Intensity-modulated radiotherapy for breast and head-and-neck cancer

Intensity-modulated radiotherapy (IMRT) is an advanced form of radiotherapy; the beam intensity can thereby be modulated. IMRT can be used to create a highly conformal dose distribution around a tumor, while reducing the dose to the surrounding normal tissue. IMRT can also be used to deliver a heterogeneous dose within the tumor. A higher dose is delivered to areas of high risk, such as a part of the tumor containing more tumor cells. In this thesis, IMRT is applied to the irradiation of breast and oropharyngeal cancer. An IMRT technique for irradiation of breast cancer has been developed, based on the on the division of the tangential fields in four segments shaped by a multi-leaf collimator. The shape of these segments was obtained from an equivalent path length map of the irradiated volume. Using this IMRT technique, a more homogeneous dose distribution was achieved compared to the conventional technique. Furthermore the dose to the lung was reduced. A more complex case is the treatment of oropharyngeal cancer. Different dose levels are delivered to the primary tumor, the volume containing subclinical malignant disease and the lymph nodes. The dose to the spinal cord, brain and parotid gland should be minimized. The relation between the quality of the treatment plan and the number of beams in combination with the number of segments was investigated in order to obtain a clinically acceptable and deliverable plan. Seven beams were sufficient to achieve acceptable dose homogeneity while the dose to the spinal cord and brain was acceptable. The dose to the parotid glands was reduced without compromising the dose to the targets. Special attention should be paid to the localization of the tumor when using IMRT to assure that the dose is delivered at the right location. A margin, taken for geometrical uncertainties, is therefore added to prevent underdosage of the target volumes. Due to this margin, the dose to the surrounding healthy tissues increases. In a theoretical study it was shown that a realistic reduction of this margin might result in a reduction of the probability for radiation induced xerostomia of approximately 20%. In order to reduce the margin, the reliability and toxicity of the use of implanted gold markers for position verification during the irradiation of head-and-neck cancer was investigated. These markers were visualized using an a-Si flat panel imager. No acute major complications were observed. In order to prevent movement of the markers, they should be deep-seated. The random error of the geometric uncertainties obtained without correction during radiotherapy was 1-2 mm. The intrafraction motions of the larynx were investigated during radiotherapy using an a-Si flat panel imager. Motions occurred due to swallowing, breathing, or movement of the tongue. An extra margin of approximately 3.5 mm should be applied to take into account frequent motions, which are probably related to breathing. Two different segmental IMRT techniques have been developed in this thesis for respectively irradiation of the breast and the oropharynx. Both techniques have been implemented clinically. Furthermore, the position verification and intra-fraction motion for head-and-neck irradiation have been investigate

Supine MRI for regional breast radiotherapy: Imaging axillary lymph nodes before and after sentinel-node biopsy

Regional radiotherapy (RT) is increasingly used in breast cancer treatment. Conventionally, computed tomography (CT) is performed for RT planning. Lymph node (LN) target levels are delineated according to anatomical boundaries. Magnetic resonance imaging (MRI) could enable individual LN delineation. The purpose was to evaluate the applicability of MRI for LN detection in supine treatment position, before and after sentinel-node biopsy (SNB). Twenty-three female breast cancer patients (cTis-3N0M0) underwent 1.5 T MRI, before and after SNB, in addition to CT. Endurance for MRI was monitored. Axillary levels were delineated. LNs were identified and delineated on MRI from before and after SNB, and on CT, and compared by Wilcoxon signed-rank tests. LN locations and LN-based volumes were related to axillary delineations and associated volumes. Although postoperative effects were visible, LN numbers on postoperative MRI (median 26 LNs) were highly reproducible compared to preoperative MRI when adding excised sentinel nodes, and higher than on CT (median 11, p < 0.001). LN-based volumes were considerably smaller than respective axillary levels. Supine MRI of LNs is feasible and reproducible before and after SNB. This may lead to more accurate RT target definition compared to CT, with potentially lower toxicity. With the MRI techniques described here, initiation of novel MRI-guided RT strategies aiming at individual LNs could be possible

Tumor Response After Neoadjuvant Magnetic Resonance Guided Single Ablative Dose Partial Breast Irradiation

PURPOSE: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs). METHODS AND MATERIALS: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, ≥70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software). RESULTS: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed. CONCLUSIONS: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients

Dynamic Contrast-enhanced and Diffusion-weighted Magnetic Resonance Imaging for Response Evaluation After Single-Dose Ablative Neoadjuvant Partial Breast Irradiation

