Erik Van Limbergen

The influence of patient, tumor and treatment factors on the cosmetic results after breast-conserving therapy in the EORTC ‘boost vs. no boost’ trial

PURPOSE To analyze the influence of different patient, tumor, and treatment parameters on the cosmetic outcome after breast-conserving therapy at 3-year follow-up. A subjective and an objective cosmetic scoring method was used and the results of both methods were compared. PATIENTS AND METHODS In EORTC trial 22881/10882, 5569 early-stage breast cancer patients were treated with tumorectomy and axillary dissection, followed by tangential fields irradiation of the breast to a dose of 50 Gy in 5 weeks, at 2 Gy per fraction. A total of 5318 patients, having a microscopically complete tumorectomy, were randomized between no further treatment and a boost of 16 Gy to the primary tumor bed. The cosmetic result at 3-year follow-up was assessed by a panel for 731 patients, and by digitizer measurements, measuring the displacement of the nipple, for 1141 patients. Univariate and multivariate analyses were used to evaluate the correlation between various patient, tumor, and treatment factors and cosmesis. RESULTS The factors associated with a worsened cosmesis according to the panel evaluation were: an inferior tumor location, a large excision volume, the presence of postoperative breast complications, and the radiotherapy boost. According to the digitizer measurements, a central/superior tumor location, a large excision volume, an increased pathological tumor size, an increased radiation dose inhomogeneity, and an increased bra cup size resulted in an increased asymmetry in nipple position. It appeared that the evaluation of the nipple position (whether by panel or by digitizer) is only moderately representative of the overall cosmetic outcome. CONCLUSION To achieve a good cosmesis, it is necessary to excise the tumor with a limited margin, to avoid postoperative complications, to assess the need for a boost in the individual patient, and to give the radiation dose as homogeneously as possible. As far as the method of evaluation is concerned, the panel evaluation is the most appropriate method for giving an overall impression of the cosmetic result after breast-conserving therapy (BCT). The use of the digitizer is recommended for comparing the cosmetic outcome of two different approaches to BCT or for analyzing cosmetic changes over time.

Breast conserving therapy versus mastectomy for stage I-II breast cancer: 20 year follow-up of the EORTC 10801 phase 3 randomised trial

BACKGROUND The EORTC 10801 trial compared breast-conserving therapy (BCT) with modified radical mastectomy (MRM) in patients with tumours 5 cm or smaller and axillary node negative or positive disease. Compared with BCT, MRM resulted in better local control, but did not affect overall survival or time to distant metastases. We report 20-year follow-up results. METHODS The EORTC 10801 trial was open for accrual between 1980 and 1986 in eight centres in the UK, the Netherlands, Belgium, and South Africa. 448 patients were randomised to BCT and 420 to MRM. Randomisation was done centrally, stratifying patients by institute, carcinoma stage (I or II), and menopausal status. BCT comprised of lumpectomy and complete axillary clearance, followed by breast radiotherapy and a tumour-bed boost. The primary endpoint was time to distant metastasis. This analysis was done on all eligible patients, as they were randomised. FINDINGS After a median follow-up of 22·1 years (IQR 18·5-23·8), 175 patients (42%) had distant metastases in the MRM group versus 207 (46%) in the BCT group. Furthermore, 506 patients (58%) died (232 [55%] in the MRM group and 274 [61%] in the BCT group). No significant difference was observed between BCT and MRM for time to distant metastases (hazard ratio 1·13, 95% CI 0·92-1·38; p=0·23) or for time to death (1·11, 0·94-1·33; 0·23). Cumulative incidence of distant metastases at 20 years was 42·6% (95% CI 37·8-47·5) in the MRM group and 46·9% (42·2-51·6) in the BCT group. 20-year overall survival was estimated to be 44·5% (95% CI 39·3-49·5) in the MRM group and 39·1% (34·4-43·9) in the BCT group. There was no difference between the groups in time to distant metastases or overall survival by age (time to distant metastases: <50 years 1·09 [95% CI 0·79-1·51] vs ≥50 years 1·16 [0·90-1·50]; overall survival <50 years 1·17 [0·86-1·59] vs ≥50 years 1·10 [0·89-1·37]). INTERPRETATION BCT, including radiotherapy, offered as standard care to patients with early breast cancer seems to be justified, since long-term follow-up in this trial showed similar survival to that after mastectomy. FUNDING European Organisation for Research and Treatment of Cancer (EORTC).

Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy.

