Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences.

AIMS: Proton therapy is a radiation technique that yields less dose in normal tissues than photon therapy. In the Netherlands, proton therapy is reimbursed if the reduced dose to normal tissues is predicted to translate into a prespecified reduction in toxicity, based on nationally approved validated models. The aim of this paper is to present the development of a national indication protocol for proton therapy (NIPP) for model-based selection of breast cancer patients and to report on first clinical experiences. MATERIALS AND METHODS: A national proton therapy working group for breast cancer (PWG-BC) screened the literature for prognostic models able to estimate the individual risk of specific radiation-induced side-effects. After critical appraisal and selection of suitable models, a NIPP for breast cancer was written and subjected to comments by all stakeholders. The approved NIPP was subsequently introduced to select breast cancer patients who would benefit most from proton therapy. RESULTS: The model of Darby et al. (N Engl J Med 2013; 368:987-82) was the only model fulfilling the criteria prespecified by the PWG-BC. The model estimates the relative risk of an acute coronary event (ACE) based on the mean heart dose. The absolute lifetime risk of ACE <80 years was calculated by applying this model to the Dutch absolute incidence of ACE for female and male patients, between 40 and 70 years at breast cancer radiotherapy, with/without cardiovascular risk factors. The NIPP was approved for reimbursement in January 2019. Based on a threshold value of a 2% absolute lower risk on ACE for proton therapy compared with photons, 268 breast cancer patients have been treated in the Netherlands with proton therapy between February 2019 and January 2021. CONCLUSION: The NIPP includes a model that allows the estimation of the absolute risk on ACE <80 years based on mean heart dose. In the first 2 years, 268 breast cancer patients have been treated with proton therapy in The Netherlands.

A patient decision aid for breast cancer patients deciding on their radiation treatment, no change in decisional conflict but better informed choices.

BACKGROUND AND PURPOSE: In selected breast cancer patients, radiation treatment (RT) lowers the recurrence risk, with minor or no improvement of survival. In these patients, the choice to undergo RT is considered a preference-sensitive decision. To facilitate shared decision-making (SDM) for this choice, a patient decision aid was made. We aimed to evaluate the effect of the PtDA on decisional conflict. MATERIAL AND METHODS: We performed a multi-center pre- and post-intervention study (BRASA-trial). The first 214 patients made a choice without support of the PtDA; the subsequent 189 patients received a link to the PtDA. The primary endpoint was decisional conflict; secondary endpoints were perceived SDM and knowledge on treatment options. Patients filled out questionnaires immediately after, and three months after their decision. Data were analyzed with multi-level regression analysis. RESULTS: After correcting for the difference in age and educational level, the mean (±SD) decisional conflict for the intervention group (27.3 ± 11.4) was similar to the control group (26.8 ± 11.4; difference = 0.86, 95 %CI 1.67,3.36) three months after their decision. This also applied to perceived SDM. Patients exposed to the PtDA pursued additional treatment less often (45% vs 56%, odds ratio 0.59, 95 %CI 0.37,0.95) and scored significantly higher on the knowledge test (7.4 ± 2.5 vs 6.1 ± 2.7, corrected difference = 1.0, 95 %CI 0.50,1.49). There was no significant increase in consultation time. CONCLUSIONS: Handing out the PtDA was not associated with improved scores in decisional conflict or perceived SDM, but it was associated with a choice for less additional treatment and better knowledge about the treatment options.

Implementing a patient decision aid, a process evaluation of a large-scale pre- and post-implementation trial.

PURPOSE: Patient decision aids (PtDAs) have been reported to have a positive influence on patients making a health care decision in trials. Nevertheless, post-trial implementation is poor. The aim of this study is to explore patient, clinician, and organizational success factors for implementing a PtDA designed for breast cancer patients, facing a decision on their radiation treatment. METHODS: We performed a process evaluation within a multi-center pre- and post-implementation trial. The PtDA was incorporated as much as possible in the logistics of 13 participating centers. Tracking data were collected on PtDA use. Process characteristics were recorded by both clinicians and patients. A logistic regression method was applied to investigate which process characteristics were significantly related to the probability that patients logged in to the PtDA. RESULTS: 189 patients received the PtDA of whom140 (77%) used the PtDA. If patients received the link via the surgery department they were more likely to use the PtDA (OR 9.77 (1.28-74.51)), compared to patients that received the link via the radiation oncology department. If the report of the multidisciplinary team stated that radiation treatment "had to be discussed with the patient", patients were more likely to use the PtDA (OR 2.29 (1.12-4.71)). Educational level was not related to the probability of PtDA use. CONCLUSIONS: We accomplished a high level of PtDA use. Patients were more likely to use the PtDA if they received the link via the surgery department and if "to be discussed with the patient" was written in the multidisciplinary team report.

