Health-related quality of life of early-stage breast cancer patients after different radiotherapy regimens.

PURPOSE: To evaluate and compare health-related quality of life (HRQL) of women with early-stage breast cancer (BC) treated with different radiotherapy (RT) regimens. METHODS: Data were collected from five prospective cohorts of BC patients treated with breast-conserving surgery and different RT regimens: intraoperative RT (IORT, 1 × 23.3 Gy; n = 267), external beam accelerated partial breast irradiation (EB-APBI, 10 × 3.85 Gy; n = 206), hypofractionated whole breast irradiation(hypo-WBI, 16 × 2.67 Gy; n = 375), hypo-WBI + boost(hypo-WBI-B, 21-26 × 2.67 Gy; n = 189), and simultaneous WBI + boost(WBI-B, 28 × 2.3 Gy; n = 475). Women ≥ 60 years with invasive/in situ carcinoma ≤ 30 mm, cN0 and pN0-1a were included. Validated EORTC QLQ-C30/BR23 questionnaires were used to asses HRQL. Multivariable linear regression models adjusted for confounding (age, comorbidity, pT, locoregional treatment, systemic therapy) were used to compare the impact of the RT regimens on HRQL at 12 and 24 months. Differences in HRQL over time (3-24 months) were evaluated using linear mixed models. RESULTS: There were no significant differences in HRQL at 12 months between groups except for breast symptoms which were better after IORT and EB-APBI compared to hypo-WBI at 12 months (p < 0.001). Over time, breast symptoms, fatigue, global health status and role functioning were significantly better after IORT and EB-APBI than hypo-WBI. At 24 months, HRQL was comparable in all groups. CONCLUSION: In women with early-stage breast cancer, the radiotherapy regimen did not substantially influence long-term HRQL with the exception of breast symptoms. Breast symptoms are more common after WBI than after IORT or EB-APBI and improve slowly until no significant difference remains at 2 years posttreatment.

Survival after whole brain radiotherapy for brain metastases from lung cancer and breast cancer is poor in 6325 Dutch patients treated between 2000 and 2014.

BACKGROUND: Whole brain radiotherapy (WBRT) is considered standard of care for patients with multiple brain metastases or unfit for radical treatment modalities. Recent studies raised discussion about the expected survival after WBRT. Therefore, we analysed survival after WBRT for brain metastases 'in daily practice' in a large nationwide multicentre retrospective cohort. METHODS: Between 2000 and 2014, 6325 patients had WBRT (20 Gy in 4 Gy fractions) for brain metastases from non-small cell lung cancer (NSCLC; 4363 patients) or breast cancer (BC; 1962 patients); patients were treated in 15 out of 21 Dutch radiotherapy centres. Survival was calculated by the Kaplan-Meier method from the first day of WBRT until death as recorded in local hospital data registration or the Dutch Municipal Personal Records Database. FINDINGS: The median survival was 2.7 months for NSCLC and 3.7 months for BC patients (p < .001). For NSCLC patients aged <50, 50-60, 60-70 and >70 years, survival was 4.0, 3.0, 2.8 and 2.1 months, respectively (p < .001). For BC patients, survival was 4.5, 3.8, 3.2 and 2.9 months, respectively (p = .047). In multivariable analyses, higher age was related to poorer survival with hazard ratios (HR) for patients aged 50-60, 60-70 and >70 years being 1.05, 1.19 and 1.34, respectively. Primary BC (HR: 0.83) and female sex (HR: 0.85) were related to better survival (p < .001). INTERPRETATION: The survival of patients after WBRT for brain metastases from NSCLC treated in Dutch 'common radiotherapy practice' is poor, in breast cancer and younger patients it is disappointingly little better. These results are in line with the results presented in the QUARTZ trial and we advocate a much more restrictive use of WBRT. In patients with a more favourable prognosis the optimal treatment strategy remains to be determined. Prospective randomized trials and individualized prognostic models are needed to identify these patients and to tailor treatment.

