Caroline Weltens

Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial

BACKGROUND Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. METHODS Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. FINDINGS Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). INTERPRETATION A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. FUNDING Fonds Cancer, Belgium.

Tumor perfusion rate determined noninvasively by dynamic computed tomography predicts outcome in head-and-neck cancer after radiotherapy

PURPOSE To investigate the value of CT-determined tumor perfusion as a predictive factor of local and regional failure and cause-specific survival in head-and-neck cancer treated by radiotherapy. MATERIALS AND METHODS In 105 patients, the perfusion of a primary head-and-neck squamous cell carcinoma was estimated using dynamic CT. A contrast agent bolus was rapidly injected i.v., while during the first pass a dynamic data acquisition was performed at the level of the largest axial tumor surface. The perfusion in the selected tumor region of interest was calculated by dividing the slope of the tumor-time density curve by the maximal value in arterial density. Primary and nodal tumor volume was calculated from the CT images. All patients were treated by radiotherapy with curative intent; in 15 patients, adjuvant concomitant chemotherapy was administered. Mean follow-up time was 2.2 years. Actuarial (life-table) statistical analysis was done; multivariate analysis was performed using the Cox proportional hazards model. RESULTS When the patients were stratified according to the median perfusion value (83.5 mL/min/100 g), those with the lower perfusion rate had a significantly higher local failure rate (p < 0.05). In the multivariate analysis, perfusion rate (p = 0.01) and T category (p = 0.03) were found to be the independent predictors of local failure. Perfusion rate had predictive value regarding neither regional control nor cause-specific survival. CONCLUSIONS CT-determined tumor perfusion rate was found to be an independent predictor of local outcome in irradiated head-and-neck cancer. The results of this study confirm the hypothesis that less-perfused tumors respond poorly to radiotherapy.

Interobserver variations in gross tumor volume delineation of brain tumors on computed tomography and impact of magnetic resonance imaging

PURPOSE (1) To assess the interobserver variability of brain tumor delineation on computed tomography (CT). (2) To assess the impact of the addition of magnetic resonance imaging (MRI) information. METHODS Nine physicians were asked to delineate the gross tumor volume (GTV) of five patients with supratentorial inoperable brain tumors on CT scans and 2 weeks (or more) later on MRIs. The delineations were performed on a computer screen. During delineation on MRI, the registered CT images (without delineation) were displayed on the screen (MRI+CT). RESULTS A high interobserver variability in GTV delineation on CT is found: the ratio of the largest to the smallest defined volumes varies for the five patients by factors of resp. 2.8, 1.8, 1.8, 1.9 and 1.7. The interobserver variability is as large on MRI+CT as on CT alone (ratio largest/smallest volume: 2.4, 1.7, 1.9, 2.7 and 1.5). Volumes delineated on MRI+CT (mean: 69.6 cm(3)) are larger than on CT alone (mean: 59.5 cm(3)). Residual volumes (volume delineated on one image modality but not on the other) are >0 for CT alone and for MRI+CT. CONCLUSIONS A large interobserver variability in GTV delineation of brain tumors is demonstrated. The addition of MRI to CT does not reduce interobserver variability. GTVs delineated on MRI+CT are larger than on CT alone, but some volumes are delineated on CT and not on MRI. Therefore, a combination of the two image modalities is recommended for brain tumor delineation for treatment planning.

Quality assessment of medical decision making in radiation oncology: variability in target volume delineation for brain tumours.

The enormous developments in radiation technology open new horizons for improvements in local tumour control. However, the evolution from conventional external beam radiotherapy planning to conformal therapy might be hampered by the potential risk of over-reliance on the physicians capability of estimating the tumour extent from imaging modalities. The variability between 12 volunteering physicians in the delineation of tumour and target volume on the lateral orthogonal localisation radiograph from CT was assessed for 5 brain tumours. The estimated tumour and target sizes varied, respectively with a factor of 1.3-2.6 and with a factor of 1.3-2.1. The anatomical location of the volumes showed maximum variations from 11 to 27 mm in the cranio-caudal direction and from 14 to 21 mm in the fronto-occipital direction. For the 5 test cases, the tumour area on which all radiation oncologists agreed, represented only 25-73% of the corresponding mean tumour area. Although the introduction of computed tomography in radiation treatment planning was proved to be a major step forwards for treatment planning in many tumour sites, the results of the present study on brain tumours demonstrate that the subjective interpretation of the tumour extent based on CT images might be one of the largest factors contributing to the overall uncertainty in radiation treatment planning. Moreover, this study endorses the need for uncertainty analysis of the medical decision-making process. It may be that the process of making uncertainties explicit can contribute to the improvement of our present concept of radiation treatment planning.(ABSTRACT TRUNCATED AT 250 WORDS)