Risk communication in a patient decision aid for radiotherapy in breast cancer: How to deal with uncertainty?

BACKGROUND AND AIM: Patient decision aids for oncological treatment options, provide information on the effect on recurrence rates and/or survival benefit, and on side-effects and/or burden of different treatment options. However, often uncertainty exists around the probability estimates for recurrence/survival and side-effects which is too relevant to be ignored. Evidence is lacking on the best way to communicate these uncertainties. The aim of this study is to develop a method to incorporate uncertainties in a patient decision aid for breast cancer patients to support their decision on radiotherapy. METHODS: Firstly, qualitative interviews were held with patients and health care professionals. Secondly, in the development phase, thinking aloud sessions were organized with four patients and 12 health care professionals, individual and group-wise. RESULTS: Consensus was reached on a pictograph illustrating the whole range of uncertainty for local recurrence risks, in combination with textual explanation that a more exact personalized risk would be given by their own physician. The pictograph consisted of 100 female icons in a 10 x 10 array. Icons with a stepwise gradient color indicated the uncertainty margin. The prevalence and severity of possible side-effects were explained using verbal labels. CONCLUSIONS: We developed a novel way of visualizing uncertainties in recurrence rates in a patient decision aid. The effect of this way of communicating risk uncertainty is currently being tested in the BRASA study (NCT03375801).

What do patients and health care professionals view as important attributes in radiotherapy decisions? Input for a breast cancer patient decision aid.

BACKGROUND AND AIM: There is increased attention for shared decision making (SDM) when deciding on radiotherapy for selected patients with Stage 0-2 breast cancer. This study aimed to explore patients' and health care professionals' experiences, decisional attributes and needs as input for the development of a patient decision aid to facilitate SDM. METHODS: Qualitative semi-structured interviews were held with fifteen breast cancer patients, being confronted with a radiotherapy decision one month to eight years earlier. Another fifteen interviews were held with professionals specialized in breast cancer care. Interviews were transcribed verbatim and independently coded by two researchers, who agreed upon relevant issues. RESULTS: Most patients made their decision by weighing the advantages of radiotherapy, i.e. comparing the decrease in recurrence risk with and without radiotherapy, and disadvantages, i.e. possible side effects. Patients and professionals agreed that recurrence risks should be communicated, but not on how to deal with uncertainty. There was wide variation in which, and how, side effects were explained by professionals. The most common side effects mentioned by both patients and professionals were skin toxicity, fatigue and breast deformity. CONCLUSION: Patients and professionals appeared to agree on what type of attributes should be communicated during SDM on radiotherapy, but how this should be done is up for discussion. To ensure the patient's voice these attributes and needs need to be incorporated in the risk communication and value elicitation part of the patient decision aid. The format in which the attributes are communicated should be critically evaluated.

Major Reduction in Axillary Lymph Node Dissections After Neoadjuvant Systemic Therapy for Node-Positive Breast Cancer by combining PET/CT and the MARI Procedure.

BACKGROUND: Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy. METHODS: All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node. RESULTS: The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment. CONCLUSION: Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN + breast cancer patients.

Quantification of patient-reported outcome measures of radiation-induced skin reactions for use in clinical trial design.

PURPOSE: Skin toxicity is a common effect from radiotherapy, although difficult to predict on an individual basis, and there is little evidence-based management. This study aimed to quantify inter-patient variation in patient-reported outcome measures for radiation-induced skin reactions (RISR) to enable the determination of the number of patients required for adequate power in a comparative trial of RISR management strategies. METHODS: The study included 154 patients scheduled to receive breast cancer radiotherapy. Patients filled in a weekly questionnaire during and up to 4 weeks following the end of radiotherapy scoring five aspects of their experience of RISR: skin redness, and bother from redness like itching, burning sensation and tenderness/pain. RESULTS: Assessment of patients' reported experience of their RISR was shown to be feasible, with 91 % of patients returning at least two questionnaires. The mean score increase between weeks 1 and 4 was 25 points (p value <0.0001, 95 % CI 21-29), and the estimated standard deviation at 4 weeks was 18 (95 % CI 16-21). CONCLUSIONS: Patients' assessment of their reaction was not predicted on the basis of treatment and patient-related characteristics. Based on the observed variance in scores at 4 weeks, we could calculate the sample size required for a comparative study of two RISR management policies would be 200 patients to have statistical power to detect a clinically significant difference in patient-rated scores of their skin reactions. A trial employing this tool would help provide an evidence base to guide policy in advising patients how to manage their RISR.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

Treatment strategies in elderly breast cancer patients: Is there a need for surgery?