Single dose IOERT versus whole breast irradiation : Cosmetic results in breast-conserving therapy.

BACKGROUND: Scarce data are available about the cosmetic result of single dose intraoperative electron radiotherapy (IOERT) in breast-conserving radiotherapy. METHODS AND MATERIALS: We included 71 breast cancer patients. Breast-conserving surgery and sentinel node procedure had started almost 3 years earlier. Subsequently, 26 patients were treated with IOERT and 45 patients received postoperative whole breast irradiation (WBI). For both groups we determined seven dimensionless asymmetry features. We compared the subjectively and the objectively derived cosmetic scores with each other. RESULTS: For four asymmetry features we noted significantly smaller differences for patients treated with IOERT when compared to those treated with WBI: relative breast contour difference, relative breast area difference and relative breast overlap difference. After correcting for excision volume a significant difference was noticed also for relative lower breast contour. For the IOERT group the cosmetic scores "excellent or good" as determined by each patient and one physician were 88 and 96 %, respectively. When the overall cosmetic scores for patients treated with IOERT and WBI were compared to those of the objectively derived scores, there was a fair level of agreement. CONCLUSION: For patients treated with IOERT we noted less asymmetry and high rates of "good or excellent" subjectively derived cosmetic scores. The level of agreement between the subjectively and the objectively derived cosmetic scores was limited. Due to the small sample size and the design of the study no definitive conclusions can be drawn.

Long-term survival data of triple modality treatment of stage IIB-III-IVA cervical cancer with the combination of radiotherapy, chemotherapy and hyperthermia - an update.

BACKGROUND: Advanced cervical cancer is routinely treated with radiotherapy and cisplatin-containing chemotherapy. Hyperthermia has been shown to improve the results of both radiotherapy and cisplatin. The feasibility of the combination of all three modalities was demonstrated and reported in a study of 68 previously untreated cervical cancer patients in 2005. Long-term follow-up is presented here. METHODS: Sixty-eight patients with advanced cervical cancer were prospectively registered in the USA, Norway and the Netherlands, and treated with a combination of radiotherapy (external beam radiotherapy and brachytherapy for a biologically effective dose of at least 86.7 Gy), chemotherapy (at least four courses of weekly cisplatin (40 mg/m(2))) and locoregional hyperthermia (four weekly sessions). Long-term follow-up was gathered and recurrence-free survival (RFS) and overall survival (OS) curves and survival estimates were obtained. RESULTS: Median follow-up was 81 months. Tumours in 28 patients have recurred, 21 of whom have died. Five-year RFS from the day of registration in the study is 57.5% (95%CI: 46.6-71.0) and five-year OS is 66.1% (95%CI: 55.1-79.3). Differences between countries can be explained by patient characteristics. CONCLUSION: The long-term survival results of the combination of full-dose radiotherapy, chemotherapy and hyperthermia fall well within previous reports for this patient group in randomised trials. The small trial size and lack of randomisation do not permit further interpretation.

Accelerated Partial Breast Irradiation Using External Beam or Intraoperative Electron Radiation Therapy: 5-Year Oncological Outcomes of a Prospective Cohort Study.

