Wilfried De Neve

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.

Accuracy of patient dose calculation for lung IMRT: A comparison of Monte Carlo, convolution/superposition, and pencil beam computations

The accuracy of dose computation within the lungs depends strongly on the performance of the calculation algorithm in regions of electronic disequilibrium that arise near tissue inhomogeneities with large density variations. There is a lack of data evaluating the performance of highly developed analytical dose calculation algorithms compared to Monte Carlo computations in a clinical setting. We compared full Monte Carlo calculations (performed by our Monte Carlo dose engine MCDE) with two different commercial convolution/superposition (CS) implementations (Pinnacle-CS and Helax-TMSs collapsed cone model Helax-CC) and one pencil beam algorithm (Helax-TMSs pencil beam model Helax-PB) for 10 intensity modulated radiation therapy (IMRT) lung cancer patients. Treatment plans were created for two photon beam qualities (6 and 18 MV). For each dose calculation algorithm, patient, and beam quality, the following set of clinically relevant dose-volume values was reported: (i) minimal, median, and maximal dose (Dmin, D50, and Dmax) for the gross tumor and planning target volumes (GTV and PTV); (ii) the volume of the lungs (excluding the GTV) receiving at least 20 and 30 Gy (V20 and V30) and the mean lung dose; (iii) the 33rd percentile dose (D33) and Dmax delivered to the heart and the expanded esophagus; and (iv) Dmax for the expanded spinal cord. Statistical analysis was performed by means of one-way analysis of variance for repeated measurements and Tukey pairwise comparison of means. Pinnacle-CS showed an excellent agreement with MCDE within the target structures, whereas the best correspondence for the organs at risk (OARs) was found between Helax-CC and MCDE. Results from Helax-PB were unsatisfying for both targets and OARs. Additionally, individual patient results were analyzed. Within the target structures, deviations above 5% were found in one patient for the comparison of MCDE and Helax-CC, while all differences between MCDE and Pinnacle-CS were below 5%. For both Pinnacle-CS and Helax-CC, deviations from MCDE above 5% were found within the OARs: within the lungs for two (6 MV) and six (18 MV) patients for Pinnacle-CS, and within other OARs for two patients for Helax-CC (for Dmax of the heart and D33 of the expanded esophagus) but only for 6 MV. For one patient, all four algorithms were used to recompute the dose after replacing all computed tomography voxels within the patients skin contour by water. This made all differences above 5% between MCDE and the other dose calculation algorithms disappear. Thus, the observed deviations mainly arose from differences in particle transport modeling within the lungs, and the commissioning of the algorithms was adequately performed (or the commissioning was less important for this type of treatment). In conclusion, not one pair of the dose calculation algorithms we investigated could provide results that were consistent within 5% for all 10 patients for the set of clinically relevant dose-volume indices studied. As the results from both CS algorithms differed significantly, care should be taken when evaluating treatment plans as the choice of dose calculation algorithm may influence clinical results. Full Monte Carlo provides a great benchmarking tool for evaluating the performance of other algorithms for patient dose computations.

Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience

Charged particle therapy is generally regarded as cutting-edge technology in oncology. Many proton therapy centres are active in the USA, Europe, and Asia, but only a few centres use heavy ions, even though these ions are much more effective than x-rays owing to the special radiobiological properties of densely ionising radiation. The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. So far, more than 8000 patients have had this treatment at NIRS, and the centre thus has by far the greatest experience in carbon ion treatment worldwide. A panel of radiation oncologists, radiobiologists, and medical physicists from the USA and Europe recently completed peer review of the carbon ion therapy at NIRS. The review panel had access to the latest developments in treatment planning and beam delivery and to all updated clinical data produced at NIRS. A detailed comparison with the most advanced results obtained with x-rays or protons in Europe and the USA was then possible. In addition to those tumours for which carbon ions are known to produce excellent results, such as bone and soft-tissue sarcoma of the skull base, head and neck, and pelvis, promising data were obtained for other tumours, such as locally recurrent rectal cancer and pancreatic cancer. The most serious impediment to the worldwide spread of heavy ion therapy centres is the high initial capital cost. The 20 years of clinical experience at NIRS can help guide strategic decisions on the design and construction of new heavy ion therapy centres.

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.

Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

PURPOSE To investigate the feasibility of adaptive intensity-modulated radiation therapy (IMRT) using dose painting by numbers (DPBN) for head-and-neck cancer. METHODS AND MATERIALS Each patients treatment used three separate treatment plans: fractions 1-10 used a DPBN ([(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography [(18)F-FDG-PET]) voxel intensity-based IMRT plan based on a pretreatment (18)F-FDG-PET/computed tomography (CT) scan; fractions 11-20 used a DPBN plan based on a (18)F-FDG-PET/CT scan acquired after the eighth fraction; and fractions 21-32 used a conventional (uniform dose) IMRT plan. In a Phase I trial, two dose prescription levels were tested: a median dose of 80.9 Gy to the high-dose clinical target volume (CTV(high_dose)) (dose level I) and a median dose of 85.9 Gy to the gross tumor volume (GTV) (dose level II). Between February 2007 and August 2009, 7 patients at dose level I and 14 patients at dose level II were enrolled. RESULTS All patients finished treatment without a break, and no Grade 4 acute toxicity was observed. Treatment adaptation (i.e., plans based on the second (18)F-FDG-PET/CT scan) reduced the volumes for the GTV (41%, p = 0.01), CTV(high_dose) (18%, p = 0.01), high-dose planning target volume (14%, p = 0.02), and parotids (9-12%, p < 0.05). Because the GTV was much smaller than the CTV(high_dose) and target adaptation, further dose escalation at dose level II resulted in less severe toxicity than that observed at dose level I. CONCLUSION To our knowledge, this represents the first clinical study that combines adaptive treatments with dose painting by numbers. Treatment as described above is feasible.

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.

An implementation strategy for IMRT of ethmoid sinus cancer with bilateral sparing of the optic pathways.

PURPOSE To develop a protocol for the irradiation of ethmoid sinus cancer, with the aim of sparing binocular vision; of developing a strategy of intensity-modulated radiation therapy (IMRT) planning that produces dose distributions that (1) are consistent with the protocol prescriptions and (2) are deliverable by static segmental IMRT techniques within a 15-minute time slot; of fine tuning the implementation strategy to a class solution approach that is sufficiently automated and efficient, allowing routine clinical application; of reporting on the early clinical implementation involving 11 patients between February 1999 and July 2000. patients and methods: Eleven consecutive T1-4N0M0 ethmoid sinus cancer patients were enrolled in the study. For Patients 1-8, a first protocol was implemented, defining a planning target volume prescription dose of 60 to 66 Gy in 30-33 fractions and a maximum dose (Dmax) of 50 Gy to optic pathway structures and spinal cord and limit of 60 Gy to brainstem. For Patients 9-11, an adapted (now considered mature) protocol was implemented, defining a (planning target volume) prescription dose of 70 Gy in 35 fractions and a Dmax to optic pathway structures and brainstem of 60 Gy and to spinal cord of 50 Gy. RESULTS The class solution-directed strategy developed during this study reduced the protocol translation process from a few days to about 2 hours of planner time. The mature class solution involved the use of 7 beam incidences (20-37 segments), which could be delivered within a 15-minute time slot. Acute side effects were limited and mild. None of the patients developed dry eye syndrome or other visual disturbances. The follow-up period is too short for detection of retinopathy or optic nerve and chiasm toxicity. CONCLUSION Conventional radiotherapy of ethmoid sinus tumors is associated with serious morbidity, including blindness. We hypothesize that IMRT has the potential to save binocular vision. The dose to the optic pathway structures can be reduced selectively by IMRT. Further enrollment of patients and longer follow-up will show whether the level of reduction tested by the clinical protocol is sufficient to save binocular vision. An adaptive strategy of IMRT planning was too inefficient for routine clinical practice. A class solution-directed strategy improved efficiency by eliminating human trial and error during the IMRT planning process.

Postoperative intensity-modulated radiotherapy in sinonasal carcinoma - Clinical results in 39 patients

Carcinoma of the paranasal sinuses is rare. Standard therapeutic modalities consist of surgery and radiotherapy (RT). Because of the often advanced stage and the vicinity of optic structures, RT‐induced ocular toxicity is a feared side effect of conventional RT. Intensity‐modulated radiotherapy (IMRT) is a relatively new technique, which is implemented with the hypothesis that, compared with conventional RT, it would result in a lower rate of ocular toxicity for an equal local control (LC).