Liv Veldeman

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.

Acute Normal Tissue Reactions in Head-and-Neck Cancer Patients Treated With IMRT: Influence of Dose and Association With Genetic Polymorphisms in DNA DSB Repair Genes

PURPOSE To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy. MATERIALS AND METHODS The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volume histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays. RESULTS The mean dose (D(mean)) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%. CONCLUSIONS The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D(mean) to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.

Hypofractionated whole breast irradiation for patients with large breasts: A randomized trial comparing prone and supine positions

BACKGROUND AND PURPOSE Comparison of acute toxicity of whole-breast irradiation (WBI) in prone and supine positions. MATERIALS AND METHODS This non-blinded, randomized, prospective, mono-centric trial was undertaken between December 29, 2010, and December 12, 2012. One hundred patients with large breasts were randomized between supine multi beam (MB) and prone tangential field (TF) intensity modulated radiotherapy (IMRT). Dose-volume parameters were assessed for the breast, heart, left anterior descending coronary artery (LAD), ipsilateral lung and contralateral breast. The primary endpoint was acute moist skin desquamation. Secondary endpoints were dermatitis, edema, pruritus and pain. RESULTS Prone treatment resulted in: improved dose coverage (p<0.001); better homogeneity (p<0.001); less volumes of over-dosage (p=0.001); reduced acute skin desquamation (p<0.001); a 3-fold decrease of moist desquamation p=0.04 (chi-square), p=0.07 (Fishers exact test)); lower incidence of dermatitis (p<0.001), edema (p=0.005), pruritus (p=0.06) and pain (p=0.06); 2- to 4-fold reduction of grades 2-3 toxicity; lower ipsilateral lung (p<0.001) and mean LAD (p=0.007) dose; lower, though statistically non-significant heart and maximum LAD. CONCLUSIONS This study provides level I evidence for replacing the supine standard treatment by prone IMRT for whole-breast irradiation in patients with large breasts. A confirmatory trial in a multi-institutional setting is warranted.

Whole breast radiotherapy in prone and supine position: is there a place for multi-beam IMRT?

BackgroundEarly stage breast cancer patients are long-term survivors and finding techniques that may lower acute and late radiotherapy-induced toxicity is crucial. We compared dosimetry of wedged tangential fields (W-TF), tangential field intensity-modulated radiotherapy (TF-IMRT) and multi-beam IMRT (MB-IMRT) in prone and supine positions for whole-breast irradiation (WBI).MethodsMB-IMRT, TF-IMRT and W-TF treatment plans in prone and supine positions were generated for 18 unselected breast cancer patients. The median prescription dose to the optimized planning target volume (PTVoptim) was 50 Gy in 25 fractions. Dose-volume parameters and indices of conformity were calculated for the PTVoptim and organs-at-risk.ResultsProne MB-IMRT achieved (p<0.01) the best dose homogeneity compared to WTF in the prone position and WTF and MB-IMRT in the supine position. Prone IMRT scored better for all dose indices. MB-IMRT lowered lung and heart dose (p<0.05) in supine position, however the lowest ipsilateral lung doses (p<0.001) were in prone position. In left-sided breast cancer patients population averages for heart sparing by radiation dose was better in prone position; though non-significant. For patients with a PTVoptim volume ≥600 cc heart dose was consistently lower in prone position; while for patients with smaller breasts heart dose metrics were comparable or worse compared to supine MB-IMRT. Doses to the contralateral breast were similar regardless of position or technique. Dosimetry of prone MB-IMRT and prone TF-IMRT differed slightly.ConclusionsMB-IMRT is the treatment of choice in supine position. Prone IMRT is superior to any supine treatment for right-sided breast cancer patients and left-sided breast cancer patients with larger breasts by obtaining better conformity indices, target dose distribution and sparing of the organs-at-risk. The influence of treatment techniques in prone position is less pronounced; moreover dosimetric differences between TF-IMRT and MB-IMRT are rather small.

Alternated prone and supine whole-breast irradiation using IMRT: setup precision, respiratory movement and treatment time.

PURPOSE The objective of this study was to compare setup precision, respiration-related breast movement and treatment time between prone and supine positions for whole-breast irradiation. METHODS AND MATERIALS Ten patients with early-stage breast carcinoma after breast-conserving surgery were treated with prone and supine whole breast-irradiation in a daily alternating schedule. Setup precision was monitored using cone-beam computed tomography (CBCT) imaging. Respiration-related breast movement in the vertical direction was assessed by magnetic sensors. The time needed for patient setup and for the CBCT procedure, the beam time, and the length of the whole treatment slot were also recorded. RESULTS Random and systematic errors were not significantly different between positions in individual patients for each of the three axes (left-right, longitudinal, and vertical). Respiration-related movement was smaller in prone position, but about 80% of observations showed amplitudes <1 mm in both positions. Treatment slots were longer in prone position (21.2 ± 2.5 min) than in supine position (19.4 ± 0.8 min; p = 0.044). CONCLUSION Comparison of setup precision between prone and supine position in the same patient showed no significant differences in random and systematic errors. Respiratory movement was smaller in prone position. The longer treatment slots in prone position can probably be attributed to the higher repositioning need.