PURPOSE: To evaluate the ipsilateral breast tumor recurrence (IBTR) after 2 accelerated partial breast irradiation (APBI) techniques (intraoperative electron radiation therapy [IOERT] and external beam APBI [EB-APBI]) in patients with early-stage breast cancer. METHODS AND MATERIALS: Between 2011 and 2016, women ≥60 years of age with breast carcinoma or Ductal Carcinoma In Situ (DCIS) of ≤30 mm and cN0 undergoing breast-conserving therapy were included in a 2-armed prospective multicenter cohort study. IOERT (1 × 23.3 Gy prescribed at the 100% isodose line) was applied in 1 hospital and EB-APBI (10 × 3.85 Gy daily) in 2 other hospitals. The primary endpoint was IBTR (all recurrences in the ipsilateral breast irrespective of localization) at 5 years after lumpectomy. A competing risk model was used to estimate the cumulative incidences of IBTR, which were compared using Fine and Gray's test. Secondary endpoints were locoregional recurrence rate, distant recurrence, disease-specific survival and overall survival. Univariate Cox regression models were estimated to identify risk factors for IBTR. Analyses were performed of the intention to treat (ITT) population (IOERT n = 305; EB-APBI n = 295), and sensitivity analyses were done of the per-protocol population (IOERT n = 270; EB-APBI n = 207). RESULTS: The median follow-up was 5.2 years (IOERT) and 5 years (EB-APBI). Cumulative incidence of IBTR in the ITT population at 5 years after lumpectomy was 10.6% (95% confidence interval, 7.0%-14.2%) after IOERT and 3.7% (95% confidence interval, 1.2%-5.9%) after EB-APBI (P = .002). The locoregional recurrence rate was significantly higher after IOERT than EB-APBI (12.1% vs 4.5%, P = .001). There were no differences between groups in other endpoints. Sensitivity analysis showed similar results. For both groups, no significant risk factors for IBTR were identified in the ITT population. In the per-protocol population, surgical margin status of the DCIS was the only significant risk factor for developing IBTR in both treatment groups. CONCLUSIONS: Ipsilateral breast tumor recurrences and locoregional recurrence rates were unexpectedly high in patients treated with IOERT, and acceptable in patients treated with EB-APBI.

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.

In vivo dosimetry with MOSFETs and GAFCHROMIC films during electron IORT for Accelerated Partial Breast Irradiation.

PURPOSE: The purpose of this study was to compare the delivered dose to the expected intraoperative radiation therapy (IORT) dose with in vivo dosimetry. For IORT using electrons in accelerated partial breast irradiation, this is especially relevant since a high dose is delivered in a single fraction. METHODS: For 47 of breast cancer patients, in vivo dosimetry was performed with MOSFETs and/or GAFCHROMIC EBT2 films. A total dose of 23.33 Gy at dmax was given directly after completing the lumpectomy procedure with electron beams generated with an IORT dedicated mobile accelerator. A protection disk was used to shield the thoracic wall. RESULTS: The results of in vivo MOSFET dosimetry for 27 patients and GAFROMIC film dosimetry for 20 patients were analysed. The entry dose for the breast tissue, measured with MOSFETs, (mean value 22.3 Gy, SD 3.4%) agreed within 1.7% with the expected dose (mean value 21.9 Gy). The dose in breast tissue, measured with GAFCHROMIC films (mean value 23.50 Gy) was on average within 0.7% (SD = 3.7%, range -5.5% to 5.6%) of the prescribed dose of 23.33 Gy. CONCLUSIONS: The dose measured with MOSFETs and GAFROMIC EBT2 films agreed well with the expected dose. For both methods, the dose to the thoracic wall, lungs and heart for left sided patents was lower than 2.5 Gy even when 12 MeV was applied. The positioning time of GAFCHROMIC films is negligible and based on our results we recommend its use as a standard tool for patient quality assurance during breast cancer IORT.

Acute and late gastrointestinal toxicity after radiotherapy in prostate cancer patients: consequential late damage.