BACKGROUND: The aim of this study was to determine the role of surgery in elderly patients with breast cancer. METHODS: Between 1999 and 2009, 153 consecutive women, ≥80 years old with breast cancer were treated at our hospital. Surgically and non-surgically treated patients were compared with respect to characteristics and survival. RESULTS: Treatment was surgical in 102 patients (67%). The non-surgically treated patients were older than surgically treated patients, had more co-morbidity and were more often diagnosed with a clinically T3/T4 tumour and distant metastasis. Patients not receiving surgery, had an 11% overall survival rate at 5-year versus 48% in surgically treated patients (P < 0.001). Independent factors for survival were clinical N0 status, M0 status at presentation and surgery. CONCLUSION: One in three patients of 80 years and older did not have surgical treatment for breast cancer. Patient not treated surgically are older, have more severe co-morbidity and are diagnosed with more advanced disease than patients who underwent surgery.The selection of patients, who have a poor prognosis, is made on clinical grounds not measurable with a common co-morbidity survey. Better and evidence-based selection criteria for surgical and non-surgical treatment in these patients are needed.

Understanding radiation-induced cardiovascular damage and strategies for intervention.

There is a clear association between therapeutic doses of thoracic irradiation and an increased risk of cardiovascular disease (CVD) in cancer survivors, although these effects may take decades to become symptomatic. Long-term survivors of Hodgkin's lymphoma and childhood cancers have two-fold to more than seven-fold increased risks for late cardiac deaths after total tumour doses of 30-40 Gy, given in 2 Gy fractions, where large volumes of heart were included in the field. Increased cardiac mortality is also seen in women irradiated for breast cancer. Breast doses are generally 40-50 Gy in 2 Gy fractions, but only a small part of the heart is included in the treatment fields and mean heart doses rarely exceeded 10-15 Gy, even with older techniques. The relative risks of cardiac mortality (1.1-1.4) are consequently lower than for Hodgkin's lymphoma survivors. Some epidemiological studies show increased risks of cardiac death after accidental or environmental total body exposures to much lower radiation doses. The mechanisms whereby these cardiac effects occur are not fully understood and different mechanisms are probably involved after high therapeutic doses to the heart, or part of the heart, than after low total body exposures. These various mechanisms probably result in different cardiac pathologies, e.g. coronary artery atherosclerosis leading to myocardial infarct, versus microvascular damage and fibrosis leading to congestive heart failure. Experimental studies can help to unravel some of these mechanisms and may identify suitable strategies for managing or inhibiting CVD. In this overview, the main epidemiological and clinical evidence for radiation-induced CVD is summarised. Experimental data shedding light on some of the underlying pathologies and possible targets for intervention are also discussed.

Vascular damage as an underlying mechanism of cardiac and cerebral toxicity in irradiated cancer patients.

Radiation is an independent risk factor for cardiovascular and cerebrovascular disease in cancer patients. Modern radiotherapy techniques reduce the volume of the heart and major coronary vessels exposed to high doses, but some exposure is often unavoidable. Radiation damage to the myocardium is caused primarily by inflammatory changes in the microvasculature, leading to microthrombi and occlusion of vessels, reduced vascular density, perfusion defects and focal ischemia. This is followed by progressive myocardial cell death and fibrosis. Clinical studies also demonstrate regional perfusion defects in non-symptomatic breast cancer patients after radiotherapy. The incidence and extent of perfusion defects are related to the volume of left ventricle included in the radiation field. Irradiation of endothelial cells lining large vessels also increases expression of inflammatory molecules, leading to adhesion and transmigration of circulating monocytes. In the presence of elevated cholesterol, invading monocytes transform into activated macrophages and form fatty streaks in the intima, thereby initiating the process of atherosclerosis. Experimental studies have shown that radiation predisposes to the formation of inflammatory plaque, which is more likely to rupture and cause a fatal heart attack or stroke. This paper presents a brief overview of the current knowledge on mechanisms for development of radiation-induced cardiovascular and cerebrovascular damage. It does not represent a comprehensive review of the literature, but reference is made to several excellent recent reviews on the topic.

The relevance of breast cancer subtypes in the outcome of neoadjuvant chemotherapy.