Delineation of the Postprostatectomy Prostate Bed Using Computed Tomography: Interobserver Variability Following the EORTC Delineation Guidelines

PURPOSE The present study aims to assess the interobserver agreement of prostate bed delineation after radical prostatectomy using CT alone as proposed by the European Organization for Research and Treatment of Cancer (EORTC) guidelines. METHODS AND MATERIALS Six observers delineated the postoperative prostate bed (PB) and the original seminal vesicle position or remnants (SV) of 10 patients according to the EORTC guidelines. Contours were then compared for agreement between observers (the apparent volume overlap and generalized kappa statistics). Standard deviations were also calculated to measure the variability of the position of the outer margins. RESULTS The mean volume of 100% agreement (±1 standard deviation, SD) was only 5.0 (±3.3) ml for the PB and 0.9 (±1.5) ml for the SV, whereas the mean union of all contours (±1 SD) was 41.1 (±11.8) ml and 25.3 (±13.4) ml, respectively. The mean overall agreement corrected for chance was moderate for both the PB (mean kappa, 0.49; range, 0.35-0.62) and SV (mean kappa, 0.42; range, 0.22-0.59). The overall SD of the outer margins of the PB ranged from 4.6 to 7.0 mm CONCLUSION The delineation of the postprostatectomy bed using CT shows only a moderate observer agreement when following the EORTC guidelines.

Heart dose reduction by prone deep inspiration breath hold in left-sided breast irradiation

BACKGROUND AND PURPOSE Cardiac disease has been related to heart dose after left-sided breast radiotherapy. This trial evaluates the heart sparing ability and feasibility of deep inspiration breath hold (DIBH) in the prone position for left-sided whole breast irradiation (WBI). MATERIALS AND METHODS Twelve patients underwent CT-simulation in supine shallow breathing (SB), supine DIBH, prone SB and prone DIBH. A validation cohort of 38 patients received prone SB and prone DIBH CT-scans; the last 30 patients were accepted for prone DIBH treatment. WBI was planned with a prescription dose of 40.05 Gy. RESULTS DIBH was able to reduce (p<0.001) heart dose in both positions, with results for prone DIBH at least as favorable as for supine DIBH. Mean heart dose was lowered from 2.2 Gy for prone SB to 1.3 Gy for prone DIBH (p<0.001), while preserving the lung sparing ability of prone positioning. Moreover prone DIBH nearly consistently reduced mean heart dose to less then 2 Gy, regardless of breast volume. All patients were able to perform the simulation procedure, 28/30 patients were treated with prone DIBH. CONCLUSIONS This trial demonstrates the ability and feasibility of prone DIBH to acquire optimal heart and lung sparing for left-sided WBI.

Vessel based delineation guidelines for the elective lymph node regions in breast cancer radiation therapy - PROCAB guidelines

OBJECTIVE A national project to improve the quality of breast radiation therapy was started, named PROCAB (PROject on CAncer of the Breast). One of the objectives was to reach a national consensus guideline for the delineation of the regional lymph node areas in breast radiation therapy. METHODS The realization of the new guidelines was a step by step process that started with multiple expert meetings where the existing guidelines were analyzed and the delineations of the lymph node regions were performed together with a surgeon, specialized in the anatomy of the drainage of the breast. RESULTS The delineation guidelines are vessel-based. Since the occurrence of pathological lymph nodes is typically around the veins, the cranial and caudal borders of all different nodal regions are based on a 5mm margin around the veins, except for the parasternal lymph node area. Compared to the existing guidelines there are some major changes. CONCLUSION With this project a national as well as a European (ESTRO) consensus guideline for the delineation of the regional lymph node areas in breast RT is reached. The new delineation atlas is vessel-based and no longer field-based.

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model. Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

In vitro cellular radiosensitivity in relationship to late normal tissue reactions in breast cancer patients: a multi-endpoint case-control study

Abstract Purpose: A minority of patients exhibits severe late normal tissue toxicity after radiotherapy (RT), possibly related to their inherent individual radiation sensitivity. This study aimed to evaluate four different candidate in vitro cellular radiosensitivity assays for prediction of late normal tissue reactions, in a retrospective matched case-control set-up of breast cancer patients. Methods: The study population consists of breast cancer patients expressing severe radiation toxicity (12 cases) and no or minimal reactions (12 controls), with a follow-up for at least 3 years. Late adverse reactions were evaluated by comparing standardized photographs pre- and post-RT resulting in an overall cosmetic score and by clinical examination using the LENT-SOMA scale. Four cellular assays on peripheral blood lymphocytes reported to be associated with normal tissue reactions were performed after in vitro irradiation of patient blood samples to compare case and control radiation responses: radiation-induced CD8+ late apoptosis, residual DNA double-strand breaks, G0 and G2 micronucleus assay. Results: A significant difference was observed for all cellular endpoints when matched cases and controls were compared both pairwise and grouped. However, it is important to point out that most case-control pairs showed a substantial overlap in standard deviations, which questions the predictive value of the individual assays. The apoptosis assay performed best, with less apoptosis seen in CD8+ lymphocytes of the cases (average: 14.45%) than in their matched controls (average: 30.64%) for 11 out of 12 patient pairs (p < .01). The number of residual DNA DSB was higher in cases (average: 9.92 foci/cell) compared to their matched control patients (average: 9.17 foci/cell) (p < .01). The average dose response curve of the G0 MN assay for cases lies above the average dose response curve of the controls. Finally, a pairwise comparison of the G2 MN results showed a higher MN yield for cases (average: 351 MN/1000BN) compared to controls (average: 219 MN/1000BN) in 9 out of 10 pairs (p < .01). Conclusion: This matched case-control study in breast cancer patients, using different endpoints for in vitro cellular radiosensitivity related to DNA repair and apoptosis, suggests that patients’ intrinsic radiosensitivity is involved in the development of late normal tissue reactions after RT. Larger prospective studies are warranted to validate the retrospective findings and to use in vitro cellular assays in the future to predict late normal tissue radiosensitivity and discriminate individuals with marked RT responses.