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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. [ABSTRACT FROM AUTHOR]

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.

Genetic counseling and DNA testing (GCT) for breast cancer is increasingly being actively offered to newly diagnosed patients. Little is known about the consequences of such an approach. Therefore, the long-term psychosocial and medical impact of referring breast cancer patients for GCT during an early phase of treatment was studied. A group of 112 breast cancer patients who had been actively offered GCT during adjuvant radiotherapy 7-14 years earlier, returned a self-report questionnaire. We compared their experiences with a group of 127 breast cancer patients who had not met the criteria for GCT. In total, 239 women participated in this long-term follow-up study (72% response rate). Nearly 75% of them had received regular mammography surveillance in the past 3 years. Preventive surgery was reported more often in the counseling group (specifically in the BRCA1/2 mutation carriers). Like the comparative group, only a minority of patients who had received GCT were experiencing high levels of depression (5%) or psychological distress (14%). Breast cancer patients can be actively approached and referred for GCT at the beginning of their radiotherapy without a threat to psychological functioning in the long term., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: In breast cancer treated with breast-conserving radiotherapy, the influence of the boost dose on cosmetic outcome after long-term follow-up is unknown., Patients and Methods: We included 348 patients participating in the EORTC 'boost versus no boost' mega trial with a minimum follow-up of 6 years. Digitalised pictures were analysed using specific software, enabling quantification of seven relative asymmetry features associated with different aspects of fibrosis., Results: After 3 years, we noted a statistically significantly poorer outcome for the boost patients for six features compared with those of the no boost patients. Up to 9 years of follow-up, results continued to worsen in the same magnitude for the both patient groups. We noted the following determinants for poorer outcome: (i) boost treatment, (ii) larger excision volumes, (iii) younger age, (iv) tumours located in the central lower quadrants of the breast and (v) a boost dose administered with photons., Conclusions: A boost dose worsens the change in breast appearance in the first 3 years. Moreover, the development of fibrosis associated with whole-breast irradiation, as estimated with the relative asymmetry features, is an ongoing process until (at least) 9 years after irradiation.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

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.

This study explores knowledge about hereditary breast cancer, attitudes about BRCA testing and referral pattern to a family cancer clinic among medical specialists. A total of 92 questionnaires were completed by surgeons (38), medical oncologists (29), radiation oncologists (13) and radiologists (12). The response rate was 51%. A substantial (11-56%) proportion of medical specialists do not refer patients who meet current criteria for BRCA testing. Although questions on inheritance were less well answered, overall knowledge was good. They had a positive attitude, but were concerned about the distress DNA testing might cause to family members. The majority (75%) stated that the best time for referral is after adjuvant therapy or during follow-up, but another important determinant was the patient's wish or need (12%). Further studies are needed to gain insight into the actual referral process, while ongoing training of medical specialists about genetic aspects of breast cancer is also necessary.

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.

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.

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.

Purpose: To investigate the impact of the boost dose to the primary tumour bed in the framework of breast conserving therapy on local control, cosmetic results, fibrosis and overall survival for patients with early stage breast cancer., Patients and Methods: Five thousand five hundred and sixty-nine patients after lumpectomy followed by whole breast irradiation of 50 Gy were randomised. After a microscopically complete lumpectomy (5318 patients), the boost doses were either 0 or 16 Gy, while after a microscopically incomplete (251 patients) lumpectomy randomisation was between 10 and 26 Gy. The results at a median follow-up of 10 years are presented., Results: At 10 years, the cumulative incidence of local recurrence was 10.2% versus 6.2% for the 0 Gy and the 16 Gy boost groups (p < 0.0001) and 17.5% versus 10.8% for the 10 and 26 Gy boost groups, respectively (p > 0.1). There was no statistically significant interaction per age group but recurrences tended to occur earlier in younger patients. As younger patients had a higher cumulative risk of local relapse by year 10, the magnitude of the absolute 10-year risk reduction achieved with the boost decreased with increasing age. Development of fibrosis was significantly dependent on the boost dose with a 10-year rate for severe fibrosis of 1.6% after 0 Gy, 3.3% after 10 Gy, 4.4% after 16 Gy and 14.4% after 26 Gy, respectively., Conclusion: An increase of the dose with 16 Gy improved local control for patients after a complete lumpectomy only. The development of fibrosis was clearly dose dependent. With 10 years median follow-up, no impact of survival was observed.