Preservation of parotid function with uncomplicated conformal radiotherapy

BACKGROUND AND PURPOSE To evaluate (1) parotid function, (2) subjective xerostomia and (3) pattern of relapses after conformal parotid-sparing radiotherapy (RT) for head and neck cancer. (4) To study dose-response curves of parotid glands. MATERIAL AND METHODS From September 1999 to November 2000, 39 head and neck cancer patients requiring bilateral neck RT were treated with a fairly simple conformal RT technique (three-field set-up+anterior lower neck field; two opposed oblique boost fields). The contralateral parotid was spared. Parotid function was assessed by salivary gland scintigraphies performed before, early (median 4 weeks) and late (median 28 weeks) after RT. Xerostomia was monitored by visual analogue scales (VAS) and LENT SOMA scores. Location of locoregional recurrences was studied in relation to the radiation fields. A dose-response curve of parotids was created using logistic regression. RESULTS (1) Early after RT, on salivary gland scintigraphy, the mean loss of secretion function in the spared parotid was 67% and total in the non-spared. Late after RT, the mean loss remained 19% in the spared and total in the non-spared parotid. Normal excretion function was regained in 75% of the spared parotids. (2) Late after RT, 78% of patients had no, minimal or acceptable subjective xerostomia. (3) No recurrence was seen near the spared parotid (11/39 locoregional recurrences). (4) The dose-response curve of parotids showed that the mean parotid dose should preferentially be < or =20 Gy, to obtain a good chance (> or =70%) for preservation of its function on scintigraphy. CONCLUSIONS An easy conformal parotid-sparing RT technique prevents moderate or severe subjective xerostomia in 78% of patients. In the spared parotids, nearly complete to complete recovery is obtained after 6-12 months.

ESTRO consensus guideline on target volume delineation for elective radiation therapy of early stage breast cancer

BACKGROUND AND PURPOSE Delineation of clinical target volumes (CTVs) is a weak link in radiation therapy (RT), and large inter-observer variation is seen in breast cancer patients. Several guidelines have been proposed, but most result in larger CTVs than based on conventional simulator-based RT. The aim was to develop a delineation guideline obtained by consensus between a broad European group of radiation oncologists. MATERIAL AND METHODS During ESTRO teaching courses on breast cancer, teachers sought consensus on delineation of CTV through dialogue based on cases. One teacher delineated CTV on CT scans of 2 patients, followed by discussion and adaptation of the delineation. The consensus established between teachers was sent to other teams working in the same field, both locally and on a national level, for their input. This was followed by developing a broad consensus based on discussions. RESULTS Borders of the CTV encompassing a 5mm margin around the large veins, running through the regional lymph node levels were agreed, and for the breast/thoracic wall other vessels were pointed out to guide delineation, with comments on margins for patients with advanced breast cancer. CONCLUSION The ESTRO consensus on CTV for elective RT of breast cancer, endorsed by a broad base of the radiation oncology community, is presented to improve consistency.

Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging

ObjectiveArthralgia, skeletal and muscle pain have been reported in postmenopausal women under treatment with third generation aromatase inhibitors (AIs). However, the pathogenesis and anatomic correlate of musculoskeletal pains have not been thoroughly evaluated. Moreover, the impact of AI-induced musculoskeletal symptoms on normal daily functioning needs to be further explored.Patients and methodsWe examined 12 consecutive non-metastatic breast cancer patients who reported severe musculoskeletal pain under a third generation AI; 11 were on letrozole and 1 on exemestane. Clinical rheumatological examination and serum biochemistry were performed. Radiological evaluation of the hand/wrist joints were performed using ultrasound (US) and/or magnetic resonance imaging (MRI).ResultsThe most common reported symptom was severe early morning stiffness and hand/wrist pain causing impaired ability to completely close/stretch the hand/fingers and to perform daily activities and work-related skills. Six patients had to discontinue treatment due to severe symptoms. Trigger finger and carpal tunnel syndrome were the most frequently reported clinical signs. US showed fluid in the tendon sheath surrounding the digital flexor tendons. On MRI, an enhancement and thickening of the tendon sheath was a constant finding in all 12 patients.ConclusionsMusculoskeletal pains in breast cancer patients under third generation AIs can be severe, debilitating, and can limit compliance. Characteristic tenosynovial, and in some patients joint changes on US and MRI were observed in this series and have not been reported before.

