[Show abstract][Hide abstract] ABSTRACT: Purpose To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer. Methods and Materials We analyzed data from a case-control study with 35 cases and 140 controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis. Results Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trend became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m2. Conclusions Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer.
International journal of radiation oncology, biology, physics 11/2015; 93(3):658-667. DOI:10.1016/j.ijrobp.2015.07.2270 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
This Phase I study evaluated continuous- and intermittent-dosing (every other week) of afatinib plus nintedanib in patients with advanced solid tumours.
In the dose-escalation phase (n=45), maximum tolerated doses (MTDs) were determined for continuous/intermittent afatinib 10, 20, 30 or 40 mg once daily plus continuous nintedanib 150 or 200 mg twice daily. Secondary objectives included safety and efficacy. Clinical activity of continuous afatinib plus nintedanib at the MTD was further evaluated in an expansion phase (n=25).
The most frequent dose-limiting toxicities were diarrhoea (11%) and transaminase elevations (7%). Maximum tolerated doses were afatinib 30 mg continuously plus nintedanib 150 mg, and afatinib 40 mg intermittently plus nintedanib 150 mg. Treatment-related adverse events (mostly Grade ⩽3) included diarrhoea (98%), asthenia (64%), nausea (62%) and vomiting (60%). In the dose-escalation phase, two patients had partial responses (PRs) and 27 (60%) had stable disease (SD). In the expansion phase, one complete response and three PRs were observed (all non-small cell lung cancer), with SD in 13 (52%) patients. No pharmacokinetic interactions were observed.
MTDs of continuous or intermittent afatinib plus nintedanib demonstrated a manageable safety profile with proactive management of diarrhoea. Antitumour activity was observed in patients with solid tumours.British Journal of Cancer advance online publication, 29 October 2015; doi:10.1038/bjc.2015.374 www.bjcancer.com.
British Journal of Cancer 10/2015; 113(10). DOI:10.1038/bjc.2015.374 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
This phase I study (EudraCT No. 2006-001177-25) investigated aflibercept, a vascular endothelial growth factor decoy receptor protein (VEGF Trap), in combination with docetaxel, cisplatin, and 5-fluorouracil in patients with advanced solid tumors.
Patients and methods:
Patients received 2, 4, or 6 mg/kg of intravenous aflibercept with docetaxel 75 mg/m2, cisplatin 75 mg/m2, and 5-fluorouracil 750 mg/m2 in 3-week cycles until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLTs) during cycle 1 and to determine the recommended phase II dose. Pharmacokinetics, tolerability, and antitumor activity were also investigated.
Forty-four patients were enrolled and treated (29 patients in a dose-escalation phase and 15 patients in an expansion cohort). Following three cases of febrile neutropenia in patients receiving aflibercept at 4 mg/kg, the protocol was amended to allow earlier granulocyte colony-stimulating factor support (from day 6) and prophylactic use of ciprofloxacin. Subsequently, there were two DLTs: febrile neutropenia (2 mg/kg) and grade 4 pulmonary embolism (6 mg/kg). An excess of free over VEGF-bound aflibercept was observed at 6 mg/kg. The most frequent grade 3/4 adverse events (AEs) were neutropenia (54.5%), lymphopenia (47.7%), and stomatitis (38.6%). AEs associated with VEGF blockade (any grade) included epistaxis (61.4%), dysphonia (40.9%), hypertension (38.6%), and proteinuria (11.4%). There were 15 partial responses, including 9 in patients with gastroesophageal cancers. Thirteen patients had stable disease.
Aflibercept 6 mg/kg administered every 3 weeks in combination with docetaxel, cisplatin, and 5- fluorouracil is the recommended dose for further clinical development based on tolerability, pharmacokinetics, and antitumor activity.
[Show abstract][Hide abstract] ABSTRACT: Background:
-Cardiac disease (CD) is one of the major side effects of childhood cancer therapy, but until now little has been known about the relationship between heart radiation dose (HRD) received during childhood and risk of CD.