PURPOSE: Late gastrointestinal (GI) toxicity after radiotherapy can be partly explained by late effects of acute toxicity (consequential late damage). We studied whether there is a direct relationship between acute and late GI toxicity. PATIENTS AND METHODS: A total of 553 evaluable patients from the Dutch dose escalation trial (68 Gy vs. 78 Gy) were included. We defined three outcomes for acute reactions: 1) maximum Radiation Therapy Oncology Group acute toxicity, 2) maximum acute mucous discharge (AMD), and 3) maximum acute proctitis. Within a multivariable model, late endpoints (overall toxicity and five toxicity indicators) were studied as a function of acute toxicity, pretreatment symptoms, and relevant dose parameters. RESULTS: At multivariable analysis, AMD and acute proctitis were strong predictors for overall toxicity, "intermittent bleeding," and "incontinence pads" (p < or = 0.01). For "stools > or =6/day" all three were strong predictors. No significant associations were found for "severe bleeding" and "use of steroids." The predictive power of the dose parameters remained at the same level or became weaker for most late endpoints. CONCLUSIONS: Acute GI toxicity is an independent significant predictor of late GI toxicity. This suggests a significant consequential component in the development of late GI toxicity.

Localized volume effects for late rectal and anal toxicity after radiotherapy for prostate cancer.

PURPOSE: To identify dosimetric parameters derived from anorectal, rectal, and anal wall dose distributions that correlate with different late gastrointestinal (GI) complications after three-dimensional conformal radiotherapy for prostate cancer. METHODS AND MATERIALS: In this analysis, 641 patients from a randomized trial (68 Gy vs. 78 Gy) were included. Toxicity was scored with adapted Radiation Therapy Oncology Group/European Organization for the Research and Treatment of Cancer (RTOG/EORTC) criteria and five specific complications. The variables derived from dose-volume histogram of anorectal, rectal, and anal wall were as follows: % receiving > or =5-70 Gy (V5-V70), maximum dose (Dmax), and mean dose (D(mean)). The anus was defined as the most caudal 3 cm of the anorectum. Statistics were done with multivariate Cox regression models. Median follow-up was 44 months. RESULTS: Anal dosimetric variables were associated with RTOG/EORTC Grade > or =2 (V5-V40, D(mean)) and incontinence (V5-V70, D(mean)). Bleeding correlated most strongly with anorectal V55-V65, and stool frequency with anorectal V40 and D(mean). Use of steroids was weakly related to anal variables. No volume effect was seen for RTOG/EORTC Grade > or =3 and pain/cramps/tenesmus. CONCLUSION: Different volume effects were found for various late GI complications. Therefore, to evaluate the risk of late GI toxicity, not only intermediate and high doses to the anorectal wall volume should be taken into account, but also the dose to the anal wall.

Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling.

PURPOSE: To analyze whether inclusion of predisposing clinical features in the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model improves the estimation of late gastrointestinal toxicity. METHODS AND MATERIALS: This study includes 468 prostate cancer patients participating in a randomized trial comparing 68 with 78 Gy. We fitted the probability of developing late toxicity within 3 years (rectal bleeding, high stool frequency, and fecal incontinence) with the original, and a modified LKB model, in which a clinical feature (e.g., history of abdominal surgery) was taken into account by fitting subset specific TD50s. The ratio of these TD50s is the dose-modifying factor for that clinical feature. Dose distributions of anorectal (bleeding and frequency) and anal wall (fecal incontinence) were used. RESULTS: The modified LKB model gave significantly better fits than the original LKB model. Patients with a history of abdominal surgery had a lower tolerance to radiation than did patients without previous surgery, with a dose-modifying factor of 1.1 for bleeding and of 2.5 for fecal incontinence. The dose-response curve for bleeding was approximately two times steeper than that for frequency and three times steeper than that for fecal incontinence. CONCLUSIONS: Inclusion of predisposing clinical features significantly improved the estimation of the NTCP. For patients with a history of abdominal surgery, more severe dose constraints should therefore be used during treatment plan optimization.

Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial.