BACKGROUND: Breast cancer is increasingly considered a heterogeneous disease. The aim of this study was to assess the differences between histological and receptor-based subtypes in breast-conserving surgery and pathological complete response (pCR) after neoadjuvant chemotherapy. METHOD: A consecutive series of 254 patients with operable breast cancer treated with neoadjuvant chemotherapy was analyzed. Tumors were classified according to their receptor status in estrogen receptor (ER)-positive tumors (HER2-negative), triple-negative tumors, and HER2-positive tumors. The type of surgery feasible prior to neoadjuvant chemotherapy was compared with the actual surgery performed. RESULTS: The overall increase in breast-conserving surgery was 37% (73 of 198). In patients with ductal and lobular carcinomas this increase was 41% (63 of 152, 95% confidence interval [95% CI] 0.34-0.49) and 20% (7 of 35, 95% CI 0.10-0.36), respectively (P = 0.02). Half of the patients with lobular carcinoma had to undergo a secondary mastectomy because of incomplete resection margins. In ER-positive, triple-negative and HER2-positive tumors, the increase in breast-conserving surgery was 39% (42 of 109, 95% CI 0.30-0.48), 24% (11 of 45, 95% CI 0.14-0.38), and 45% (20 of 44, 95% CI 0.32-0.60) (P = 0.11). The pCR rate in ductal and lobular carcinomas was 12% (23 of 195) and 2% (1 of 42), respectively (P = 0.09). In ER-positive, triple-negative and HER2-positive tumors the pCR rates were 2% (3 of 138), 28% (16 of 57), and 18% (10 of 56), respectively. Multivariate analysis showed that the receptor-based subtype was the only significant predictor of pCR (P = 0.004). CONCLUSION: In lobular tumors the benefit with regard to breast-conserving surgery of neoadjuvant chemotherapy is questionable. Although in ER-positive tumors the pCR rate is low, the increase in breast-conserving surgery was remarkable in ductal ER-positive tumors.

The role of FDG PET/CT in patients with locoregional breast cancer recurrence: a comparison to conventional imaging techniques.

PURPOSE: The aim of this study was to evaluate the impact of (18)F-fluorodeoxyglucose positron-emission tomography/computed tomography (FDG PET/CT) on clinical management in patients with locoregional breast cancer recurrence amenable for locoregional treatment and to compare the PET/CT results with the conventional imaging data. PATIENTS AND METHODS: From January 2006 to August 2008, all patients with locoregional breast cancer recurrence underwent whole-body PET/CT. PET/CT findings were compared with results of the conventional imaging techniques and final pathology. The impact of PET/CT results on clinical management was evaluated based on clinical decisions obtained from patient files. RESULTS: 56 patients were included. In 32 patients (57%) PET/CT revealed additional tumour localisations. Distant metastases were detected in 11 patients on conventional imaging and in 23 patients on PET/CT images (p < 0.01). In 25 patients (45%), PET/CT detected additional lesions not visible on conventional imaging. PET/CT had an impact on clinical management in 27 patients (48%) by detecting more extensive locoregional disease or distant metastases. In 20 patients (36%) extensive surgery was prevented and treatment was changed to palliative treatment. The sensitivity, specificity, accuracy, positive and negative predictive values of FDG PET/CT were respectively 97%, 92%, 95%, 94% and 96%. CONCLUSIONS: PET/CT, in addition to conventional imaging techniques, plays an important role in staging patients with locoregional breast cancer recurrence since its result changed the clinical management in almost half of the patients. PET/CT could potentially replace conventional staging imaging in patients with a locoregional breast cancer recurrence.

Towards rational axillary treatment in relation to neoadjuvant therapy in breast cancer.

AIMS: The purpose of this study is to analyse nodal staging and axillary response in breast cancer patients treated with neoadjuvant chemotherapy (NAC) to explore venues to safely spare patients axillary clearance whenever it could be avoided. METHODS: In 327 patients we determined the nodal status before NAC by ultrasound-guided cytology and if indicated by sentinel node biopsy (SNB). In patients with proven metastasis we analysed the axillary response after NAC. RESULTS: Before NAC, the ultrasound-guided cytology was positive in 252 patients. In the remaining 75 patients SNB was performed prior to NAC. The SNB was negative in 53 patients, thus in these patients axillary clearance could be avoided. All 274 patients with proven axillary metastases at diagnosis underwent axillary clearance after NAC. Twenty percent of the cytology-positive patients (50/252) had an axillary pathological complete remission (pCR) and 68% of the SNB-positive patients (15/22) had no lymph node (LN) metastasis after NAC. Subgroups with a high axillary pCR rate were patients with triple-negative tumours (57%) and human epidermal growth-factor receptor 2 (HER2)-positive tumours (68%) who had a pCR of the primary tumour. CONCLUSIONS: Twenty percent of the patients with proven metastasis by cytology prior to NAC have an axillary pCR. The axillary pCR rate is very high in certain subgroups. Identification of these patients, could result in more axilla-conserving therapies.

