[Show abstract][Hide abstract] ABSTRACT: Purpose
In epidemiologic research radiation-associated late effects after childhood cancer are usually analyzed without considering fraction dose. According to radiobiological principles, fraction dose is an important determinant of late effects. We aim to provide the rationale for using equivalent dose in 2-Gy fractions (EQD2α/β) as the measure of choice rather than total physical dose as prescribed according to the clinical
Between 1966 and 1996, 597 (43.8 %) children in our cohort of 1,362 5-year childhood cancer survivors(CCS) received radiotherapy before the age of 18 years as part of their primary cancer treatment. Detailed information from individual patients’ charts was collected and physical doses were converted into the EQD2α/β, which includes total dose, fraction dose, and the tissue-specific α/β ratio. The use of EQD2α/β is illustrated in examples studies describing different analyses using EQD2α/β and physical dose.
Radiotherapy information was obtained for 510 (85.4 %) CCS. Multivariable analyses rendered different risk
estimates for total body irradiation in EQD2α/β-based vs. physical-dose-based models. For other radiotherapy regimens, risk estimates were similar.
Using the total physical dose is not adequate for advanced analyses of radiation-associated late effects in CCS. Therefore, it is advised that for future studies the EQD2α/β is used, because the EQD2α/β incorporates the fraction dose, and the tissue-specific α/β ratio. Furthermore, it enables comparisons across fractionation regimens and allows for summing doses delivered by various contemporary and future radiation
Implications for Cancer Survivors
Risk estimates of radiation-associated side effects expressed in EQD2α/β provide more precise, clinically relevant information for cancer survivor screening guidelines.
Journal of Cancer Survivorship 06/2014; · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Over 20% of all newly diagnosed Dutch patients with small-cell lung cancer (SCLC) are aged ≥75years. Uncertainties still exist about safety and efficacy of chemotherapy and chemoradiation in elderly patients. We evaluated the association between patient characteristics and (completion of) treatment and also evaluated toxicity, response and survival in elderly patients with SCLC.
Population-based data from patients aged 75years or older and diagnosed with limited SCLC in 1997-2004 in The Netherlands were used (N=368). Additional data on co-morbidity, motive for deviating from guidelines, grades 3-5 toxicity, response and survival were gathered from medical records.
Although only relatively fit elderly were selected for chemotherapy, almost 70% developed toxicity, leading to early termination of chemotherapy in over half of all patients. Median survival time was 6.7months, but differed strongly according to type and completion of treatment (13.5months for chemoradiation, 7.1months for chemotherapy, 2.9months for best supportive care, 11.5months for patients receiving at least 4cycles of chemotherapy and 3.6months for less than 4cycles).
Although toxicity rate was high and many patients could not complete the full chemotherapy, those who received chemotherapy or chemoradiation had a significantly better survival. We hypothesize that a better selection by proper geriatric assessments is needed to achieve a more favourable balance between benefit and harm.
Journal of Geriatric Oncology 01/2014; 5(1):71-77. · 1.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study incidence of local recurrences, postoperative complications and survival, in patients with rectal carcinoma aged 75 years and older, treated with either surgery and pre-operative 5 × 5 Gy radiotherapy or surgery alone.
A random sample of patients aged over 75 years with pT2-T3, N0-2, M0 rectal carcinoma diagnosed between 2002 and 2004 in the Netherlands was included, treated with surgery alone (N = 296) or surgery in combination with pre-operative radiotherapy (N = 346). Information on local recurrent disease, postoperative complications, ECOG-performance score and comorbidity was gathered from the medical files.
Local recurrences developed less frequently in patients treated with pre-operative radiotherapy compared to surgery alone (2% vs 6%, p = 0.002). Postoperative complications developed more frequently in irradiated patients (58% vs 42%, p < 0.0001). Especially deep infections (anastomotic leakage, pelvic abscess) were significantly increased in this group (16% vs 10%, p = 0.02). 30-day mortality was equal in both groups (8%). A significant increase in postoperative complication rate and 30-day mortality was only seen in those with "severe comorbidity" compared to patients without comorbidity (respectively 58% and 10% vs 43% and 3%), COPD (59% and 12%), diabetes (60% and 11%) and cerebrovascular disease (62% and 14%). In multivariable analysis, postoperative complications predicted 5-year survival.