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.

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.

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.

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.

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.

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.

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.

In the application of regional hyperthermia, optimization of the temperature distribution remains necessary. One of the tools that might be used is a modest increase in the systemic temperature to diminish cooling by blood perfusion. This study investigates (1) if it is feasible to increase the systemic temperature by applying other cooling strategies, without inducing unacceptable systemic stress, and (2) whether a rise in systemic temperature results in improvement of tumour temperatures. Eleven patients with locally advanced cervical carcinoma and 12 patients with locally advanced prostate carcinoma were treated with our Coaxial TEM regional hyperthermia system. In this system, the temperature of the open water bolus can be easily adjusted. Two cooling methods were applied alternately, one with a relatively low water temperature (method A), the other with a higher water bolus temperature in combination with extensive head/chest cooling by a hand shower (method B). Method B resulted in significantly higher systemic temperatures, for both patient groups separately (0.8, respectively, 0.5 degrees C) and for the total patient group (0.7 degrees C). Additionally, all tumour index temperatures were higher. For the combined group (for T50: 0.4 degrees C) and for the cervix group (for T50: 0.7 degrees C), it reached statistical significance. The raise in core temperature led to a significantly higher increase in heart rate. For the group of cervix patients, higher systemic temperatures resulted in more treatment-limiting systemic stress. For the prostate patients, systemic stress was not an important issue. Since the raise in systemic temperature did not influence the overall tolerance of treatment, method B could be applied to this group. However, the increases in tumour temperatures were small, and potential hazards of systemic temperature increase should be considered.

A study was performed on regional hyperthermia for patients with locally advanced prostate carcinoma. The primary objective was to analyse the thermometry data with an emphasis on the possibility of replacing invasive thermometry by tumour-related intra-luminal thermometry. Fourteen patients were treated with a combination of conformal external beam radiotherapy (70 Gy) and hyperthermia. Hyperthermia was delivered using the Coaxial TEM system, one treatment per week, to a total of five treatments. Thermometry was performed in bladder, urethra, rectum and esophagus. Invasive thermometry in the prostate was carried out during one or two treatments for each patient by placing transperineally a central and a peripheral catheter. Heterogeneous temperature distributions were measured in the prostate. The mean average invasive temperature range was 1.1 degrees C. Due to the temperature heterogeneity and a limited number of thermometry sensors (mean 7, range 2-13), large variability between treatments and patients existed regarding achieved temperatures and dose. The mean invasive T90 was 40.2 +/- 0.6 degrees C and T50 was 40.8 +/- 0.6 degrees C. The mean Cum min T90>40.5 degrees C per treatment was 22 (range 0-50). Importantly, intra-luminal temperatures did not reliably predict invasively measured temperatures. Invasive thermometry, therefore, remains compulsory to calculate a thermal dose for an individual patient. Changes in temperature during treatment, measured by the urethral sensors, corresponded well with changes in temperature measured by the individual invasive sensors. Similar comparison of rectal temperature changes with intra-prostatic temperature changes was not as predictive. The similarity in temperature changes between the urethral and interstial sites, suggests that urethral temperatures are sufficient for treatment optimization. The SAR profile did not correspond with the temperature profile indicating heterogeneous perfusion. Although regional hyperthermia in combination with external beam radiotherapy for locally advanced prostate carcinoma is clinically feasible, the question on the importance of invasive thermometry remains.

