Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.

BACKGROUND: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

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.

Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial.

BACKGROUND: Exercise started shortly after breast cancer diagnosis might prevent or diminish fatigue complaints. The Physical Activity during Cancer Treatment (PACT) study was designed to primarily examine the effects of an 18-week exercise intervention, offered in the daily clinical practice setting and starting within 6 weeks after diagnosis, on preventing an increase in fatigue. METHODS: This multi-centre controlled trial randomly assigned 204 breast cancer patients to usual care (n = 102) or supervised aerobic and resistance exercise (n = 102). By design, all patients received chemotherapy between baseline and 18 weeks. Fatigue (i.e., primary outcome at 18 weeks), quality of life, anxiety, depression, and physical fitness were measured at 18 and 36 weeks. RESULTS: Intention-to-treat mixed linear model analyses showed that physical fatigue increased significantly less during cancer treatment in the intervention group compared to control (mean between-group differences at 18 weeks: -1.3; 95 % CI -2.5 to -0.1; effect size -0.30). Results for general fatigue were comparable but did not reach statistical significance (-1.0, 95%CI -2.1; 0.1; effect size -0.23). At 18 weeks, submaximal cardiorespiratory fitness and several muscle strength tests (leg extension and flexion) were significantly higher in the intervention group compared to control, whereas peak oxygen uptake did not differ between groups. At 36 weeks these differences were no longer statistically significant. Quality of life outcomes favoured the exercise group but were not significantly different between groups. CONCLUSIONS: A supervised 18-week exercise programme offered early in routine care during adjuvant breast cancer treatment showed positive effects on physical fatigue, submaximal cardiorespiratory fitness, and muscle strength. Exercise early during treatment of breast cancer can be recommended. At 36 weeks, these effects were no longer statistically significant. This might have been caused by the control participants' high physical activity levels during follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on December 9th, 2009.

Distress in couples approached for genetic counseling and BRCA1/2 testing during adjuvant radiotherapy.

OBJECTIVE: Breast cancer patients mostly rely on their partners for support in dealing with their cancer diagnosis and treatment. Genetic counseling and BRCA1/2 testing during primary treatment may add to demands made on their partners. This study aimed to gain insight into the extent of psychological distress in partners of recently diagnosed patients and to find factors to help identify couples vulnerable to high psychological distress after an active approach for genetic counseling. METHODS: Breast cancer patients and their partners (n=110) completed psychological distress measures (HADS and IES) prior to the approach for counseling (T0), after the approach (T1), and after leaving the genetic counseling protocol (T2). Couples not approached for counseling (n=85) completed similar questionnaires. RESULTS: Partners reported an equal or lower level of distress than patients, with a positive correlation between the two, although partners and patients differed in the course of their distress. Couples approached for genetic counseling did not differ in the level or course of either distress measure from not approached couples. A high baseline distress best predicts long-term high distress in patients and their partners. Younger patients were found to be particularly vulnerable. CONCLUSIONS: The approach for genetic counseling during adjuvant radiotherapy was not associated with extra psychological distress in partners or patients in the first year following the breast cancer diagnosis. A partner's long-term level of distress was significantly associated with that of the patient. Highly distressed patients with highly distressed partners were most likely to experience high distress in the long term.

Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial.

PURPOSE: The local failure rate in patients with locoregionally advanced cervical cancer is 41-72% after radiotherapy (RT) alone, whereas local control is a prerequisite for cure. The Dutch Deep Hyperthermia Trial showed that combining RT with hyperthermia (HT) improved 3-year local control rates of 41-61%, as we reported earlier. In this study, we evaluate long-term results of the Dutch Deep Hyperthermia Trial after 12 years of follow-up. METHODS AND MATERIALS: From 1990 to 1996, a total of 114 women with locoregionally advanced cervical carcinoma were randomly assigned to RT or RT+HT. The RT was applied to a median total dose of 68 Gy. The HT was given once weekly. The primary end point was local control. Secondary end points were overall survival and late toxicity. RESULTS: At the 12-year follow-up, local control remained better in the RT+HT group (37% vs. 56%; p=0.01). Survival was persistently better after 12 years: 20% (RT) and 37% (RT+HT; p=0.03). World Health Organization (WHO) performance status was a significant prognostic factor for local control. The WHO performance status, International Federation of Gynaecology and Obstetrics (FIGO) stage, and tumor diameter were significant for survival. The benefit of HT remained significant after correction for these factors. European Organization for Research and Treatment of Cancer Grade 3 or higher radiation-induced late toxicities were similar in both groups. CONCLUSIONS: For locoregionally advanced cervical cancer, the addition of HT to RT resulted in long-term major improvement in local control and survival without increasing late toxicity. This combined treatment should be considered for patients who are unfit to receive chemotherapy. For other patients, the optimal treatment strategy is the subject of ongoing research.