Elderly patients receiving pre-operative radiotherapy show a lower local recurrence rate. However, as incidence rates of local recurrent disease are low and incidence of postoperative complications is increased in irradiated patients, omitting preoperative RT may be suitable in elderly patients with additional risks for complications or early death.
European journal of surgical oncology: the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 08/2013; · 2.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Concurrent radiochemotherapy (RCT) is the treatment of choice for patients with locally advanced non-small-cell lung cancer (NSCLC). Two meta-analyses were inconclusive in an attempt to define the optimal concurrent RCT scheme. Besides efficacy, treatment toxicity will influence the appointed treatment of choice. A systematic review of the literature was performed to record the early and late toxicities, as well as overall survival, of concurrent RCT regimens in patients with NSCLC. The databases of PubMed, Ovid, Medline, and the Cochrane Library were searched for articles on concurrent RCT published between January 1992 and December 2009. Publications of phase II and phase III trials with ≥ 50 patients per treatment arm were selected. Patient characteristics, chemotherapy regimen (mono- or polychemotherapy, high or low dose) and radiotherapy scheme, acute and late toxicity, and overall survival data were compared. Seventeen articles were selected: 12 studies with cisplatin-containing regimens and 5 studies using carboplatin. A total of 13 series with mono- or polychemotherapy schedules-as single dose or double or triple high-dose or daily cisplatin-containing (≤ 30 mg/m(2)/wk) chemotherapy were found. Acute esophagitis ≥ grade 3 was observed in up to 18% of the patients. High-dose cisplatin regimens resulted in more frequent and severe hematologic toxicity, nausea, and vomiting than did other schemes. The toxicity profile was more favorable in low-dose chemotherapy schedules. From phase II and III trials published between 1992 and 2010, it can be concluded that concurrent RCT with monochemotherapy consisting of daily cisplatin results in favorable acute and late toxicity compared with concurrent RCT with single high-dose chemotherapy, doublets, or triplets.
Clinical Lung Cancer 06/2013; · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Backgroun. Due to improved visibility on MRI, contouring of the prostate is improved compared to CT. The aim of this study was to quantify the benefits of using MRI for treatment planning as compared to CT-based planning for temporary implant prostate brachytherapy. Material and methods. CT and MRI image data of 13 patients were used to delineate the prostate and organs at risk (OARs) and to reconstruct the implanted catheters (typically 12). An experienced treatment planner created plans on the CT-based structure sets (CT-plan) and on the MRI-based structure sets (MRI-plan). Then, active dwell-positions and weights of the CT-plans were transferred to the MRI-based structure sets (CT-plan(MRI-contours)) and resulting dosimetric parameters and tumour control probabilities (TCPs) were studied. Results. For the CT-plan(MRI-contours) a statistically significant lower target coverage was detected: mean V(100) was 95.1% as opposed to 98.3% for the original plans (p < 0.01). Planning on CT caused cold-spots that influence the TCP. MRI-based planning improved the TCPs by 6-10%, depending on the parameters of the radiobiological model used for TCP calculation. Basing the treatment plan on either CT- or MRI-delineations does not influence plan quality. Conclusion. Evaluation of CT-based treatment planning by transferring the plan to MRI reveals underdosage of the prostate, especially at the base side. Planning on MRI can prevent cold-spots in the tumour and improves the TCP.
[Show abstract][Hide abstract] ABSTRACT: - The standard treatment for muscle-invasive bladder cancer is surgical removal of the bladder and construction of a neobladder. Recently, important improvements have been made in the potential for bladder-conserving treatment using radiotherapy.- External beam radiotherapy has undergone technological improvements, as a result of which it is possible to radiate the tumour more precisely while decreasing radiation to healthy tissue.- Radiochemotherapy improves local recurrence-free and overall survival compared with radiotherapy alone. The results of this combined treatment are comparable with those of surgery.- Additionally, Dutch radiotherapy departments have collected data in a national database of 1040 selected patients with confined bladder cancer. These patients were treated with external beam radiation, limited surgery and brachytherapy. The 5-year local recurrence-free survival was 75%.- Bladder conserving treatment options for muscle-invasive bladder cancer should be discussed during the multidisciplinary meeting.