Objective: The aim of this study was to determine the rates of local control and survival after relapse in patients with stage I endometrial cancer treated in the multicenter randomized PORTEC trial., Methods: The PORTEC trial included 715 patients with stage 1 endometrial cancer, either grade 1 or 2 with deep (>50%) myometrial invasion or grade 2 or 3 with <50% invasion. In all cases an abdominal hysterectomy was performed, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy) or no further treatment., Results: The analysis was done by intention-to-treat. A total of 714 patients were evaluated. At a median follow-up of 73 months, 8-year actuarial locoregional recurrence rates were 4% in the RT group and 15% in the control group (P < 0.0001). The 8-year actuarial overall survival rates were 71 (RT group) and 77% (control group, P = 0.18). Eight-year rates of distant metastases were 10 and 6% (P = 0.20). The majority of the locoregional relapses were located in the vagina, mainly in the vaginal vault. Of the 39 patients with isolated vaginal relapse, 35 (87%) were treated with curative intent, usually with external RT and brachytherapy, and surgery in some. A complete remission (CR) was obtained in 31 of the 35 patients (89%), and 24 patients (77%) were still in CR after further follow-up. Five patients subsequently developed distant metastases, and 2 had a second vaginal recurrence. The 3-year survival after first relapse was 51% for patients in the control group and 19% in the RT group (P = 0.004). The 3-year survival after vaginal relapse was 73%, in contrast to 8 and 14% after pelvic and distant relapse (P < 0.001). At 5 years, the survival after vaginal relapse was 65% in the control group compared to 43% in the RT group., Conclusion: Survival after relapse was significantly better in the patient group without previous RT. Treatment for vaginal relapse was effective, with 89% CR and 65% 5-year survival in the control group, while there was no difference in survival between patients with pelvic relapse and those with distant metastases. As pelvic RT was shown to improve locoregional control significantly, but without a survival benefit, its use should be limited to those patients at sufficiently high risk (15% or over) for recurrence in order to maximize local control and relapse-free survival.

Purpose: To compare the treatment complications for patients with Stage I endometrial cancer treated with surgery and pelvic radiotherapy (RT) or surgery alone in a multicenter randomized trial., Methods and Materials: The Postoperative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial included patients with endometrial cancer confined to the uterine corpus, either Grade 1 or 2 with more than 50% myometrial invasion, or Grade 2 or 3 with less than 50% myometrial invasion. Surgery consisted of an abdominal hysterectomy and oophorectomy, without lymphadenectomy. After surgery, patients were randomized to receive pelvic RT (46 Gy), or no further treatment. A total of 715 patients were randomized. Treatment complications were graded using the French-Italian glossary., Results: The analysis was done at a median follow-up duration of 60 months. 691 patients were evaluable. Five-year actuarial rates of late complications (Grades 1-4) were 26% in the RT group and 4% in the control group (p < 0.0001). Most were Grade 1 complications, with 5-year rates of 17% in the RT group and 4% in the control group. All severe (Grade 3-4) complications were observed in the RT group (3%). Most complications were of the gastrointestinal tract. The symptoms resolved after some years in 50% of the patients. Grade 1-2 genitourinary complications occurred in 8% of the RT patients, and 4% of the controls. Bone complications occurred in 4 RT patients (1%). Seven patients (2%) discontinued their RT due to acute RT-related symptoms. Patients with acute morbidity had an increased risk of late RT complications (p = 0.001). The 4-field box technique was associated with a lower risk of late complications (p = 0.06)., Conclusion: Pelvic RT increases the morbidity of treatment in Stage I endometrial cancer. In the PORTEC trial, severe complications occurred in 3% of treated patients, and over 20% experienced mild (mostly Grade 1) symptoms. Patients with acute RT-related morbidity had an increased risk of late complications. As pelvic RT in Stage I endometrial carcinoma was shown to significantly reduce the rate of locoregional recurrence, but without a survival benefit, its use in the adjuvant setting requires careful patient selection (treating those at increased risk of relapse), and the use of treatment schemes with the lowest risk of morbidity.