Barriers to participating in genetic counseling and BRCA testing during primary treatment for breast cancer.

PURPOSE: Little is known about reasons why eligible breast cancer patients decline BRCA mutation testing. They may withdraw at different stages during genetic counseling for different reasons. We prospectively studied perceived benefits and barriers to genetic counseling and BRCA testing in 102 newly diagnosed breast cancer patients approached for genetic counseling at the start of radiotherapy. METHODS: Patients completed questionnaires and participated in interviews at different stages of the counseling protocol. RESULTS: Participation was not influenced by distress, knowledge about hereditary breast cancer, previous genetic testing in relatives, or perceived risks and barriers. Immediate decliners (n = 23) do not believe genetic testing is relevant for them. Patients who decline after pedigree compilation (n = 14) are more hesitant and anxious about the influence of the test result on their future often wishing to postpone further testing. Late decliners (n = 7) withdraw afraid of the test result and/or after a relative's objection. These decliners are not easily identified upon approach because they are similar to patients who receive a DNA test result (n = 58). Notwithstanding their decline, 81% agreed to the timing or would have preferred an earlier approach for genetic counseling. CONCLUSION: Decliners may make more informed decisions after tailored health education, including adequate risk information.

Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical Trial.

IMPORTANCE: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy. OBJECTIVE: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years. INTERVENTIONS: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI. MAIN OUTCOMES AND MEASURES: Time to ipsilateral breast tumor recurrence (IBTR) as first event. RESULTS: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present). CONCLUSIONS AND RELEVANCE: The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02295033.

Short term psychological distress in patients actively approached for genetic counselling after diagnosis of breast cancer.

This prospective study assessed anxiety, depression and breast cancer-specific distress in recently diagnosed breast cancer patients before and after an active approach for genetic counselling at the beginning of adjuvant radiotherapy (mean: 52 days after surgery). Patients completed the hospital anxiety and depression scale (HADS) and the impact of event scale (IES). Psychological distress did not increase after the approach. High anxiety decreased in the comparison group (n=182), whereas breast cancer specific distress decreased in the approached group (n=220). It is concluded that breast cancer patients can be approached for genetic counselling shortly after surgery without additional short-term psychological burden. Patients who are young, single with little social support, less optimistic, use an avoiding coping style, experience a lower quality of life or who are highly distressed prior to approach for genetic counselling, need extra attention. Medical history did not prove to be relevant.

Outcome of high-risk stage IC, grade 3, compared with stage I endometrial carcinoma patients: the Postoperative Radiation Therapy in Endometrial Carcinoma Trial.

PURPOSE: Stage IC, grade 3 endometrial cancer is regarded as a high-risk category. Stage IC, grade 3 patients were not eligible for the randomized Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial, but were registered and received postoperative radiotherapy. PATIENTS AND METHODS: The PORTEC trial included 715 patients with stage IC, grade 1 or 2, and stage IB, grade 2 or 3 endometrial cancer. Patients were randomly assigned after surgery to receive pelvic radiotherapy (RT) or no further treatment. A total of 104 patients with stage IC, grade 3 endometrial cancer were registered, of whom 99 could be evaluated. Patterns of relapse and survival were compared with PORTEC patients receiving RT. Median follow-up was 83 months. RESULTS: The actuarial 5-year rates of locoregional relapse were 1% to 3% for PORTEC patients who received RT, compared with 14% for stage IC, grade 3 patients. Five-year distant metastases rates were 3% to 8% for grade 1 and 2 tumors; 20% for stage IB, grade 3 tumors; and 31% for stage IC, grade 3 tumors. Overall survival rates were 83% to 85% for grades 1 and 2; 74% for stage IB, grade 3; and 58% for stage IC, grade 3 patients (P <.001). In multivariate analysis grade 3 was the most important adverse prognostic factor for relapse and death as a result of endometrial cancer (hazard ratios, 5.4 and 5.5; P <.0001). CONCLUSION: Patients with stage IC, grade 3 endometrial carcinoma are at high risk of early distant spread and endometrial carcinoma-related death. Novel strategies for adjuvant therapy should be explored to improve survival for this patient group.

A prospective study on predictive factors linked to the presence of BRCA1 and BRCA2 mutations in breast cancer patients.