BACKGROUND: Chemoradiation (RT-CT) is standard treatment for locally advanced cervical cancer (LACC). This study tried to establish if radiotherapy combined with hyperthermia (RT-HT) should be preferred in bulky and/or FIGO-stage ⩾III. METHODS: In this open-label, multicenter randomized trial, patients with LACC were randomly assigned by a computer-generated, biased coin minimization technique to RT-CT or RT-HT. Central randomization was done with stratification by FIGO-stage, tumour diameter and nodal status. Primary endpoint was event free survival (EFS). Secondary endpoints were pelvic recurrence free survival (PRFS), overall survival (OS) and treatment related toxicity. Analysis was done by intention to treat. RESULTS: The trial was closed prematurely (87 of 376 planned patients enrolled: 43 RT-CT; 44 RT-HT). Median follow-up time was 7.1 years. The cumulative incidence of an event was 33% in the RT-CT group and 35% in the RT-HT group. The corresponding hazard rate (HR) for EFS was 1.15 (CI: 0.56-2.36, p=0.7). Also the hazards for PRFS (0.94; CI 0.36-2.44) and OS (1.04; CI 0.48-2.23) at 5 years were comparable between both treatment arms as was grade ⩾3 radiation related late toxicity (6 RT-CT and 5 RT-HT patients). CONCLUSION: After 25% of intended accrual, data suggest comparable outcome for RT-CT and RT-HT.

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.

Gastrointestinal toxicity and its relation to dose distributions in the anorectal region of prostate cancer patients treated with radiotherapy.

PURPOSE: To study the correlations between the dose distributions in the anorectal region and late GI symptoms in patients treated for localized prostate carcinoma. METHODS AND MATERIALS: Data from a randomized study were analyzed. In this trial, patients were treated with either rectangular or conformal fields with a dose of 66 Gy. Data concerning GI symptoms were collected from questionnaires of 197 patients. The distributions of the anorectal region were projected on maps, and the dose parameters were calculated. The incidences of complaints were studied as a function of the dose-area parameters and clinical parameters, using a proportional hazard regression model. Finally, we tested a series of dose parameters originating from different parts of the anorectal region. RESULTS: Analyzing the total region, only a statistically significant dose-area effect relation for bleeding was found (p < 0.01). Defining subareas, we found effect relations for bleeding, soiling, fecal incontinence, and mucus loss. For bleeding and mucus loss, the strongest correlation was found for the dose received by the upper 70-80% of the anorectal region (p < 0.01). For soiling and fecal incontinence, we found the strongest association with the dose to the lower 40-50% (p < 0.05). CONCLUSION: We found evidence that complaints originate from specific regions of the irradiated lower GI tract. Bleeding and mucus loss are probably related to irradiation of the upper part of the rectum. Soiling and fecal incontinence are more likely related to the dose to the anal canal and the lower part of the rectum.

Volume and hormonal effects for acute side effects of rectum and bladder during conformal radiotherapy for prostate cancer.