Nederlands tijdschrift voor geneeskunde 01/2013; 157(19):A5556.
[Show abstract][Hide abstract] ABSTRACT: With daily portal images and repeated CT scans from 20 patients with gold markers (GM) an adaptive margin radiotherapy strategy (AMRT) was simulated and compared to traditional bony anatomy (BA) and standard GM verification protocols. AMRT is comparable with BA. GM protocols are superior.
Radiotherapy and Oncology 11/2012; · 4.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: To evaluate the prevalence and severity of clinical adverse events (AEs) and treatment-related risk factors in childhood cancer survivors treated with cranial radiation therapy (CRT), with the aim of assessing dose-effect relationships. METHODS AND MATERIALS: The retrospective study cohort consisted of 1362 Dutch childhood cancer survivors, of whom 285 were treated with CRT delivered as brain irradiation (BI), as part of craniospinal irradiation (CSI), and as total body irradiation (TBI). Individual CRT doses were converted into the equivalent dose in 2-Gy fractions (EQD(2)). Survivors had received their diagnoses between 1966 and 1996 and survived at least 5 years after diagnosis. A complete inventory of Common Terminology Criteria for Adverse Events grade 3.0 AEs was available from our hospital-based late-effect follow-up program. We used multivariable logistic and Cox regression analyses to examine the EQD(2) in relation to the prevalence and severity of AEs, correcting for sex, age at diagnosis, follow-up time, and the treatment-related risk factors surgery and chemotherapy. RESULTS: There was a high prevalence of AEs in the CRT group; over 80% of survivors had more than 1 AE, and almost half had at least 5 AEs, both representing significant increases in number of AEs compared with survivors not treated with CRT. Additionally, the proportion of severe, life-threatening, or disabling AEs was significantly higher in the CRT group. The most frequent AEs were alopecia and cognitive, endocrine, metabolic, and neurologic events. Using the EQD(2), we found significant dose-effect relationships for these and other AEs. CONCLUSION: Our results confirm that CRT increases the prevalence and severity of AEs in childhood cancer survivors. Furthermore, analyzing dose-effect relationships with the cumulative EQD(2) instead of total physical dose connects the knowledge from radiation therapy and radiobiology with the clinical experience.
International journal of radiation oncology, biology, physics 09/2012; · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Childhood cancer survivors (CCS) are a growing group of young individuals with a high risk of morbidity and mortality. We evaluated the prevalence and risk factors of hepatic late adverse effects, defined as elevated liver enzymes, in a large cohort of CCS. METHODS: The cohort consisted of all five-year CCS treated in the EKZ/AMC between 1966 and 2003, without hepatitis virus infection and history of veno-occlusive disease (VOD). Liver enzyme tests included serum levels of alanine aminotransferase (ALT) for hepatocellular injury and gamma-glutamyltransferase (γGT) for biliary tract injury. We performed multivariable linear and logistic regression analyses. RESULTS: The study population consisted of 1404 of 1795 eligible CCS, of whom 1362 performed liver enzyme tests at a median follow-up of 12years after diagnosis. In total, 118 (8.7%) of 1362 CCS had hepatic late adverse effects defined as ALT or γGT above the upper limit of normal. Abnormal ALT and γGT levels were found in 5.8% and 5.3%, respectively. In multivariable regression analyses treatment with radiotherapy involving the liver, higher body mass index, higher alcohol intake and longer follow-up time were significantly associated with elevated ALT and γGT levels; older age at diagnosis was only significantly associated with elevated γGT levels (all p<0.05). CONCLUSION: One in twelve CCS showed signs of hepatic late adverse effects after a median follow-up of 12years. Several risk factors have been identified. Future studies should focus on the course of long-term liver related outcomes and on the influence of radiotherapy and chemotherapy dose.
