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.

FDG-PET-CT for staging of high-risk breast cancer patients reduces the number of further examinations: A pilot study.

AIM: To determine the additional value of FDG-PET-CT as compared to conventional staging (CS) in high-risk breast cancer patients. PATIENTS AND METHODS: Thirty-one high-risk breast cancer patients, 14 of whom had recurrent breast cancer, were included in this study, which took place between June 2005 and March 2008. None of the patients had clinical signs of distant metastases. FDG-PET-CT scanning was added to CS, which consisted of a chest x-ray, liver ultrasonography or CT, and bone scintigraphy. Median follow-up was 17 months (6-41 months). FDG-PET-CT was considered to have additional value to CS if it led to a change in treatment plan or if it made additional examinations to confirm or deny findings on CS unnecessary. RESULTS: FDG-PET-CT was considered to have additional value to CS in 13 patients (42% [95% CI: 23-61]). In five patients (16% [95% CI: 1-31]), FDG-PET-CT led to a change in treatment plan by identifying nodal metastases in the internal mammary chain (IMC; N = 3) or in the mediastinum (N = 2). In nine patients (29% [95% CI: 11-47]), FDG-PET-CT would have prevented the need for additional examinations; in seven of these nine patients, distant metastases were suggested in bone or liver on CS, but these did not show FDG uptake. CONCLUSIONS: FDG-PET-CT was found to have additional value to CS in 42% of the patients. To optimize cost-effectiveness, the main challenge now is to improve the selection of patients in whom FDG-PET-CT has additional value to CS.

Prone breast irradiation for pendulous breasts.

The purpose of this study was to quantify the differences in doses in the organs at risk and to compare the PTV coverage and dose homogeneity of patients with pendulous breasts between prone and supine position. In 10 patients a CT-based treatment plan was made in prone and supine position. Data about dose homogeneity and doses to organs at risk were collected. Dose homogeneity turned out to be better in prone position and doses in organs at risk were lower, but with the current technique, this occurred at the cost of a reduced PTV coverage.

Radiation-induced bullous pemphigoid: a systematic review of an unusual radiation side effect.

BACKGROUND: Percutaneous radiotherapy (RT) may cause a range of acute and late side effects of the skin within the irradiated area. In rare cases radiotherapy can cause bullous pemphigoid (BP). BP is reported to occur mainly within irradiated fields following radiation treatment. Exceptionally, BP may arise during RT. It is unclear which mechanism exactly triggers BP following megavoltage irradiation and whether there is a potential association with hormonal anticancer treatment. METHODS: A systematic literature based review was performed. Publications reporting histologically confirmed BP and a treatment with RT were retrieved based on a standardized query using electronic databases. A standardized quality assessment was applied. RESULTS: Out of 306 potentially relevant publications 21 were identified to be relevant and included in this review. An association between RT and BP was reported in 27 patients. The majority developed BP after RT and a median dose of 50 Gy. Four patients developed BP during RT after a minimal dose of 20 Gy. CONCLUSIONS: BP induced by RT was observed predominantly in patients with breast cancer. In all reported cases, there is a clear relationship with RT. Therefore, BP may be considered as RT-induced side effect. RT can induce a BP following a minimal dose of 20 Gy. New biological agents may play a role in the future treatment of BP.

Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882.

PURPOSE: To determine whether the effect of an additional "boost" radiation after breast conservative therapy (BCT) on local control depends on age and evaluate the impact of a treatment policy with a threshold for age. PATIENTS AND METHODS: We used data from EORTC 22881-10882 trial, with median follow-up of 77.4 months. Patients receiving BCT and 50Gy whole breast irradiation were randomized to no boost and 16Gy boost (N=5318). RESULTS: In univariate analysis, a boost reduced local failure by a factor of 2 (P<0.0001). Multivariate analysis showed local control increased with age (P=0.0003). There was no evidence that the relative effect of a boost on local control depends on age (P=0.97) However in younger patients the 5-year local failure was higher, therefore the absolute reduction was greater. If the threshold-age for boost treatment were set at 40 years, 8.4% of the study population would receive a boost, resulting in a 5-year local failure of 6.1% in the study population. Changing the threshold-age to 60 years, 67% of the study population would receive a boost and the 5-year local failure would be reduced to 4.4%. CONCLUSIONS: In younger patients a boost dose resulted in a greater absolute reduction of local failure. The relative risk reduction was however similar for all ages. Applying a treatment policy with a threshold-age of 60 would result in 0.6% increase in local failure in the total study population, while sparing the boost to 1/3 of the patients.

