Gert De Meerleer

Evidence behind use of intensity-modulated radiotherapy: a systematic review of comparative clinical studies

Since its introduction more than a decade ago, intensity-modulated radiotherapy (IMRT) has spread to most radiotherapy departments worldwide for a wide range of indications. The technique has been rapidly implemented, despite an incomplete understanding of its advantages and weaknesses, the challenges of IMRT planning, delivery, and quality assurance, and the substantially increased cost compared with non-IMRT. Many publications discuss the theoretical advantages of IMRT dose distributions. However, the key question is whether the use of IMRT can be exploited to obtain a clinically relevant advantage over non-modulated external-beam radiation techniques. To investigate which level of evidence supports the routine use of IMRT for various disease sites, we did a review of clinical studies that reported on overall survival, disease-specific survival, quality of life, treatment-induced toxicity, or surrogate endpoints. This review shows evidence of reduced toxicity for various tumour sites by use of IMRT. The findings regarding local control and overall survival are generally inconclusive.

Radiotherapy of prostate cancer with or without intensity modulated beams: a planning comparison

PURPOSE To evaluate whether intensity modulated radiotherapy (IMRT) by static segmented beams allows the dose to the main portion of the prostate target to escalate while keeping the maximal dose at the anterior rectal wall at 72 Gy. The value of such IMRT plans was analyzed by comparison with non-IMRT plans using the same beam incidences. METHODS AND MATERIALS We performed a planning study on the CT data of 32 consecutive patients with localized adenocarcinoma of the prostate. Three fields in the transverse plane with gantry angles of 0 degrees, 116 degrees, and 244 degrees were isocentered at the center of gravity of the target volume (prostate and seminal vesicles). The geometry of the beams was determined by beams eye view autocontouring of the target volume with a margin of 1.5 cm. In study 1, the beam weights were determined by a human planner (3D-man) or by computer optimization using a biological objective function with (3D-optim-lim) or without (3D-optim-unlim) a physical term to limit target dose inhomogeneity. In study 2, the 3 beam incidences mentioned above were used and in-field uniform segments were added to allow IMRT. Plans with (IMRT-lim) or without (IMRT-unlim) constraints on target dose inhomogeneity were compared. In the IMRT-lim plan, target dose inhomogeneity was constrained between 15% and 20%. After optimization, plans in both studies were normalized to a maximal rectal dose of 72 Gy. Biological (tumor control probability [TCP], normal tissue complication probability [NTCP]) and physical indices for tumor control and normal tissue complication probabilities were computed, as well as the probability of the uncomplicated local control (P+). RESULTS The IMRT-lim plan was superior to all other plans concerning TCP (p < 0.0001). The IMRT-unlim plan had the worst TCP. Within the 3D plans, the 3D-optim-unlim had the best TCP, which was significantly different from the 3D-optim-lim plan (p = 0.0003). For rectal NTCP, both IMRT plans were superior to all other plans (p < 0.0001). The IMRT-unlim plan was significantly better than the IMRT-lim plan (p < 0.0001). Again, 3D-optim-unlim was superior to the other 3D plans (p < 0. 0007). Physical endpoints for target showed the mean minimal target dose to be the lowest in the IMRT-unlim plan, caused by a large target dose inhomogeneity (TDI). Medial target dose, 90th percentile, and maximal target dose were significantly higher in both IMRT plans. Physical endpoints for the rectum showed the IMRT-unlim plan to be superior compared to all other plans. There was a strong correlation between the 65th percentile (Rp65) and rectal NTCP (correlation coefficient > or =89%). For bladder, maximal bladder dose was significantly higher in the IMRT-unlim plan compared to all other plans (p < or = 0.0001).P+ was significantly higher in both IMRT-plans than in all other plans. The 3D-optim-unlim plan was significantly better than the two other 3D plans (p < 0.0001). CONCLUSION IMRT significantly increases the ratio of TCP over NTCP of the rectum in the treatment of prostate cancer. However, constraints for TDI are needed, because a high degree of TDI reduced minimal target dose. IMRT improved uncomplicated local control probability. In our department, IMRT by static segmented beams is planned and delivered in a cost-effective way. IMRT-lim has replaced non-modulated conformal radiotherapy as the standard treatment for prostate cancer.