European journal of cancer (Oxford, England: 1990) 08/2012; · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND OBJECTIVES: Little is known about renal function and blood pressure (BP) in long-term childhood cancer survivors. This cross-sectional study evaluated prevalence of these outcomes and associated risk factors in long-term childhood cancer survivors at their first visit to a specialized outpatient clinic. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Estimated GFR; percentages of patients with albuminuria, hypomagnesemia, and hypophosphatemia; and BP were assessed in 1442 survivors ≥5 years after diagnosis. Multivariable logistic regression analyses were used to estimate effect of chemotherapy, nephrectomy, and radiation therapy on the different outcomes. RESULTS: At a median age of 19.3 years (interquartile range, 15.6-24.5 years), 28.1% of all survivors had at least one renal adverse effect or elevated BP. The median time since cancer diagnosis was 12.1 years (interquartile range, 7.8-17.5 years). High BP and albuminuria were most prevalent, at 14.8% and 14.5%, respectively. Sixty-two survivors (4.5%) had an estimated GFR <90 ml/min per 1.73 m(2). Survivors who had undergone nephrectomy had the highest risk for diminished renal function (odds ratio, 8.6; 95% confidence interval [CI], 3.4-21.4). Combined radiation therapy and nephrectomy increased the odds of having elevated BP (odds ratio, 4.92; 95% CI, 2.63-9.19), as did male sex, higher body mass index, and longer time since cancer treatment. CONCLUSION: Almost 30% of survivors had renal adverse effects or high BP. Therefore, monitoring of renal function in high-risk groups and BP in all survivors may help clinicians detect health problems at an early stage and initiate timely therapy to prevent additional damage.
Clinical Journal of the American Society of Nephrology 07/2012; 7(9):1416-1427. · 5.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Several French, Belgian and Dutch radiation oncologists have reported good results with the combination of limited surgery after external beam radiotherapy (EBRT) followed by brachytherapy in early-stage muscle-invasive bladder cancer. Patients and Methods Data from 12 of 13 departments which are using this approach have been collected retrospectively, in a multicenter database, resulting in 1040 patients: 811 males and 229 females with a median age of 66 years, range 28-92 years. Results were analyzed according to tumor stage and diameter, histology grade, age and brachytherapy technique, continuous low-dose rate (CLDR) and pulsed dose rate (PDR). Results At 1, 3 and 5 years, the local recurrence-free probability was 91%, 80% and 75%, metastasis-free probability was 91%, 80% and 74%, disease-free probability was 85%, 68% and 61% and overall survival probability was 91%, 74% and 62%, respectively. The differences in the outcome between the contributing departments were small. After multivariate analysis, the only factor influencing the local control rate was the brachytherapy technique. Toxicity consisted mainly of 24 fistula, 144 ulcers/necroses and 93 other types. Conclusions EBRT followed by brachytherapy, combined with limited surgery, offers excellent results in terms of bladder sparing for selected groups of patients suffering from bladder cancer.
Annals of Oncology 06/2012; 23(11):2948-53. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: We investigated whether the content of information provided by radiation oncologists and their information giving performance increase patients' trust in them. METHODS: Questionnaires were used to assess radiotherapy patients (n=111) characteristics before their first consultation, perception of information giving after the first consultation and trust before the follow-up consultation. Videotaped consultations were scored for the content of the information provided and information giving performance. RESULTS: Patients mean trust score was 4.5 (sd=0.77). The more anxious patients were, the less they tended to fully trust their radiation oncologist (p=0.03). Patients' age, gender, educational attainment and anxious disposition together explained 7%; radiation oncologists' information giving (content and performance) explained 3%, and patients' perception of radiation oncologists' information-giving explained an additional 4% of the variance in trust scores. CONCLUSION: It can be questioned whether trust is a sensitive patient reported outcome of quality of communication in highly vulnerable patients. PRACTICE IMPLICATIONS: It is important to note that trust may not be a good patient reported outcome of quality of care. Concerning radiation oncologists' information giving performance, our data suggest that they can particularly improve their assessments of patients' understanding.
Patient Education and Counseling 06/2012; · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the possibility of localization of intraprostatic lesions (IL) with contrast-enhanced ultrasound (CEUS) to support the brachytherapy treatment planning of temporary implants.