Germline mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ovarian cancer. Identification of breast cancer patients carrying mutations of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of the disease or both. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary breast/ovarian cancer, we identified a germline mutation in the BRCA2 gene (3034del4) in a patient with early onset breast cancer and no strong family history of the disease. Subsequent molecular analysis in her parents showed that neither of them carried the mutation. Paternity was confirmed using a set of highly polymorphic markers, showing that the proband carried a de novo germline mutation in the BRCA2 gene. Interestingly, 3034del4 is a recurrent mutation occurring in a putative mutation prone region of the BRCA2 gene. Our study presents the first case in which a de novo germline mutation in the BRCA2 gene has been identified, and supports previous results of haplotype studies, confirming that the 3034del4 mutation has multiple independent origins.

Background: Postoperative radiotherapy for International Federation of Gynaecology and Obstetrics (FIGO) stage-1 endometrial carcinoma is a subject of controversy due to the low relapse rate and the lack of data from randomised trials. We did a multicentre prospective randomised trial to find whether postoperative pelvic radiotherapy improves locoregional control and survival for patients with stage-1 endometrial carcinoma., Methods: Patients with stage-1 endometrial carcinoma (grade 1 with deep [> or =50%] myometrial invasion, grade 2 with any invasion, or grade 3 with superficial [<50%] invasion) were enrolled. After total abdominal hysterectomy and bilateral salpingo-oophorectomy, without lymphadenectomy, 715 patients from 19 radiation oncology centres were randomised to pelvic radiotherapy (46 Gy) or no further treatment. The primary study endpoints were locoregional recurrence and death, with treatment-related morbidity and survival after relapse as secondary endpoints., Findings: Analysis was done according to the intention-to-treat principle. Of the 715 patients, 714 could be evaluated. The median duration of follow-up was 52 months. 5-year actuarial locoregional recurrence rates were 4% in the radiotherapy group and 14% in the control group (p<0.001). Actuarial 5-year overall survival rates were similar in the two groups: 81% (radiotherapy) and 85% (controls), p=0.31. Endometrial-cancer-related death rates were 9% in the radiotherapy group and 6% in the control group (p=0.37). Treatment-related complications occurred in 25% of radiotherapy patients, and in 6% of the controls (p<0.0001). Two-thirds of the complications were grade 1. Grade 3-4 complications were seen in eight patients, of which seven were in the radiotherapy group (2%). 2-year survival after vaginal recurrence was 79%, in contrast to 21% after pelvic recurrence or distant metastases. Survival after relapse was significantly (p=0.02) better for patients in the control group. Multivariate analysis showed that for locoregional recurrence, radiotherapy and age below 60 years were significant favourable prognostic factors., Interpretation: Postoperative radiotherapy in stage-1 endometrial carcinoma reduces locoregional recurrence but has no impact on overall survival. Radiotherapy increases treatment-related morbidity. Postoperative radiotherapy is not indicated in patients with stage-1 endometrial carcinoma below 60 years and patients with grade-2 tumours with superficial invasion.

Percutaneous endoscopic gastrostomy catheters are frequently placed in patients with pharyngeal tumors. In this article, we report a patient with a metastasis of a large hypopharyngeal carcinoma in the gastrostomy tract, probably caused by placement of a percutaneous endoscopic gastrostomy catheter by the pull method. The metastasis decreased considerably in size after high-dose radiation therapy (as had the original hypopharyngeal tumor). The patient subsequently had a curative resection of the residual metastatic tumor, but one month after the operation he died of a cerebrovascular accident.

In the period from 1981 to 1986, 85 patients with ovarian carcinoma stage I and II were treated in a prospective study. All patients underwent primary surgery: bilateral salpingo-oophorectomy, hysterectomy and omentectomy followed by a staging procedure. In 46 patients, the staging was completed by a retroperitoneal lymph-node dissection, whereas in 39 patients, this procedure was omitted. Total abdominal irradiation (25 Gy/1.50 Gy per fraction) was followed by a pelvic boost dose (25 Gy/1.75 Gy per fraction). Patients with stage I and IIa well differentiated tumours received no adjuvant radiotherapy and are not reported here. The 5-year actuarial recurrence-free survival rate for the irradiated group was 75%. Stage according to FIGO appeared to be of significant prognostic influence. There was no difference in survival between completely and incompletely staged patients. Serious (small) bowel complications occurred however in 6 out of 45 patients who had undergone complete staging.