Metastasis-directed Therapy of Regional and Distant Recurrences After Curative Treatment of Prostate Cancer: A Systematic Review of the Literature

CONTEXT The introduction of novel imaging modalities has increased the detection of oligometastatic prostate cancer (PCa) recurrence, potentially justifying the use of a metastasis-directed therapy (MDT) with surgery or radiotherapy (RT) rather than a systemic approach. OBJECTIVE To perform a systematic review of MDT for oligometastatic PCa recurrence. EVIDENCE ACQUISITION This systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. We searched the Medline and Embase databases from 1946 to February 2014 for studies reporting on biochemical or clinical progression and/or toxicity or complications of MDT (RT or surgery). Reports were excluded if these end points could not be ascertained or separately analysed, or if insufficient details were provided. Methodological quality was assessed using an 18-item validated quality appraisal tool for case series. EVIDENCE SYNTHESIS Fifteen single-arm case series reporting on a total of 450 patients met the inclusion criteria. Seven studies were considered of acceptable quality. Oligometastatic PCa recurrence was diagnosed with positron emission tomography with coregistered computed tomography in most of the patients (98%). Nodal, bone, and visceral metastases were treated in 78%, 21%, and 1%, respectively. Patients were treated with either RT (66%) or lymph node dissection (LND) (34%). Adjuvant androgen deprivation was given in 61% of patients (n=275). In the case of nodal metastases, prophylactic nodal irradiation was administered in 49% of patients (n=172). Overall, 51% of patients were progression free 1-3 yr after salvage MDT, with most of them receiving adjuvant treatment. For RT, grade 2 toxicity was observed in 8.5% of patients, with one case of grade 3 toxicity. In the case of LND, 11% and 12% of grade 2 and grade 3 complications, respectively, were reported. CONCLUSIONS MDT is a promising approach for oligometastatic PCa recurrence, but the low level of evidence generated by small case series does not allow extrapolation to a standard of care. PATIENT SUMMARY We performed a systematic review to assess complications and outcomes of treating oligometastatic prostate cancer recurrence with surgery or radiotherapy. We concluded that although this approach is promising, it requires validation in randomised controlled trials.

Interobserver Delineation Variation Using CT versus Combined CT + MRI in Intensity–Modulated Radiotherapy for Prostate Cancer

Purpose:To quantify interobserver variation of prostate and seminal vesicle delineations using CT only versus CT + MRI in consensus reading with a radiologist.Material and Methods:The prostate and seminal vesicles of 13 patients treated with intensity–modulated radiotherapy for prostatic adenocarcinoma were retrospectively delineated by three radiation oncologists on CT only and on CT + MRI in consensus reading with a radiologist. The volumes and margin positions were calculated and intermodality and interobserver variations were assessed for the clinical target volume (CTV), seminal vesicles, prostate and three prostatic subdivisions (apical, middle and basal third).Results:Using CT + MRI as compared to CT alone, the mean CTV, prostate and seminal vesicle volumes significantly decreased by 6.54%, 5.21% and 10.47%, respectively. More importantly, their standard deviations significantly decreased by 63.06%, 62.65% and 44.83%, respectively. The highest level of variation was found at the prostatic apex, followed by the prostatic base and seminal vesicles.Conclusion: Addition of MRI to CT in consensus reading with a radiologist results in a moderate decrease of the CTV, but an important decrease of the interobserver delineation variation, especially at the prostatic apex.Ziel:Quantifizierung der Interobserver–Variation bei der Abgrenzung von Prostata und Samenblasen im CT im Vergleich zur Kombination CT und MRT nach einer Konsensusbefundung mit einem Radiologen.Material und Methodik: Die Prostata und die Samenblasen von 13 Patienten, die für eine intensitätsmodulierte Strahlentherapie wegen Adenokarzinoms der Prostata vorgesehen waren, wurden retrospektiv im CT und mit der Kombination CT und MRT durch drei Strahlentherapeuten nach einer Konsensusbefundung mit einem Radiologen abgegrenzt. Volumen und Randpositionen wurden berechnet und die Intermodalitäts- bzw. Interobservervariationen für das klinische Zielvolumen (CTV), die Samenblasen, die Prostata und drei Prostatasegmente (apikales, mittleres und basales Drittel) beurteilt.Ergebnisse:Mit der Kombination von CT und MRT verringerte sich im Vergleich zur alleinigen CT der Mittelwert für das CTV, Prostata– und Samenblasenvolumen signifikant um 6,54%, 5,21% und 10,47%. Von größerer Bedeutung war die signifikante Abnahme der Standardabweichungen um 63,06%, 62,65% und 44,83%. Die höchste Variation wurde im Apex der Prostata festgestellt, gefolgt von der Basis der Prostata und den Samenblasen.Schlussfolgerung:Die Kombination von CT und MRT nach Konsensus mit einem Radiologen resultiert in einer bedeutenden Abnahme der Interobservervariation bei der anatomischen Abgrenzung, insbesondere im Bereich des Apex der Prostata, und zusätzlich in einer moderaten Verringerung des CTV.