PURPOSE: To identify dosimetric variables predictive of acute gastrointestinal (GI) and genitourinary (GU) toxicity and to determine whether hormonal therapy (HT) is independently associated with acute GI and GU toxicity in prostate cancer patients treated with conformal radiotherapy (RT). METHODS AND MATERIALS: This analysis was performed on 336 patients participating in a multicenter (four hospitals) randomized trial comparing 68 Gy and 78 Gy. The clinical target volume consisted of the prostate with or without the seminal vesicles, depending on the risk of seminal vesicle involvement. The margin from the clinical target volume to the planning target volume was 1 cm. For these patients, the treatment plan for a total dose of 68 Gy was used, because nearly all toxicity appeared before the onset of the 10-Gy boost. Acute toxicity (<120 days) was scored according to the Radiation Therapy Oncology Group criteria. The dosimetric parameters were obtained from the relative and absolute dose-volume/surface histograms derived from the rectal wall (rectal wall volume receiving > or =5-65 Gy) and the bladder surface (bladder surface receiving > or =5-65 Gy). Additionally, relative and absolute dose-length histograms of the rectum were created, and the lengths of rectum receiving more than a certain dose over the whole circumference (rectal length receiving > or =5-65 Gy) were computed. The clinical variables taken into account for GI toxicity were neoadjuvant HT, hospital, and dose-volume group; for GU toxicity, the variables pretreatment GU symptoms, neoadjuvant HT, and transurethral resection of the prostate were analyzed. The variable neoadjuvant HT was divided into three categories: no HT, short-term neoadjuvant HT (started < or =3 months before RT), and long-term neoadjuvant HT (started >3 months before RT). RESULTS: Acute GI toxicity Grade 2 or worse was seen in 46% of the patients. Patients with long-term neoadjuvant HT experienced less Grade 2 or worse toxicity (27%) compared with those receiving short-term neoadjuvant HT (50%) and no HT (50%). The volumes of the prostate and seminal vesicles were significantly smaller in both groups receiving neoadjuvant HT compared with those receiving no HT. In multivariate logistic regression analysis, including the two statistically significant clinical variables neoadjuvant HT and hospital, a volume effect was found for the relative, as well as absolute, rectal wall volumes exposed to intermediate and high doses. Of all the length parameters, the relative rectal length irradiated to doses of > or =5 Gy and > or =30 Gy and absolute lengths receiving > or =5-15 and 30 Gy were significant. Acute GU toxicity Grade 2 or worse was reported in 56% of cases. For patients with pretreatment GU symptoms, the rate was 93%. The use of short-term and long-term neoadjuvant HT resulted in more GU toxicity (73% and 71%) compared with no HT (50%). In multivariate analysis, containing the variables pretreatment symptoms and neoadjuvant HT, only the absolute dose-surface histogram parameters (absolute surface irradiated to > or =40, 45, and 65 Gy) were significantly associated with acute GU toxicity. CONCLUSION: A volume effect was found for acute GI toxicity for relative, as well as absolute, volumes. With regard to acute GU toxicity, an area effect was found, but only for absolute dose-surface histogram parameters. Neoadjuvant HT appeared to be an independent prognostic factor for acute toxicity, resulting in less acute GI toxicity, but more acute GU toxicity. The presence of pretreatment GU symptoms was the most important prognostic factor for GU symptoms during RT.

Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy.

PURPOSE: To compare acute and late gastrointestinal (GI) and genitourinary (GU) side effects in prostate cancer patients randomized to receive 68 Gy or 78 Gy. METHODS AND MATERIALS: Between June 1997 and February 2003, 669 prostate cancer patients were randomized between radiotherapy with a dose of 68 Gy and 78 Gy, in 2 Gy per fraction and using three-dimensional conformal radiotherapy. All T stages with prostate-specific antigen (PSA) <60 ng/mL were included, except any T1a and well-differentiated T1b-c tumors with PSA < or =4 ng/mL. Stratification was done for four dose-volume groups (according to the risk of seminal vesicles [SV] involvement), age, hormonal treatment (HT), and hospital. The clinical target volume (CTV) consisted of the prostate with or without the SV, depending on the estimated risk of SV invasion. The CTV-planning target volume (PTV) margin was 1 cm for the first 68 Gy and was reduced to 0.5 cm (0 cm toward the rectum) for the last 10 Gy in the 78 Gy arm. Four Dutch hospitals participated in this Phase III trial. Evaluation of acute and late toxicity was based on 658 and 643 patients, respectively. For acute toxicity (<120 days), the Radiation Therapy Oncology Group (RTOG) scoring system was used and the maximum score was reported. Late toxicity (>120 days) was scored according to the slightly adapted RTOG/European Organization for Research and Treatment of Cancer (EORTC) criteria. RESULTS: The median follow-up time was 31 months. For acute toxicity no significant differences were seen between the two randomization arms. GI toxicity Grade 2 and 3 was reported as the maximum acute toxicity in 44% and 5% of the patients, respectively. For acute GU toxicity, these figures were 41% and 13%. No significant differences between both randomization arms were seen for late GI and GU toxicity, except for rectal bleeding requiring laser treatment or transfusion (p = 0.007) and nocturia (p = 0.05). The 3-year cumulative risk of late RTOG/EORTC GI toxicity grade > or =2 was 23.2% for 68 Gy, and 26.5% for 78 Gy (p = 0.3). The 3-year risks of late RTOG/EORTC GU toxicity grade > or =2 were 28.5% and 30.2% for 68 Gy and 78 Gy, respectively (p = 0.3). Factors related to acute GI toxicity were HT (p < 0.001), a higher dose-volume group (p = 0.01), and pretreatment GI symptoms (p = 0.04). For acute GU toxicity, prognostic factors were: pretreatment GU symptoms (p < 0.001), HT (p = 0.003), and prior transurethral resection of the prostate (TURP) (p = 0.02). A history of abdominal surgery (p < 0.001) and pretreatment GI symptoms (p = 0.001) were associated with a higher incidence of late GI grade > or =2 toxicity, whereas HT (p < 0.001), pretreatment GU symptoms (p < 0.001), and prior TURP (p = 0.006) were prognostic factors for late GU grade > or =2. CONCLUSIONS: Raising the dose to the prostate from 68 Gy to 78 Gy resulted in higher incidences of acute and late GI and GU toxicity, but these differences were not significant, except for late rectal bleeding requiring treatment and late nocturia. Other factors than the studied dose levels appeared to be important in predicting toxicity after radiotherapy, especially previous surgical interventions (abdominal surgery or TURP), hormonal therapy, and the presence of pretreatment symptoms.

