in liver volume, with statistically significant differences in patients given lanreotide (P < .01 for both diseases). CONCLUSIONS In patients with polycystic liver, 6 months of treatment with lanreotide reduces liver volume.

18F-FLT PET/CT for Early Response Monitoring and Dose Escalation in Oropharyngeal Tumors

Accelerated tumor cell proliferation is an important mechanism adversely affecting therapeutic outcome in head and neck cancer. 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) is a PET tracer to noninvasively image tumor cell proliferation. The aims of this study were to monitor early tumor response based on repetitive 18F-FLT PET/CT scans and to identify subvolumes with high proliferative activity eligible for dose escalation. Methods: Ten patients with oropharyngeal tumors underwent an 18F-FLT PET/CT scan before and twice during radiotherapy. The primary tumor and metastatic lymph nodes (gross tumor volume, or GTV) were delineated on CT (GTVCT) and after segmentation of the PET signal using the 50% isocontour of the maximum signal intensity or an adaptive threshold based on the signal-to-background ratio (GTVSBR). GTVs were calculated, and similarity between GTVCT and GTVSBR was assessed. Within GTVSBR, the maximum and mean standardized uptake value (SUVmax and SUVmean, respectively) was calculated. Within GTVCT, tumor subvolumes with high proliferative activity based on the 80% isocontour (GTV80%) were identified for radiotherapy planning with dose escalation. Results: The GTVCT decreased significantly in the fourth week but not in the initial phase of treatment. SUVmax and SUVmean decreased significantly as early as 1 wk after therapy initiation and even further before the fourth week of treatment. For the primary tumor, the average (±SD) SUVmean of the GTVSBR was 4.7 ± 1.6, 2.0 ± 0.9, and 1.3 ± 0.2 for the consecutive scans (P < 0.0001). The similarity between GTVCT and GTVSBR decreased during treatment, indicating an enlargement of GTVSBR outside GTVCT caused by the increasing difficulty of segmenting tracer uptake in the tumor from the background and by proliferative activity in the nearby tonsillar tissue. GTV80% was successfully identified in all primary tumors and metastatic lymph nodes, and dose escalation based on the GTV80% was demonstrated to be technically feasible. Conclusion: 18F-FLT is a promising PET tracer for imaging tumor cell proliferation in head and neck carcinomas. Signal changes in 18F-FLT PET precede volumetric tumor response and are therefore suitable for early response assessment. Definition of tumor subvolumes with high proliferative activity and dose escalation to these regions are technically feasible.

A novel iterative method for lesion delineation and volumetric quantification with FDG PET.

ObjectivesThe determination of lesion boundaries on FDG PET is difficult due to the point-spread blurring and unknown uptake of activity within a lesion. Standard threshold-based methods for volumetric quantification on PET usually neglect any size dependence and are biased by dependence on the signal-to-background ratio (SBR). A novel, model-based method is hypothesized to provide threshold levels independent f the SBR and to allow accurate measurement of volumes down to the resolution of the PET scanner. MethodsA background-subtracted relative-threshold level (RTL) method was derived, based on a convolution of the point-spread function and a sphere with diameter D. Validation of the RTL method was performed using PET imaging of a Jaszczak phantom with seven hollow spheres (D=10–60 mm). Activity concentrations for the background and spheres (signal) were varied to obtain SBRs of 1.5–10. An iterative procedure was introduced for volumetric quantification, as the optimal RTL depends on a priori knowledge of the volume. The feasibility of the RTL method was tested in two patients with liver metastases and compared to a standard method using a fixed percentage of the signal. ResultsPhantom data validated that the theoretically optimal RTL depends on the sphere size, but not on the SBR. Typically, RTL=40% (D=15–60 mm), and RTL>50% for small spheres (D<12 mm). The RTL method is better applicable to patient data than the standard method. ConclusionsBased on an iterative procedure, the RTL method has been shown to provide optimal threshold levels independent of the SBR and to be applicable in phantom and in patient studies. It is a promising tool for lesion delineation and volumetric quantification of PET lesions.

The long-term outcome of patients with polycystic liver disease treated with lanreotide

Aliment Pharmacol Ther 2012; 35: 266–274

Derivative-free generation and interpolation of convex Pareto optimal IMRT plans

In inverse treatment planning for intensity-modulated radiation therapy (IMRT), beamlet intensity levels in fluence maps of high-energy photon beams are optimized. Treatment plan evaluation criteria are used as objective functions to steer the optimization process. Fluence map optimization can be considered a multi-objective optimization problem, for which a set of Pareto optimal solutions exists: the Pareto efficient frontier (PEF). In this paper, a constrained optimization method is pursued to iteratively estimate the PEF up to some predefined error. We use the property that the PEF is convex for a convex optimization problem to construct piecewise-linear upper and lower bounds to approximate the PEF from a small initial set of Pareto optimal plans. A derivative-free Sandwich algorithm is presented in which these bounds are used with three strategies to determine the location of the next Pareto optimal solution such that the uncertainty in the estimated PEF is maximally reduced. We show that an intelligent initial solution for a new Pareto optimal plan can be obtained by interpolation of fluence maps from neighbouring Pareto optimal plans. The method has been applied to a simplified clinical test case using two convex objective functions to map the trade-off between tumour dose heterogeneity and critical organ sparing. All three strategies produce representative estimates of the PEF. The new algorithm is particularly suitable for dynamic generation of Pareto optimal plans in interactive treatment planning.