Set-up verification and 2-dimensional electronic portal imaging device dosimetry during breath hold compared with free breathing in breast cancer radiation therapy.

PURPOSE: To compare set-up and 2-dimensional (2D) electronic portal imaging device (EPID) dosimetry data of breast cancer patients treated during voluntary moderately deep inspiration breath hold (vmDIBH) and free breathing (FB). METHODS AND MATERIALS: Set-up data were analyzed for 29 and 51 consecutively treated patients, irradiated during FB and vmDIBH, respectively. Of the 51 vmDIBH patients, the first 25 had undergone an extra trained computed tomography (CT) scan and used an additional "breathing stick" (vmDIBH_trained). The last 26 patients did not use the breathing stick and did not undergo a trained CT (vmDIBH_untrained). The delivered 2D transit dose was measured with EPID in 15 FB and 28 vmDIBH patients and compared with a 2D predicted dose by calculating global gamma values γ using 5% and 5 mm as dose difference and distance-to-agreement criteria, respectively. Measurements with a percentage of pixels with an absolute gamma value > 1 (|γ| > 1) greater than 10% were classified as deviating. RESULTS: Only small, sub-millimeter differences were seen in the set-up data between the different patient groups. The mean of means, systematic error, and random error ranged from - 0.6 mm to 3.3 mm. The percentage of pixels with |γ| > 1 for all patients was 9.8% (2-25.8). No statistically significant differences were observed between the patient groups. In total, 38% of the gamma images were classified as deviating: 43.6% in vmDIBH_untrained patients compared with 38.0% in vmDIBH_trained patients and 33.3% in FB patients (P > .05). CONCLUSION: Both set-up and 2D EPID dosimetry data indicate that reproducibility of radiation therapy for patients treated during FB and vmDIBH is similar. Small but not significant differences in 2D EPID dosimetry were observed. Further investigation with 3-dimensional EPID dosimetry is recommended to investigate the clinical relevance of deviant gamma images.

The influence of the boost technique on local control in breast conserving treatment in the EORTC 'boost versus no boost' randomised trial.

BACKGROUND AND PURPOSE: The EORTC Trial 22881/10882 investigating the role of a boost dose in breast conserving therapy demonstrated a significantly better local control rate with the higher radiotherapy dose, especially in women younger than 50 years of age. This paper investigates the potential impact of the different boost techniques on local control and on fibrosis after breast conserving therapy. PATIENTS AND METHODS: From 1989 to 1996, 2661 patients were randomised to receive a boost dose of 16Gy to the primary tumour bed after microscopically complete tumorectomy and 50Gy whole breast irradiation. The choice of the boost technique was left to the treating investigator. Treatment data were prospectively recorded as well as the clinical outcome in terms of local control and fibrosis. Sixty-three percent of the patients received a boost dose with fast electrons, 28% with photon beams and 9% with interstitial brachytherapy. RESULTS: At 5 years, local recurrences were seen in 74 of the 1635 patients who received an electron boost (4.8%, CI 3.6-5.9%), in 28 of the 753 patients who received a photon boost (4.0%, CI 3.4-5.5%) and in 6 of the 225 patients after an interstitial boost (2.5%, CI 0.3-4.6%). The grade of fibrosis in the whole breast as well as at the primary tumour bed, as scored by the treating radiation oncologist, was similar in the three groups. CONCLUSIONS: Although the three groups are of a rather unequal size, the results of the interstitial boost seem similar in terms of fibrosis and at least as good in terms of local control, despite a lower treatment volume and a longer overall treatment time.

Forward intensity-modulated radiotherapy planning in breast cancer to improve dose homogeneity: feasibility of class solutions.

PURPOSE: To explore forward planning methods for breast cancer treatment to obtain homogeneous dose distributions (using International Commission on Radiation Units and Measurements criteria) within normal tissue constraints and to determine the feasibility of class solutions. METHODS AND MATERIALS: Treatment plans were optimized in a stepwise procedure for 60 patients referred for postlumpectomy irradiation using strict dose constraints: planning target volume (PTV)(95%) of >99%; V(107%) of <1.8 cc; heart V(5 Gy) of <10% and V(10 Gy) of <5%; and mean lung dose of <7 Gy. Treatment planning started with classic tangential beams. Optimization was done by adding a maximum of four segments before adding beams, in a second step. A breath-hold technique was used for heart sparing if necessary. RESULTS: Dose constraints were met for all 60 patients. The classic tangential beam setup was not sufficient for any of the patients; in one-third of patients, additional segments were required (<3), and in two-thirds of patients, additional beams (<2) were required. Logistic regression analyses revealed central breast diameter (CD) and central lung distance as independent predictors for transition from additional segments to additional beams, with a CD cut-off point at 23.6 cm. CONCLUSIONS: Treatment plans fulfilling strict dose homogeneity criteria and normal tissue constraints could be obtained for all patients by stepwise dose intensity modification using limited numbers of segments and additional beams. In patients with a CD of >23.6 cm, additional beams were always required.