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.

[Breast-conserving surgery and radiotherapy as a one-day procedure]. / Borstsparende ingreep en bestraling in dagbehandeling.

A single dose of irradiation to the lumpectomy cavity alone after breast-conserving surgery in breast cancer patients has been available in the Netherlands since 2011. This new treatment modality is used in the Haaglanden Medical Centre in The Hague and in the Catharina Hospital in Eindhoven. The goal of intraoperative radiation therapy is to limit the patient burden caused by whole breast irradiation, while maintaining excellent local tumour control. The technique is used only in patients with a low probability of recurrent disease in the breast. Approximately 150 patients receive intraoperative radiation therapy each year In the Netherlands, an estimated 4,000 breast cancer patients were eligible in 2013 for this new treatment technique or another method of partial breast irradiation. In both hospitals the results are closely monitored. Only 15 of the first 200 patients experienced a side effect within a period of 3 months after intraoperative radiation therapy. These side effects were successfully treated either with antibiotics or with surgery.

A model to simulate day-to-day variations in rectum shape.

PURPOSE: To develop a model that predicts possible rectum configurations that can occur during radiotherapy of prostate cancer on the basis of a planning CT scan and patient group data. MATERIALS AND METHODS: We used a stochastic shape description model with a limited number of parameters (area, area difference, and curvature) on a slice-by-slice basis to simulate rectum motion. The probability distributions of the chosen parameters were obtained from a group of 9 reference patients, who each received 15-17 repeat CT scans. We used a Monte Carlo technique to generate different rectum configurations from the probability distributions. We verified the model by comparing dose-wall histograms (DWHs) of the originally delineated rectal contours and simulated rectums for a three-field treatment technique with a prescription dose of 78 Gy. The 15-17 sets of rectal contours of each patient are regarded as the golden standard and provide a good estimate of the actual dose received during the treatment. We determined the equivalent uniform dose (EUD) for a quantitative comparison between the actual dose, the dose predicted on the basis of the simulations, and the dose predicted on the basis of a single planning CT scan. RESULTS: The simulated rectum configurations yield a better estimate of the actual dose in the rectal wall than the rectum in the planning CT scan alone. The differences between the EUD based on the planning CT scan and the actual EUD ranged between -1.1 Gy and 2.1 Gy, with respect to a mean actual EUD of 69.8 Gy. This range is smaller for the EUD based on the simulated rectums, namely -0.4 Gy to 0.6 Gy. Furthermore, the simulation generates a set of rectum configurations that provides an estimate of the variation in DWHs during the course of the treatment. This estimate can be used in addition to the DWH of the planning CT scan in the analysis of gastrointestinal toxicity. CONCLUSIONS: To simulate rectum shapes, we have developed a model that can be used in addition to the information available in the planning CT scan in the analysis of the received dose to the rectal wall during radiotherapy of prostate cancer.