The GYN GEC-ESTRO working group issued three parts of recommendations and highlighted the pivotal role of MRI for the successful implementation of 3D image-based cervical cancer brachytherapy (BT). The main advantage of MRI as an imaging modality is its superior soft tissue depiction quality. To exploit the full potential of MRI for the better ability of the radiation oncologist to make the appropriate choice for the BT application technique and to accurately define the target volumes and the organs at risk, certain MR imaging criteria have to be fulfilled. Technical requirements, patient preparation, as well as image acquisition protocols have to be tailored to the needs of 3D image-based BT. The present recommendation is focused on the general principles of MR imaging for 3D image-based BT. Methods and parameters have been developed and progressively validated from clinical experience from different institutions (IGR, Universities of Vienna, Leuven, Aarhus and Ljubljana) and successfully applied during expert meetings, contouring workshops, as well as within clinical and interobserver studies. It is useful to perform pelvic MRI scanning prior to radiotherapy (“Pre-RT-MRI examination”) and at the time of BT (“BT MRI examination”) with one MR imager. Both low and high-field imagers, as well as both open and close magnet configurations conform to the requirements of 3D image-based cervical cancer BT. Multiplanar (transversal, sagittal, coronal and oblique image orientation) T2-weighted images obtained with pelvic surface coils are considered as the golden standard for visualisation of the tumour and the critical organs. The use of complementary MRI sequences (e.g. contrast-enhanced T1-weighted or 3D isotropic MRI sequences) is optional. Patient preparation has to be adapted to the needs of BT intervention and MR imaging. It is recommended to visualise and interpret the MR images on dedicated DICOM-viewer workstations, which should also assist the contouring procedure. Choice of imaging parameters and BT equipment is made after taking into account aspects of interaction between imaging and applicator reconstruction, as well as those between imaging, geometry and dose calculation. In a prospective clinical context, to implement 3D image-based cervical cancer brachytherapy and to take advantage of its full potential, it is essential to successfully meet the MR imaging criteria described in the present recommendations of the GYN GEC-ESTRO working group.

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 excision and radiotherapy as primary treatment of breast cancer. Analysis of patient and treatment parameters and local control.

From 1966 to 1979, 235 patients with operable breast cancer were treated by tumor excision and radiotherapy. The actuarial survival at 10 years was 94.8% for stage I and 58% for stage II tumors. Local recurrent cancer was seen in 23/235 patients and was related to T stage, N stage, width of surgical excision, radiation dose to the tumor bed and anatomopathological differentiation. Recurrences were seen in 1/7 of T0, 3/57 (5.2%) of T1, 11/102 (10.8%) of T2 and 2/6 of T3 tumors. Local control in the breast decreased significantly in N1b cases (p = 0.005) or when 3 or more axillary lymph nodes were positive (p = 0.0074). Local control after segmentectomy or tumorectomy was identical. However, a poorer local control was found in 20 cases treated with subtotal resection (p less than 0.05). A clear dose-local control relationship was found in this material, with a 100% local control in all T0, T1 tumors which received more than 1800 ret and all T2 tumors which received more than 2000 ret. As 19 of 23 breast recurrences were seen at the primary site in the breast we believe that booster doses should be given in order to maximise local control.

Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients.

Endocrine treatments of breast cancer patients antagonize estrogen and may lead to consequences of estrogen deprivation including menopausal symptoms. We analyzed the changes in frequency and severity of menopausal symptoms in patients receiving tamoxifen or aromatase inhibitors and identified factors influencing these symptoms. One hundred and eighty-one consecutive postmenopausal breast cancer patients scheduled to start endocrine treatment were included in this prospective study. A menopause symptom questionnaire covering vasomotor, atrophic, psychological, cognitive and somatic symptoms was filled in at baseline, and after 1 and 3 months of therapy. Both first-line tamoxifen and aromatase inhibitors induced an increase in the occurrence and severity of hot flashes (p<0.0001 and p=0.014, respectively). Musculoskeletal pain and dyspareunia significantly increased under first-line non-steroidal aromatase inhibitors (p=0.0039 and p=0.001, respectively), while patients under tamoxifen had significant decrease in sexual interest (p≤0.0001). Younger age was associated with more hot flashes and vaginal dryness at baseline, and after 1 and 3 months of therapy (all p<0.02). We conclude that there are significant differences between the early effects of tamoxifen and aromatase inhibitors on menopausal symptoms of breast cancer patients. Our results underscore the need for safe and effective non-hormonal interventions to alleviate vasomotor and musculoskeletal symptoms which were the most prevalent and severe symptoms.