Intensity-Modulated Radiotherapy as Primary Therapy for Prostate Cancer: Report on Acute Toxicity After Dose Escalation With Simultaneous Integrated Boost to Intraprostatic Lesion

PURPOSE To report on the acute toxicity of a third escalation level using intensity-modulated radiotherapy for prostate cancer (PCa) and the acute toxicity resulting from delivery of a simultaneous integrated boost (SIB) to an intraprostatic lesion (IPL) detected on magnetic resonance imaging (MRI), with or without spectroscopy. METHODS AND MATERIALS Between January 2002 and March 2007, we treated 230 patients with intensity-modulated radiotherapy to a third escalation level as primary therapy for prostate cancer. If an IPL (defined by MRI or MRI plus spectroscopy) was present, a SIB was delivered to the IPL. To report on acute toxicity, patients were seen weekly during treatment and 1 and 3 months after treatment. Toxicity was scored using the Radiation Therapy Oncology Group toxicity scale, supplemented by an in-house-developed scoring system. RESULTS The median dose to the planning target volume was 78 Gy. An IPL was found in 118 patients. The median dose to the MRI-detected IPL and MRI plus spectroscopy-detected IPL was 81 Gy and 82 Gy, respectively. No Grade 3 or 4 acute gastrointestinal toxicity developed. Grade 2 acute gastrointestinal toxicity was present in 26 patients (11%). Grade 3 genitourinary toxicity was present in 15 patients (7%), and 95 patients developed Grade 2 acute genitourinary toxicity (41%). No statistically significant increase was found in Grade 2-3 acute gastrointestinal or genitourinary toxicity after a SIB to an IPL. CONCLUSION The results of our study have shown that treatment-induced acute toxicity remains low when intensity-modulated radiotherapy to 80 Gy as primary therapy for prostate cancer is used. In addition, a SIB to an IPL did not increase the severity or incidence of acute toxicity.

Salvage Stereotactic Body Radiotherapy for Patients With Limited Prostate Cancer Metastases: Deferring Androgen Deprivation Therapy

BACKGROUND We investigated whether repeated stereotactic body radiotherapy (SBRT) of oligometastatic disease is able to defer the initiation of palliative androgen deprivation therapy (ADT) in patients with low-volume bone and lymph node metastases. PATIENTS AND METHODS Patients with up to 3 synchronous metastases (bone and/or lymph nodes) diagnosed on positron emission tomography, following biochemical recurrence after local curative treatment, were treated with (repeated) SBRT to a dose of 50 Gy in 10 fractions. Androgen deprivation therapy-free survival (ADT-FS) defined as the time interval between the first day of SBRT and the initiation of ADT was the primary end point. ADT was initiated if more than 3 metastases were detected during follow-up even when patients were still asymptomatic or in case of a prostate specific antigen elevation above 50 ng/mL in the absence of metastases. Secondary end points were local control, clinical progression-free survival, and toxicity. Toxicity was scored using the Common Terminology Criteria for Adverse Events. RESULTS We treated 24 patients with a median follow-up of 24 months. Ten patients started with ADT resulting in a median ADT-FS of 38 months. The 2-year local control and clinical progression-free survival was 100% and 42%, respectively. Eleven and 3 patients, respectively, required a second and third salvage treatment for metachronous low-volume metastatic disease. No grade 3 toxicity was observed. CONCLUSION Repeated salvage SBRT is feasible, well tolerated and defers palliative ADT with a median of 38 months in patients with limited bone or lymph node PCa metastases.

Combined magnetic resonance imaging and spectroscopy in the assessment of high grade prostate carcinoma in patients with elevated PSA: A single-institution experience of 356 patients

PURPOSE To assess the ability of combined whole-prostate magnetic resonance imaging and magnetic resonance spectroscopy imaging (MRI+MRSI) to predict the presence or absence of high grade (Gleason 4+3 or higher) prostate carcinoma in men with elevated PSA. MATERIALS AND METHODS Between March 2002 and September 2007, 356 subjects (mean serum PSA 11.5 ng/ml, range 0.4-133.0 ng/ml) were examined with fast-T2-weighted magnetic resonance imaging (MRI) and 3D-magnetic resonance spectroscopy imaging (MRSI) on a 1.5T scanner. Prostate cancer was histopathologically proven in 220 patients (41 with high grade and 179 with lower grade cancer) and non-evidence of cancer was determined after at least 12 months (mean 21 months) clinical follow-up in 136 subjects. The sensitivity, false positive rate, and negative predictive value of MRI+MRSI were calculated using histopathology and follow-up results as reference standard. RESULTS MRI+MRSI had a significantly higher sensitivity for high grade tumors (92.7%) than for lower grade tumors (67.6%), and was false positive in only 7.4% of patients with non-evidence of prostate cancer. For exclusion of a high grade tumor, MRI+MRSI had a negative predictive value of 98.4%. CONCLUSIONS MRI+MRSI holds great potential for predicting presence or absence of high grade tumors in men with elevated PSA. This can be important in the selection of patients for active surveillance, or in the decision to rebiopsy patients with prior negative biopsies.