We prospectively screened a hospital-based population of 1000 successive breast cancer patients receiving adjuvant radiotherapy for predictive factors associated with the presence of BRCA1 and BRCA2 mutations. We offered genetic counseling and DNA analysis to selected patients. About 52% of patients showed at least one presumed predictive factor. Hundred and thirty-seven patients underwent DNA analysis. We identified 14 deleterious mutations (10.2%, 95% CI: 5.2-15.3%): 8 BRCA1 mutations and 6 BRCA2 mutations and 14 variants of uncertain clinical significance. Ovarian cancer in the family history was the only factor significantly associated with the presence of a disease-causing mutation (P < 0.01). Eight of the 14 (57%) mutation carriers had no affected first-degree relatives and in 4 of these there was no family history of breast or ovarian cancer. Clinicians should offer genetic counseling and DNA testing to breast cancer patients from families with breast and ovarian cancer, and to patients who are younger than 45 years when they are diagnosed with breast cancer.

Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review.

PURPOSE: In 2000, the results of the multicenter Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial were published. This trial included 714 Stage I endometrial carcinoma patients randomly assigned to postoperative pelvic radiotherapy (RT) or no further treatment, excluding those with Stage IC, Grade 3, or Stage IB, Grade 1 lesions. Radiotherapy significantly decreased the risk of locoregional recurrence (4% vs. 14%), without affecting overall survival. In this report the long-term outcome and results with central pathology review are presented. METHODS AND MATERIALS: The slides of 569 patients (80%) could be obtained for pathology review. Median follow-up for patients alive was 97 months. Analysis was done according to the intention-to-treat principle. The primary study endpoints were locoregional recurrence and death. RESULTS: Ten-year locoregional relapse rates were 5% (RT) and 14% (controls; p < 0.0001), and 10-year overall survival was 66% and 73%, respectively (p = 0.09). Endometrial cancer related death rates were 11% (RT) and 9% (controls; p = 0.47). Pathology review showed a substantial shift from Grade 2 to Grade 1, but no significant difference for Grade 3. When cases diagnosed at review as Grade 1 with superficial myometrial invasion were excluded from the analysis, the results remained essentially the same, with 10-year locoregional recurrence rates of 5% (RT) and 17% (controls; p < 0.0001). CONCLUSIONS: In view of the significant locoregional control benefit, radiotherapy remains indicated in Stage I endometrial carcinoma patients with high-risk features for locoregional relapse.

Interobserver variability of clinical target volume delineation of glandular breast tissue and of boost volume in tangential breast irradiation.

BACKGROUND AND PURPOSE: To determine the interobserver variability of clinical target volume delineation of glandular breast tissue and of boost volume in tangential breast irradiation. PATIENTS AND METHODS: Eighteen consecutive patients with left sided breast cancer treated by breast conserving surgery agreed to participate in our study. Volumes of the glandular breast tissue (CTV breast) and of the boost (CTV boost) were delineated by five observers. We determined 'conformity indices' (CI) and the ratio between the volume of each CTV and the mean volume of all CTVs (CTV ratio). Subsequently we determined the most medial, lateral, anterior, posterior, cranial and caudal extensions both of CTV breast and CTV boost for all observers separately. RESULTS: The mean CI breast was 0.87. For one observer we noted the highest CTV ratio in 17 out of 18 cases. No association was noted between CI breast and menopausal status. The mean CI boost was 0.56. We did not find a relation between the presence or absence of clips and the CI boost. For another observer we noted the lowest CTV boost ratio in 10 out of 17 cases. CONCLUSIONS: We recommend that each institute should determine its interobserver variability with respect to CTV breast and CTV boost before implementing the delineation of target volumes by planning CT in daily practice.

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.

Effect of age on response to palliative radiotherapy and quality of life in patients with painful bone metastases.

BACKGROUND: Multimorbidity and declining performance in elderly cancer patients may result in less treatment benefit. We investigated whether age is a predictor for pain response and quality of life (QoL) after radiotherapy in patients with painful bone metastases. METHODS: The database of the Dutch Bone Metastasis Study was used (1996-1999). 1157 patients, irradiated for painful bone metastases, rated their pain, QoL-domains and overall health at baseline and during follow-up. Response was calculated taking into account changes in pain score and medication. Patients were grouped into three age cohorts: A: <65 (n=520), B: 65-74 (n=410) and C: ⩾75years (n=227). RESULTS: No significant difference existed in pain response between cohorts: 78% in cohort A, 74% in B and 67% in C. When assessing baseline QoL, a significant difference in activity level was noticed, with more impairment in elderly compared to younger patients (C versus B (p=0.01), C versus A (p<0.001)). Other QoL-domains were similar at baseline and during follow-up among cohorts. A pain response was significantly associated with improvement of health-related QoL (OR 3.74, 95% CI 2.66-5.25). CONCLUSION: The majority of elderly patients with painful bone metastases responded to radiotherapy and showed comparable overall QoL compared to their younger counterparts. Age is not a predictor for pain response or QoL.