Two brachytherapy treatment plans were generated for 8 patients treated with external beam radiotherapy and pulsed-dose rate brachytherapy boost for prostate cancer. The first and second brachytherapy treatment plan was without and with knowledge of the localization of the ILs, respectively. Pairwise comparison was performed on prostate, rectum, and urethra dose-volume parameters and total reference air kerma (TRAK)-values.
Coverage of the ILs by the 140% isodose was increased from mean 66.0-67.7% for the standard plan to mean 92.5-95.7% for the adapted plan. The mean D90 of the ILs increased from 1.49-1.57 Gy/pulse to 1.76-1.81 Gy/pulse. Dose-volume parameters for the prostate, rectum, and urethra and the TRAK did not change.
CEUS technique is a promising method for IL localization to aid in brachytherapy treatment planning. Dose coverage on the IL could be improved without any increase of dose in organs at risk.
Journal of Contemporary Brachytherapy 06/2012; 4(2):69-74.
[Show abstract][Hide abstract] ABSTRACT: To determine whether dose-guided radiotherapy (i.e., online recalculation and evaluation of the actual dose distribution) can improve decision making for lung cancer patients treated with stereotactic body radiotherapy.
For this study 108 cone-beam computed tomography (CBCT) scans of 10 non-small-cell lung cancer patients treated with stereotactic body radiotherapy were analyzed retrospectively. The treatment plans were recalculated on the CBCT scans. The V(100%) of the internal target volume (ITV) and D(max) of the organs at risk (OARs) were analyzed. Results from the recalculated data were compared with dose estimates for target and OARs by superposition of the originally planned dose distribution on CBCT geometry (i.e., the original dose distribution was assumed to be spatially invariant).
Before position correction was applied the V(100%) of the ITV was 100% in 65% of the cases when an ITV-PTV margin of 5 mm was used and 52% of the cases when a margin of 3 mm was used. After position correction, the difference of D(max) in the OARs with respect to the treatment plan was within 5% in the majority of the cases. When the dose was not recalculated but estimated assuming an invariant dose distribution, clinically relevant errors occurred in both the ITV and the OARs.
Dose-guided radiotherapy can be used to determine the actual dose in OARs when the target has moved with respect to the OARs. When the workflow is optimized for speed, it can be used to prevent unnecessary position corrections. Estimating the dose by assuming an invariant dose instead of recalculation of the dose gives clinically relevant errors.
International journal of radiation oncology, biology, physics 05/2012; 83(4):e557-62. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the long-term risk for validated symptomatic cardiac events (CEs) and associated risk factors in childhood cancer survivors (CCSs).
We determined CEs grade 3 or higher: congestive heart failure (CHF), cardiac ischemia, valvular disease, arrhythmia and/or pericarditis (according to Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) in a hospital-based cohort of 1,362 5-year CCSs diagnosed between 1966 and 1996. We calculated both marginal and cause-specific cumulative incidence of CEs and cause-specific cumulative incidence of separate events. We analyzed different risk factors in multivariable Cox regression models.
Overall, 50 CEs, including 27 cases of CHF, were observed in 42 survivors (at a median attained age of 27.1 years). The 30-year cause-specific cumulative incidence of CEs was significantly increased after treatment with both anthracyclines and cardiac irradiation (12.6%; 95% CI, 4.3% to 20.3%), after anthracyclines (7.3%; 95% CI, 3.8% to 10.7%), and after cardiac irradiation (4.0%; 95% CI, 0.5% to 7.4%) compared with other treatments. In the proportional hazards analyses, anthracycline (dose), cardiac irradiation (dose), combination of these treatments, and congenital heart disease were significantly associated with developing a CE. We demonstrated an exponential relationship between the cumulative anthracycline dose, cardiac irradiation dose, and risk of CE.
CCSs have a high risk of developing symptomatic CEs at an early age. The most common CE was CHF. Survivors treated with both anthracyclines and radiotherapy have the highest risk; after 30 years, one in eight will develop severe heart disease. The use of potentially cardiotoxic treatments should be reconsidered for high-risk groups, and frequent follow-up for high-risk survivors is needed.
Journal of Clinical Oncology 04/2012; 30(13):1429-37. · 17.88 Impact Factor