Convex reformulation of biologically-based multi-criteria intensity-modulated radiation therapy optimization including fractionation effects

Finding fluence maps for intensity-modulated radiation therapy (IMRT) can be formulated as a multi-criteria optimization problem for which Pareto optimal treatment plans exist. To account for the dose-per-fraction effect of fractionated IMRT, it is desirable to exploit radiobiological treatment plan evaluation criteria based on the linear-quadratic (LQ) cell survival model as a means to balance the radiation benefits and risks in terms of biologic response. Unfortunately, the LQ-model-based radiobiological criteria are nonconvex functions, which make the optimization problem hard to solve. We apply the framework proposed by Romeijn et al (2004 Phys. Med. Biol. 49 1991-2013) to find transformations of LQ-model-based radiobiological functions and establish conditions under which transformed functions result in equivalent convex criteria that do not change the set of Pareto optimal treatment plans. The functions analysed are: the LQ-Poisson-based model for tumour control probability (TCP) with and without inter-patient heterogeneity in radiation sensitivity, the LQ-Poisson-based relative seriality s-model for normal tissue complication probability (NTCP), the equivalent uniform dose (EUD) under the LQ-Poisson model and the fractionation-corrected Probit-based model for NTCP according to Lyman, Kutcher and Burman. These functions differ from those analysed before in that they cannot be decomposed into elementary EUD or generalized-EUD functions. In addition, we show that applying increasing and concave transformations to the convexified functions is beneficial for the piecewise approximation of the Pareto efficient frontier.

Dose-effect relationships for individual pelvic floor muscles and anorectal complaints after prostate radiotherapy.

PURPOSE To delineate the individual pelvic floor muscles considered to be involved in anorectal toxicity and to investigate dose-effect relationships for fecal incontinence-related complaints after prostate radiotherapy (RT). METHODS AND MATERIALS In 48 patients treated for localized prostate cancer, the internal anal sphincter (IAS) muscle, the external anal sphincter (EAS) muscle, the puborectalis muscle (PRM), and the levator ani muscles (LAM) in addition to the anal wall (Awall) and rectal wall (Rwall) were retrospectively delineated on planning computed tomography scans. Dose parameters were obtained and compared between patients with and without fecal urgency, incontinence, and frequency. Dose-effect curves were constructed. Finally, the effect of an endorectal balloon, which was applied in 28 patients, was investigated. RESULTS The total volume of the pelvic floor muscles together was about three times that of the Awall. The PRM was exposed to the highest RT dose, whereas the EAS received the lowest dose. Several anal and rectal dose parameters, as well as doses to all separate pelvic floor muscles, were associated with urgency, while incontinence was associated mainly with doses to the EAS and PRM. Based on the dose-effect curves, the following constraints regarding mean doses could be deduced to reduce the risk of urgency: ≤ 30 Gy to the IAS; ≤ 10 Gy to the EAS; ≤ 50 Gy to the PRM; and ≤ 40 Gy to the LAM. No dose-effect relationships for frequency were observed. Patients treated with an endorectal balloon reported significantly less urgency and incontinence, while their treatment plans showed significantly lower doses to the Awall, Rwall, and all pelvic floor muscles. CONCLUSIONS Incontinence-related complaints show specific dose-effect relationships to individual pelvic floor muscles. Dose constraints for each muscle can be identified for RT planning. When only the Awall is delineated, substantial components of the continence apparatus are excluded.

Neoadjuvant androgen deprivation for prostate volume reduction: The optimal duration in prostate cancer radiotherapy