Tumoural perfusion as measured by dynamic computed tomography in head and neck carcinoma

PURPOSE To investigate the intra- and interobserver variability, as well as the intra- and interpatient variability of CT-determined tumour perfusion in head and neck tumours, and to evaluate the preliminary value of this parameter as predictive factor of local failure after treatment by definitive radiotherapy. MATERIALS AND METHODS In 41 patients the perfusion of a primary head and neck squamous cell carcinoma was estimated using dynamic CT. A 40-ml intravenous bolus of a low-osmolar non-ionic contrast agent was rapidly injected over 5 s (8 ml/s), while a dynamic acquisition of image data was obtained during the first pass at the level of the largest axial tumour surface. A time-density curve was constructed for the primary tumour and the carotid artery. The perfusion in the selected tumour region of interest was calculated by dividing the slope of the tumour-time density curve by the maximal value in arterial density. Tumour volume was calculated on the CT-images and correlated with perfusion rate. RESULTS The mean perfusion rate was 86.4 ml/min per 100 g (median, 80.6; SD, 43.05; range, 31.7-239.8 ml/min per 100 g). No systematic difference was found between the measurements performed by two independent observers. The intratumoural COV was 0.22, the intertumoural COV 0.37. No correlation was found with tumour volume. Ten out of 20 patients with a perfusion rate < 80 ml/min per 100 g were not locally controlled, while nine out of 21 patients with a value > 80 ml/min per 100 g did show a local failure (P = 0.19). CONCLUSIONS CT-determined perfusion measurements of head and neck tumours are feasible. No correlation with tumour volume and a sufficiently large COV were found to consider this parameter as a possible prognostic factor for outcome after radiotherapy. More patients need to be investigated to test the hypothesis that tumours with a low CT determined perfusion rate have a higher risk of local failure.

Comparison of plastic and Orfit® masks for patient head fixation during radiotherapy: Precision and costs

PURPOSE Two widely used immobilization systems for head fixation during radiotherapy treatment for ear-nose-throat (ENT) tumors are evaluated. METHODS AND MATERIALS Masks made of poly vinyl-chloride (plastic) are compared to thermoplastic masks (Orfit) with respect to the accuracy of the treatment setup and the costs. For both types of material, a cut-out (windows corresponding to treatment fields) and a full mask (not cut out) are considered. Forty-three patients treated for ENT tumors were randomized into four groups, to be fixed by one of the following modalities: cut-out plastic mask (12 patients), full plastic mask (11 patients), cut-out Orfit mask (10 patients), and full Orfit mask (10 patients). RESULTS Reproducibility of the treatment setup was assessed by calculating the deviations from the mean value for each individual patient and was demonstrated to be identical for all subgroups: no differences were demonstrated between the plastic (s = 2.1 mm) and the Orfit (s = 2.1 mm) group nor between the cut-out (s = 2.0 mm) and not cut-out (s = 2.1 mm) group. The transfer chain from similar to treatment unit was checked by comparing portal images to their respective simulation image, and no differences between the four subgroups (s = +/- 3.5 mm) could be detected. A methodology was described to compare the costs of both types of masks, and illustrated with the data for a department. It was found that Orfit masks are a cheaper alternative than plastic masks; they require much less investment expenses and the workload and material cost of the first mask for each patient is also lower. Cut-out masks are more expensive than full masks, because of the higher workload and the additional material required for second and third masks that are required in case of field modifications. CONCLUSIONS No substantial difference in patient setup accuracy between both types of masks was detected, and cutting out the masks had no impact on the fixing capabilities. A first Orfit mask will typically be a cheaper alternative than a plastic mask for most departments (lower fixed and variable costs). The higher material cost of the subsequent Orfit masks, compared to the plastic masks, offset the lower investment expenses.

De Gustibus: time scale of loss and recovery of tastes caused by radiotherapy

PURPOSE To quantify the prevalence and distress of taste loss at different intervals after radiotherapy (RT) for head and neck cancer. MATERIALS AND METHODS In four different groups of head and neck cancer patients (73 patients in total), taste loss and distress due to taste loss were evaluated by taste acuity tests and taste questionnaires. Group 1 (n=17) was analyzed prior to RT. Groups 2 (n=17), 3 (n=17) and 4 (n=22) were at 2, 6 and 12-24 months after treatment, respectively. A cross-sectional analysis was performed between these four groups. RESULTS Prior to initiation of RT (group 1), partial taste loss was observed in 35, 18 and 6% of patients for bitter, salt and sweet, respectively. At 2 months after RT (group 2), taste loss (partial or total) was seen in 88, 82, 76 and 53% for bitter, salt, sweet and sour, respectively. At 6 months (group 3), partial taste loss was seen in 71, 65, 41 and 41% (bitter, salt, sweet, sour) and after 1-2 years (group 4) in 41, 50, 27 and 27% (bitter, salt, sweet, sour). Distress caused by taste loss was most frequent in group 2 (82%). CONCLUSIONS In this study, loss of taste after RT was found to be most pronounced after 2 months. Bitter and salt qualities were most impaired. Gradual recovery was seen during the first year after treatment. Partial taste loss still persisted 1-2 years after treatment and was responsible for slight to moderate discomfort.