Is contrast enhancement required to visualize a known breast tumor in a pre-operative CT scan?

BACKGROUND AND PURPOSE: A pre-operative CT scan with contrast enhancement (CE) has recently been proposed to improve tumorbed delineation in breast conserving therapy. However, it is not clear whether CE is required for visualization of a known breast tumor. The main aims of this study were to compare the sensitivity of a CE-CT scan with a native CT scan (i.e. without CE) and to identify characteristics predictive for the requirement of CE. PATIENTS AND METHODS: Both a CE-CT and a native CT were made in 58 breast cancer patients (age 37-75 yr), prior to breast conserving surgery. Visibility of the tumor on CT was scored by three observers (clearly visible/doubtful/not visible). Age, tumor size, palpable tumor yes/no, histology, and visibility on mammography were analyzed with respect to the visibility of the tumor on the native CT. RESULTS: The sensitivity for tumor detection was better for CE-CT (95%) than for native CT (83%) (p<0.001). Only mammographic visibility scores appeared to be significantly correlated with the visibility of the tumor on the native CT (p=0.013). CONCLUSION: In most patients CE is not required to visualize a known breast tumor. Mammographic visibility is a good parameter to decide on the use of CE.

Customized computed tomography-based boost volumes in breast-conserving therapy: use of three-dimensional histologic information for clinical target volume margins.

PURPOSE: To determine the difference in size between computed tomography (CT)-based irradiated boost volumes and simulator-based irradiated volumes in patients treated with breast-conserving therapy and to analyze whether the use of anisotropic three-dimensional clinical target volume (CTV) margins using the histologically determined free resection margins allows for a significant reduction of the CT-based boost volumes. PATIENTS AND METHODS: The CT data from 49 patients were used to delineate a planning target volume (PTV) with isotropic CTV margins and to delineate a PTV(sim) that mimicked the PTV as delineated in the era of conventional simulation. For 17 patients, a PTV with anisotropic CTV margins was defined by applying customized three-dimensional CTV margins, according to the free excision margins in six directions. Boost treatment plans consisted of conformal portals for the CT-based PTVs and rectangular fields for the PTV(sim). RESULTS: The irradiated volume (volume receiving > or =95% of the prescribed dose [V(95)]) for the PTV with isotropic CTV margins was 1.6 times greater than that for the PTV(sim): 228 cm(3) vs. 147 cm(3) (p < .001). For the 17 patients with a PTV with anisotropic CTV margins, the V(95) was similar to the V(95) for the PTV(sim) (190 cm(3) vs. 162 cm(3); p = NS). The main determinant for the irradiated volume was the size of the excision cavity (p < .001), which was mainly related to the interval between surgery and the planning CT scan (p = .029). CONCLUSION: CT-based PTVs with isotropic margins for the CTV yield much greater irradiated volumes than fluoroscopically based PTVs. Applying individualized anisotropic CTV margins allowed for a significant reduction of the irradiated boost volume.

Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial.

PURPOSE: To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT). PATIENTS AND METHODS: In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed. RESULTS: The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively. CONCLUSION: Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'.

The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P<0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P<0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P<0.01) if WBI was given with >6 MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis.

Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial.

PURPOSE: To investigate the long-term impact of a boost radiation dose of 16 Gy on local control, fibrosis, and overall survival for patients with stage I and II breast cancer who underwent breast-conserving therapy. PATIENTS AND METHODS: A total of 5,318 patients with microscopically complete excision followed by whole-breast irradiation of 50 Gy were randomly assigned to receive either a boost dose of 16 Gy (2,661 patients) or no boost dose (2,657 patients), with a median follow-up of 10.8 years. RESULTS: The median age was 55 years. Local recurrence was reported as the first treatment failure in 278 patients with no boost versus 165 patients with boost; at 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the no boost and the boost group, respectively (P < .0001). The hazard ratio of local recurrence was 0.59 (0.46 to 0.76) in favor of the boost, with no statistically significant interaction per age group. The absolute risk reduction at 10 years per age group was the largest in patients