Extensive soft tissue resection with autologous tissue closure for locally recurrent breast cancer: lasting local control and acceptable morbidity.

INTRODUCTION: Locoregional breast cancer recurrence can be detected at an advanced stage of the disease. To achieve local control for these larger local breast cancer recurrences, wide soft tissue resections with autologous tissue coverage of the defect is an option. The aim of this study was to assess the local control and morbidity of surgical salvage of patients with advanced local breast cancer recurrence using autologous tissue closure of the defect. MATERIAL AND METHODS: Eighty-eight patients were treated with wide soft tissue resections with autologous tissue coverage from 1993 to 2006. Two different operating techniques were used for closure of the defect; transposition of the greater omentum covered with split skin graft and the latissimus dorsi musculo-cutaneous flap. Demographic, treatment and mortality information were retrieved from original patients' files. RESULTS: Postoperatively 10 patients (11%) developed complications which required an additional operation. In patients treated with curative intent (n=67) median disease-free interval after extensive surgery was 24 months and median survival was 45 months. In 42 patients (47% of all included patients) the first recurrence after extensive surgery was a locoregional relapse. The two surgical techniques did not differ in overall survival (p=0.739) and local control. CONCLUSION: Large soft tissue resection for extensive local relapse of breast cancer may result in lasting local control in half of the patients with acceptable morbidity.

The frequency, magnitude and timing of post-diagnosis body weight gain in Dutch breast cancer survivors.

To evaluate the association between systemic treatments and post-diagnosis weight gain in breast cancer patients during longer follow-up periods, we conducted a retrospective cohort study (n=271). Information on adjuvant systemic treatments and repeated body weight measurements was obtained from medical records, and analysed using multi-level regressions. During the first year, a mean weight change of +2.0kg (SD 4.9) was observed. Overall, 29% of all breast cancer patients had gained 5kg or more in body weight during total follow-up (median: 3 years). In multi-level analyses, women who received combined systemic treatment gained significantly more weight as compared with women who received no systemic treatment (4.5kg versus 2.0kg at 5 years post-diagnosis, p<0.05). Significant weight gain occurs in breast cancer patients in the Netherlands during the first year post-diagnosis. After the first year, further weight gain mainly occurs in women who receive chemotherapy in combination with endocrine therapy.

[Neoadjuvant systemic therapy in patients with operable primary breast cancer: more benefits than breast-conserving therapy]. / Neoadjuvante systemische therapie bij het primair operabel mammacarcinoom: meer voordelen dan alleen borstsparende behandeling.

OBJECTIVE: To analyse the extent to which primary systemic therapy (PST) achieves the main goals in patients with operable primary breast cancer, these goals being breast-conserving therapy and pathological complete remission (pCR), and to evaluate the response. DESIGN: Retrospective. METHOD: In a retrospective analysis of 254 patients treated with PST in 2000-2007 in the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, patients with inoperable disease (T4 and/or N3) were excluded. The response was mostly evaluated using contrast-enhanced MRI, whereby the chemotherapy regimen was switched if the reduction in the largest diameter of contrast washout was less than 25%. pCR was defined as no evidence of invasive cancer in the breast and axilla in the resection specimen. RESULTS: In patients with ductal carcinoma and lobular carcinoma an increase in breast-conserving therapy was seen in 32% and 17% of patients respectively. The pCR rate was 12% and 2% respectively. Secondary mastectomy because of irradical resection was required in 3% and 50% respectively. Multivariate analysis indicated that molecular type, defined on the basis of the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2), i.e. luminal (oestrogen receptor-positive), basal (hormone receptor-negative and HER2-negative) and HER2-positive tumours treated with trastuzumab was the only independent predictor of pCR; 2%, 28% and 35% respectively (p=0.004). In 43 patients the chemotherapy regimen was adjusted because the tumour did not respond sufficiently. A favourable clinical response was observed in 72% (31/43) of these patients. CONCLUSION: The observed increase in the number of breast-conserving therapies after PST was clinically relevant. PST may be more effective when contrast-enhanced MRI is used for interim evaluation, based on which the treatment may be switched. There was a clear difference in histological and molecular types of tumour and therefore the choice of treatment may be adjusted accordingly.