Image guided brachytherapy in locally advanced cervical cancer: Improved pelvic control and survival in RetroEMBRACE, a multicenter cohort study

PURPOSE Image guided brachytherapy (IGBT) for locally advanced cervical cancer allows dose escalation to the high-risk clinical target volume (HRCTV) while sparing organs at risk (OAR). This is the first comprehensive report on clinical outcome in a large multi-institutional cohort. PATIENTS AND METHODS From twelve centres 731 patients, treated with definitive EBRT±concurrent chemotherapy followed by IGBT, were analysed. Kaplan-Meier estimates at 3/5years were calculated for local control (LC, primary endpoint), pelvic control (PC), overall survival (OS), cancer specific survival (CSS). In 610 patients, G3-4 late toxicity (CTCAEv3.0) was reported. RESULTS Median follow up was 43months, percent of patients per FIGO stage IA/IB/IIA 22.8%, IIB 50.4%, IIIA-IVB 26.8%. 84.8% had squamous cell carcinomas; 40.5% lymph node involvement. Mean EBRT dose was 46±2.5Gy; 77.4% received concurrent chemotherapy. Mean D90 HRCTV was 87±15Gy (EQD210), mean D2cc was: bladder 81±22Gy, rectum 64±9Gy, sigmoid 66±10Gy and bowel 64±9Gy (all EQD23). The 3/5-year actuarial LC, PC, CSS, OS were 91%/89%, 87%/84%, 79%/73%, 74%/65%. Actuarial LC at 3/5years for IB, IIB, IIIB was 98%/98%, 93%/91%, 79%/75%. Actuarial PC at 3/5years for IB, IIB, IIIB was 96%/96%, 89%/87%, 73%/67%. Actuarial 5-year G3-G5 morbidity was 5%, 7%, 5% for bladder, gastrointestinal tract, vagina. CONCLUSION IGBT combined with radio-chemotherapy leads to excellent LC (91%), PC (87%), OS (74%), CSS (79%) with limited severe morbidity.

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.

Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC “boost versus no boost” trial

PURPOSE To evaluate both qualitative and quantitative scoring methods for the cosmetic result after breast-conserving therapy (BCT), and to compare the usefulness and reliability of these methods. METHODS AND MATERIALS In EORTC trial 22881/10882, stage I and II breast cancer patients were treated with tumorectomy and axillary dissection. A total of 5318 patients were randomized between no boost and a boost of 16 Gy following whole-breast irradiation of 50 Gy. The cosmetic result was assessed for 731 patients in two ways. A panel scored the qualitative appearance of the breast using photographs taken after surgery and 3 years later. Digitizer measurements of the displacement of the nipple were also made using these photographs in order to calculate the breast retraction assessment (BRA). The cosmetic results after 3-year follow-up were used to analyze the correlation between the panel evaluation and digitizer measurements. RESULTS For the panel evaluation the intraobserver agreement for the global cosmetic score as measured by the simple Kappa statistic was 0.42, considered moderate agreement. The multiple Kappa statistic for interobserver agreement for the global cosmetic score was 0.28, considered fair agreement. The specific cosmetic items scored by the panel were all significantly related to the global cosmetic score; breast size and shape influenced the global score most. For the digitizer measurements, the standard deviation from the average value of 30.0 mm was 2.3 mm (7.7%) for the intraobserver variability and 2.6 mm (8.7%) for the interobserver variability. The two methods were significantly, though moderately, correlated; some items scored by the panel were only correlated to the digitizer measurements if the tumor was not located in the inferior quadrant of the breast. CONCLUSIONS The intra- and interobserver variability of the digitizer evaluation of cosmesis was smaller than that of the panel evaluation. However, there are some treatment sequelae, such as disturbing scars and skin changes, that can not be evaluated by BRA measurements. Therefore, the methods of cosmetic evaluation used in a study must be chosen in a way that balances reliability and comprehensiveness.

EXTERNAL BEAM RADIOTHERAPY (20 Gy, 2 Gy FRACTIONS) FAILS TO CONTROL THE GROWTH OF CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION: A Review of 111 Cases

Background: Control of the natural course of choroidal neovascularization (CNV) in age‐related macular degeneration (ARMD) is difficult, and laser photocoagulation is recommended in only a subset of patients. Alternative modalities of treatment are under investigation. Methods: We have used external beam radiotherapy (20 gray radiation units [Gy], 2 Gy fractions) to treat CNV in ARMD. A total of 111 patients have been followed for 12‐30 months after radiotherapy. This study evaluates the effect of radiotherapy on the size of CNV, which was digitally measured on serial fluorescein angiograms. Results: Analysis of results in the classic (or mixed classic and occult) CNV group was conclusive for fast growth of CNV and continuous increase of size during follow up. In the occult CNV group, a slowly progressive growth of CNV was demonstrated. In patients with vascularized pigment epithelium detachments, “hot spots„ persisted; in a few patients, flattening of the macula was observed. Nearly all treated patients experienced further loss of vision. CNV growth in the radiotherapy treated eye was usually similar to growth in the untreated fellow eye, and in some, even worse. Conclusion: External beam radiotherapy (20 Gy, 2 Gy fractions) failed to control growth of CNV and was ineffective in stabilizing vision.