OBJECTIVES For locally advanced prostate cancer, the results of radiotherapy are improved by combination with androgen deprivation therapy. Volume reduction achieved with neoadjuvant hormonal treatment can facilitate dose escalation without increasing the toxicity. The optimal duration of hormonal treatment, however, is unknown. The endpoint of this study is the optimal duration of androgen deprivation for prostate volume reduction in a cohort of patients scheduled for external beam radiotherapy. PATIENTS AND METHODS Twenty patients scheduled for external beam radiotherapy with cT2-3No/xMo prostate cancer were treated with a luteinizing hormone releasing hormone agonist (busereline) and nonsteroidal anti-androgen (nilutamide) for 9 months consecutively. Repeated CT scan examination was performed 3-monthly to measure prostate volumes until the start of radiation therapy. The analysis of volume reduction was performed with the Wilcoxon signed ranks test. RESULTS The baseline median prostate volume for the cohort of patients was 82 cc (95% CI: 61-104 cc) with a median volume reduction of 31% (95% CI: 26%-35%) (P < 0.0001) after 3 months of androgen deprivation. Between 3 and 6 months, a median volume reduction of 9% (95% CI: 4%-14%) (P < 0.0001) was observed. The effect was more pronounced in large prostates (>60 cc) than in small prostates (≤60 cc). In the total cohort of patients no significant volume reduction occurred between 6 and 9 months of maximal androgen blockade (MAB). CONCLUSIONS In this study, we have shown that the most significant prostate volume reduction is achieved after 3 months of MAB with a maximum reduction after 6 months. Therefore, the optimal duration of neoadjuvant androgen deprivation to reduce prostate volume before prostate cancer radiotherapy is 6 months. In small prostates 3 months of hormonal treatment may be enough for maximal volume reduction.

Differences in radiation dosimetry and anorectal function testing imply that anorectal symptoms may arise from different anatomic substrates.

PURPOSE To explore the influence of functional changes and dosimetric parameters on specific incontinence-related anorectal complaints after prostate external beam radiotherapy and to estimate dose-effect relations for the anal wall and rectal wall. METHODS AND MATERIALS Sixty patients, irradiated for localized prostate cancer, underwent anorectal manometry and barostat measurements to evaluate anal pressures, rectal capacity, and rectal sensory functions. In addition, 30 untreated men were analyzed as a control group. In 36 irradiated patients, the anal wall and rectal wall were retrospectively delineated on planning computed tomography scans, and dosimetric parameters were retrieved from the treatment plans. Functional and dosimetric parameters were compared between patients with and without complaints, focusing on urgency, incontinence, and frequency. RESULTS After external beam radiotherapy, reduced anal pressures and tolerated rectal volumes were observed, irrespective of complaints. Patients with urgency and/or incontinence showed significantly lower anal resting pressures (mean 38 and 39 vs. 49 and 50 mm Hg) and lower tolerated rectal pressures (mean 28 and 28 vs. 33 and 34 mm Hg), compared to patients without these complaints. In patients with frequency, almost all rectal parameters were reduced. Several dosimetric parameters to the anal wall and rectal wall were predictive for urgency (e.g., anal D(mean)>38 Gy), whereas some anal wall parameters correlated to incontinence and no dose-effect relation for frequency was found. CONCLUSIONS Anorectal function deteriorates after external beam radiotherapy. Different incontinence-related complaints show specific anorectal dysfunctions, suggesting different anatomic and pathophysiologic substrates: urgency and incontinence seem to originate from both anal wall and rectal wall, whereas frequency seems associated with rectal wall dysfunction. Also, dose-effect relations differed between these complaints. This implies that anal wall and rectal wall should be considered separate organs in radiotherapy planning.

Individualized Dose Prescription for Hypofractionation in Advanced Non-Small-Cell Lung Cancer Radiotherapy: An in silico Trial

PURPOSE Local tumor control and outcome remain poor in patients with advanced non-small-cell lung cancer (NSCLC) treated by external beam radiotherapy. We investigated the therapeutic gain of individualized dose prescription with dose escalation based on normal tissue dose constraints for various hypofractionation schemes delivered with intensity-modulated radiation therapy. METHODS AND MATERIALS For 38 Stage III NSCLC patients, the dose level of an existing curative treatment plan with standard fractionation (66 Gy) was rescaled based on dose constraints for the lung, spinal cord, esophagus, brachial plexus, and heart. The effect on tumor total dose (TTD) and biologic tumor effective dose in 2-Gy fractions (TED) corrected for overall treatment time (OTT) was compared for isotoxic and maximally tolerable schemes given in 15, 20, and 33 fractions. Rescaling was accomplished by altering the dose per fraction and/or the number of fractions while keeping the relative dose distribution of the original treatment plan. RESULTS For 30 of the 38 patients, dose escalation by individualized hypofractionation yielded therapeutic gain. For the maximally tolerable dose scheme in 33 fractions (MTD(33)), individualized dose escalation resulted in a 2.5-21% gain in TTD. In the isotoxic schemes, the number of fractions could be reduced with a marginal increase in TED. For the maximally tolerable dose schemes, the TED could be escalated up to 36.6%, and for all patients beyond the level of the isotoxic and the MTD(33) schemes (range, 3.3-36.6%). Reduction of the OTT contributed to the therapeutic gain of the shortened schemes. For the maximally tolerable schemes, the maximum esophageal dose was the dominant dose-limiting constraint in most patients. CONCLUSIONS This modeling study showed that individualized dose prescription for hypofractionation in NSCLC radiotherapy, based on scaling of existing treatment plans up to normal tissue dose constraints, enables dose escalation with therapeutic gain in 79% of the cases.