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (<10% vs ≥10% residual tumor cells). The semiquantitative MRI parameters evaluated were time to enhancement (TTE), 1-minute relative enhancement (RE 1min), percentage of enhancing voxels (%EV), distribution of washout curve types, and apparent diffusion coefficient (ADC). Results: In general, the enhancement increased 1 week after NA-PBI (baseline vs 1 week median – TTE: 15s vs 10s; RE 1min: 161% vs 197%; %EV: 47% vs 67%) and decreased from 2 months onward (6 months median – TTE: 25s; RE 1min: 86%; %EV: 12%). Median ADC increased from 0.83 × 10 −3 mm 2/s at baseline to 1.28 × 10 −3 mm 2/s at 6 months. TTE, RE 1min, and %EV showed the most potential to differentiate between radiologic responses, and TTE, RE 1min, and ADC between pathologic responses. Conclusions: Semiquantitative analyses of DCE and DW-MRI showed changes in relative enhancement and ADC 1 week after NA-PBI, indicating acute inflammation, followed by changes indicating tumor regression from 2 to 6 months after radiation therapy. A relation between the MRI parameters and radiologic and pathologic responses could not be proven in this exploratory study

Dynamic Contrast-enhanced and Diffusion-weighted Magnetic Resonance Imaging for Response Evaluation After Single-Dose Ablative Neoadjuvant Partial Breast Irradiation

Purpose: We aimed to evaluate changes in dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) magnetic resonance imaging (MRI) scans acquired before and after single-dose ablative neoadjuvant partial breast irradiation (NA-PBI), and explore the relation between semiquantitative MRI parameters and radiologic and pathologic responses. Methods and Materials: We analyzed 3.0T DCE and DW-MRI of 36 patients with low-risk breast cancer who were treated with single-dose NA-PBI, followed by breast-conserving surgery 6 or 8 months later. MRI was acquired before NA-PBI and 1 week, 2, 4, and 6 months after NA-PBI. Breast radiologists assessed the radiologic response and breast pathologists scored the pathologic response after surgery. Patients were grouped as either pathologic responders or nonresponders (<10% vs ≥10% residual tumor cells). The semiquantitative MRI parameters evaluated were time to enhancement (TTE), 1-minute relative enhancement (RE1min), percentage of enhancing voxels (%EV), distribution of washout curve types, and apparent diffusion coefficient (ADC). Results: In general, the enhancement increased 1 week after NA-PBI (baseline vs 1 week median – TTE: 15s vs 10s; RE1min: 161% vs 197%; %EV: 47% vs 67%) and decreased from 2 months onward (6 months median – TTE: 25s; RE1min: 86%; %EV: 12%). Median ADC increased from 0.83 × 10−3 mm2/s at baseline to 1.28 × 10−3 mm2/s at 6 months. TTE, RE1min, and %EV showed the most potential to differentiate between radiologic responses, and TTE, RE1min, and ADC between pathologic responses. Conclusions: Semiquantitative analyses of DCE and DW-MRI showed changes in relative enhancement and ADC 1 week after NA-PBI, indicating acute inflammation, followed by changes indicating tumor regression from 2 to 6 months after radiation therapy. A relation between the MRI parameters and radiologic and pathologic responses could not be proven in this exploratory study

Tumor Response After Neoadjuvant Magnetic Resonance Guided Single Ablative Dose Partial Breast Irradiation

Purpose: To assess the pathologic and radiologic response in patients with low-risk breast cancer treated with magnetic resonance (MR) guided neoadjuvant partial breast irradiation (NA-PBI) and to evaluate toxicity and patient-reported outcomes (PROs). Methods and Materials: For this single-arm prospective trial, women with unifocal, non-lobular tumors with a maximum diameter of 20 mm (age, 50-70 years) or 30 mm (age, ≥70 years) and tumor-negative sentinel node(s) were eligible. Patients were treated with a single ablative dose of NA-PBI followed by breast-conserving surgery after an interval of 6 to 8 months. Target volumes were defined on radiation therapy planning computed tomography scan and additional magnetic resonance imaging. Prescribed doses to gross tumor volume and clinical target volume (gross tumor volume plus 20 mm margin) were 20 Gy and 15 Gy, respectively. Primary outcome was pathologic complete response (pCR). Secondary outcomes were radiologic response (on magnetic resonance imaging), toxicity (Common Terminology Criteria for Adverse Events), PROs (European Organisation for Research and Treatment of Cancer QLQ-BR23, Hospital Anxiety and Depression Scale), and cosmesis (assessed by patient, radiation oncologist, and BCCT.core software). Results: Thirty-six patients were treated with NA-PBI, and pCR was reported in 15 patients (42%; 95% confidence interval, 26%-59%). Radiologic complete response was observed in 15 patients, 10 of whom had pCR (positive predictive value, 67%; 95% confidence interval, 39%-87%). After a median follow-up of 21 months (range, 12-41), all patients experienced grade 1 fibrosis in the treated breast volume. Transient grade 2 and 3 toxicity was observed in 31% and 3% of patients, respectively. Local recurrences were absent. No deterioration in PROs or cosmetic results was observed. Conclusions: NA-PBI has the potential to induce pCR in a substantial proportion of patients, with acceptable toxicity. This treatment seems a feasible alternative to standard postoperative irradiation and could even result in postponement or omission of surgery if pCR can be accurately predicted in selected low-risk patients