Impact of volume and location of irradiated rectum wall on rectal blood loss after radiotherapy of prostate cancer.

PURPOSE: To identify dose-volume parameters related to late rectal bleeding after radiotherapy for prostate cancer. MATERIALS AND METHODS: Clinical complication data from a randomized trial were collected and linked to the individual dose-volume data. In this trial, patients with prostate cancer were treated with either conventional (with rectangular fields) or three-dimensional conformal radiotherapy to a dose of 66 Gy. Patient complaints, including rectal blood loss, were collected for 199 patients, using questionnaires. Absolute and relative dose-volume histograms (DVHs) of the rectal wall (with and without the anal region) were calculated with and without rectal filling. A proportional hazard regression (PHR) model was applied to estimate the probability of any rectal blood loss within 3 years, as a function of several DVH parameters. In a multivariable analysis, dose-volume parameters were tested together with patient- and treatment-related parameters (age, smoking, diabetes, cardiovascular disease, tumor stage, neo-adjuvant androgen deprivation, conformal vs. conventional and rectal bleeding during treatment). RESULTS: The estimated incidence of any and moderate/severe rectal bleeding at 3 years was 33% and 8%, respectively. Differences between the conventional and conformal technique were small and not significant. The analysis of relative DVHs of the rectal wall (with and without the anal region), showed significant (p < 0.01) relations between the irradiated volume and the probability of rectal blood loss within 3 years for dose levels between 25 Gy and 60 Gy. This relationship was shown in subgroups defined by dose-volume cutoff points as well as in the PHR model, in which a continuously rising risk was seen with increasing volumes. For absolute DVHs and DVHs of the rectum including filling, less or no significant results were observed. The most significant volume-effect relation (p = 0.002) was found at 60 Gy for the rectum wall excluding the anal region. The probability of rectal bleeding increased from 10% to 63% when the irradiated rectum volume at 60 Gy increased from 25% to 100%. Other factors. including age, smoking, diabetes, cardiovascular disease, tumor stage, neo-adjuvant androgen deprivation, conformal vs. conventional, rectal bleeding during treatment, rectum length. and whole rectum volume. did not have a significant effect in the multivariable analysis. When controlling for the volumes at 60 Gy, the volumes at lower dose levels (25-55 Gy) were no longer significant (p = 0.5). CONCLUSIONS: For any rectal bleeding within 3 years, an overall incidence of 33% was observed for patients treated to 66 Gy. For this endpoint, a volume-effect relation was found for DVH parameters of the relative rectal wall volume. This relationship appeared to be most significant for the rectum without the anal region and for the higher dose levels (50-60 Gy).

Anatomy based inverse planning in HDR prostate brachytherapy.

The purpose of this study is to evaluate anatomy based inverse planning as implemented in PLATO BPS 14.2 for planning of HDR prostate implants. Six patients were analysed. The dose distributions were optimized using geometric optimization followed by graphical optimization (GO), anatomy based inverse planning or standard inverse optimization (SIO), tuned inverse optimization (TIO) and tuned inverse optimization followed by graphical optimization (GOTIO). The mean target coverage was 93+/-4%, 53+/-11%, 74+/-8%, 90+/-3%, respectively, for GO, SIO, TIO and GOTIO. The conformal index COIN was 0.74+/-0.02, 0.43+/-0.15 and 0.77+/-0.07, respectively, for GO, SIO and GOTIO. Improved dose homogeneity was found when comparing GOTIO with GO.