Fifteen-year radiotherapy outcomes of the randomized PORTEC-1 trial for endometrial carcinoma.

PURPOSE: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. PATIENTS AND METHODS: The PORTEC trial (1990-1997) included 714 patients with Stage IC Grade 1-2 or Stage IB Grade 2-3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. RESULTS: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). CONCLUSIONS: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC.

Long-term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post operative radiation therapy in endometrial carcinoma 1 (PORTEC-1) trial.

PURPOSE: To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial. PATIENTS AND METHODS: Between 1990 and 1997, 714 patients with stage IC grade 1 to 2 or IB grade 2 to 3 EC were randomly allocated to pelvic external-beam radiotherapy (EBRT) or no additional treatment (NAT). HRQL was evaluated with the Short Form 36-Item (SF-36) questionnaire; subscales from the European Organisation for Research and Treatment of Cancer (EORTC) PR25 module for bowel and bladder symptoms and the OV28 and CX24 modules for sexual symptoms; and demographic questions. Analysis was by intention-to-treat. RESULTS: Median follow-up was 13.3 years. The 15-year actuarial locoregional recurrence rates were 5.8% for EBRT versus 15.5% for NAT (P < .001), and 15-year overall survival was 52% versus 60% (P = .14). Of the 351 patients confirmed to be alive with correct address, 246 (70%) returned the questionnaire. Patients treated with EBRT reported significant (P < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after EBRT (day and night use, 42.9% v 15.2% for NAT; P < .001). Patients treated with EBRT reported lower scores on the SF-36 scales "physical functioning" (P = .004) and "role-physical" (P = .003). CONCLUSION: EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower physical and role-physical functioning, even 15 years after treatment. Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC.

Changes in excision cavity volume: prediction of the reduction in absolute volume during breast irradiation.

PURPOSE: The aim of this study was to determine the changes in the excision cavity volume due to the resolution of the surgical effects during the whole breast treatment. MATERIALS AND METHODS: Seventy-seven patients with early-stage (T1-2 N0) breast cancer treated with breast-conserving therapy were included for this study. All patients underwent a standard planning computed tomography (CT) scan before irradiation treatment. A second CT scan was performed in the week before the start of the boost. Excision cavity volumes were delineated based on the surgical clips and the (surrounding) seroma or hematoma or other surgical changes on both scans by an experienced physician. This resulted in the gross tumor volumes GTV1 and GTV2. RESULTS: The delineated volumes of the GTVs were on average 78.7 cm(3) (range, 1.1-236.0 cm(3)) and 29.7 cm(3) (range, 1.3-123.6 cm(3)) for, respectively, GTV1 and GTV2. The time between the CT scans was on average 37 days (range, 29-74 days). This resulted in a reduction of on average 62%. The absolute reduction per day of the GTV1 was -1.3 cm(3)/day (range, 0.3 to -5.4 cm(3)/day). A linear correlation (correlation coefficient r(2) = 0.81) was observed between the absolute volume of GTV1 and the absolute reduction per day. CONCLUSION: A significant reduction in excision cavity volume during whole breast irradiation was shown. The observed correlation might be helpful in the decision to perform a second CT scan to adapt the treatment plan.

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.

BRCA1/2 mutation testing in breast cancer patients: a prospective study of the long-term psychological impact of approach during adjuvant radiotherapy.

This study assessed psychological distress during the first year after diagnosis in breast cancer patients approached for genetic counseling at the start of adjuvant radiotherapy and identified those vulnerable to long-term high distress. Of the approached patients some chose to receive a DNA test result (n = 58), some were approached but did not fulfill criteria for referral (n = 118) and some declined counseling and/or testing (n = 44). The comparative group consisted of patients not eligible for genetic counseling (n = 182) and was therefore not approached. Patients actively approached for genetic counseling showed no more long-term distress than patients not eligible for such counseling. There were no differences between the subgroups of approached patients. Predictors for long-term high distress or an increase in distress over time were pre-existing high distress and a low quality of life, having children, and having no family members with breast cancer. It is concluded that breast cancer patients can be systematically screened and approached for genetic counseling during adjuvant radiotherapy without imposing extra psychological burden. Patients vulnerable to long-term high distress already displayed high distress shortly after diagnosis with no influence of their medical treatment on their level of distress at long-term.

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.