Clinical delivery of intensity modulated conformal radiotherapy for relapsed or second-primary head and neck cancer using a multileaf collimator with dynamic control

BACKGROUND AND PURPOSE Concave dose distributions generated by intensity modulated radiotherapy (IMRT) were applied to re-irradiate three patients with pharyngeal cancer. PATIENTS, MATERIALS AND METHODS Conventional radiotherapy for oropharyngeal (patients 1 and 3) or nasopharyngeal (patient 2) cancers was followed by relapsing or new tumors in the nasopharynx (patients 1 and 2) and hypopharynx (patient 3). Six non-opposed coplanar intensity modulated beams were generated by combining non-modulated beamparts with intensities (weights) obtained by minimizing a biophysical objective function. Beamparts were delivered by a dynamic MLC (Elekta Oncology Systems, Crawley, UK) forced in step and shoot mode. RESULTS AND CONCLUSIONS Median PTV-doses (and ranges) for the three patients were 73 (65-78), 67 (59-72) and 63 (48-68) Gy. Maximum point doses to brain stem and spinal cord were, respectively, 67 Gy (60% of volume below 30 Gy) and 32 Gy (97% below 10 Gy) for patient 1; 60 Gy (69% below 30 Gy) and 34 Gy (92% below 10 Gy) for patient 2 and 21 Gy (96% below 10 Gy) at spinal cord for patient 3. Maximum point doses to the mandible were 69 Gy for patient 1 and 64 Gy for patient 2 with, respectively, 66 and 92% of the volume below 20 Gy. A treatment session, using the dynamic MLC, was finished within a 15-min time slot.

Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis

UNLABELLED The literature on metastasis-directed therapy for oligometastatic prostate cancer (PCa) recurrence consists of small heterogeneous studies. This study aimed to reduce the heterogeneity by pooling individual patient data from different institutions treating oligometastatic PCa recurrence with stereotactic body radiotherapy (SBRT). We focussed on patients who were treatment naive, with the aim of determining if SBRT could delay disease progression. We included patients with three or fewer metastases. The Kaplan-Meier method was used to estimate distant progression-free survival (DPFS) and local progression-free survival (LPFS). Toxicity was scored using the Common Terminology Criteria for Adverse Events. In total, 163 metastases were treated in 119 patients. The median DPFS was 21 mo (95% confidence interval, 15-26 mo). A lower radiotherapy dose predicted a higher local recurrence rate with a 3-yr LPFS of 79% for patients treated with a biologically effective dose ≤100Gy versus 99% for patients treated with >100Gy (p=0.01). Seventeen patients (14%) developed toxicity classified as grade 1, and three patients (3%) developed grade 2 toxicity. No grade ≥3 toxicity occurred. These results should serve as a benchmark for future prospective trials. PATIENT SUMMARY This multi-institutional study pools all of the available data on the use of stereotactic body radiotherapy for limited prostate cancer metastases. We concluded that this approach is safe and associated with a prolonged treatment progression-free survival.

Soluble cadherins as cancer biomarkers

Molecular activities, regulating a balanced tissue organisation, are frequently disturbed during cancer progression. These include protein ectodomain shedding, a post-translational process that substantially changes the functional properties of the substrate protein. In comparison with normal epithelia, cancer cells almost invariably show diminished cadherin-mediated intercellular adhesion. This review will address cadherin ectodomain shedding and its functional consequence in normal physiology and in the tumor environment. Soluble cadherin fragments may retain specific biological activities during cancer cell invasion, angiogenesis and perineural invasion. When diffusion barriers disappear, soluble cadherins are detected in sera from cancer patients. Soluble N-(neural) cadherin may represent a novel diagnosis/prognostic biomarker showing a correlation with PSA in sera of prostate cancer patients. Furthermore, therapeutic monitoring in pancreas adenomacarcinoma revealed a correlation between circulating soluble N-cadherin and CA 19-9. A better understanding of cadherin regulation in cancer progression will likely increase our awareness of the importance of the combinatorial signals that regulate tissue integrity and eventually result in the identification of new therapeutics targeting cadherins.