Methods and results:
-The cohort comprised 3162 five-year survivors of childhood cancer. Chemotherapy information was collected and HRD was estimated. There were 347 CDs in 234 patients, 156 of them rated grade ≥3. Cox's and Poisson regression models were used. The cumulative incidence of any type of CD at 40 years of age was 11•0% (95%CI: 9•5-12•7) and 7•4% (95%CI: 6•2-8•9) when only the CDs of grade 3 or more were considered. Compared to patients who received no anthracycline and either no radiotherapy or an HRD<0•1Gy, the risk was multiplied by 18•4 (95%CI: 7•1-48•0) in patients who had received anthracycline and no radiotherapy or an HRD <0•1Gy, by 60•4 (95%CI: 22•4-163•0) in those who had received no anthracycline and an HRD ≥30Gy, and 61•5 (95%CI: 19•6-192•8) in those who had received both anthracycline and an HRD ≥30Gy.
-Survivors of childhood cancers treated with radiotherapy and/or anthracycline run a high dose-dependent risk of developing CD. CDs develop earlier in patients treated with anthracycline than in those treated without it.
[Show abstract][Hide abstract] ABSTRACT: Human papillomavirus driven head and neck squamous cell carcinoma (HNSCC), particularly oropharyngeal squamous cell carcinoma (OPSCC), are characterized by a significant survival advantage over their HPV-negative counterparts. Although the reasons behind this are still not fully elucidated, it is widely accepted that these tumors have a higher response to ionizing radiation that might explain their favorable outcomes. Potential underlying intrinsic mechanisms include impaired DNA repair abilities, differences in activated repopulation-signaling pathways and cell cycle control mechanisms. The role of the microenvironment is increasingly highlighted, particularly tumor oxygenation and the immune response. Recent studies have shown a distinct pattern of intratumoral immune cell infiltrates, according to HPV status, and have suggested that an increased cytotoxic T-cell based antitumor immune response is involved in improved prognosis of patients with HPV-positive OPSCC. These significant milestones, in the understanding of HPV-induced HNSCC, pave the way to new therapeutic opportunities. This article reviews the current evidence on the biological basis of increased radiosensitivity in HPV-positive HNSCC and discusses potential therapeutic implications.
Cancer Treatment Reviews 10/2015; DOI:10.1016/j.ctrv.2015.10.001 · 7.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
The aim of this work was to assess the dosimetric impact of the interfraction variations during breast radiotherapy.
Materials and methods:
Daily portal imaging measurements were prospectively performed in 10 patients treated with adjuvant whole breast irradiation (50 Gy/25 fractions). Margins between the clinical target volume and the planning target volume (PTV) were 5 mm in the three dimensions. Parameters of interest were the central lung distance (CLD) and the inferior central margin (ICM). Daily movements were applied to the baseline treatment planning (TP1) to design a further TP (TP2). The PTV coverage and organ at risk exposure were measured on both TP1 and TP2, before being compared.
A total of 241 portal images were analyzed. The random and systematic errors were 2.6 and 3.7 mm for the CLD, 4.3 and 6.9 mm for the ICM, respectively. No significant consequence on the PTV treatments was observed (mean variations: +0.1%, p = 0.56 and -1.8%, p = 0.08 for the breast and the tumor bed, respectively). The ipsilateral lung and heart exposure was not significantly modified.
In our series, the daily interfraction variations had no significant effect on the PTV coverage or healthy tissue exposure during breast radiotherapy.
Frontiers in Oncology 09/2015; 5. DOI:10.3389/fonc.2015.00199
[Show abstract][Hide abstract] ABSTRACT: Background:
Although a third of all cancers are diagnosed after the age of 75, only 9% of elderly people are recruited in clinical trials, because of fear of the risk of toxicity. The aim of this study was to compare the tolerance and efficacy observed in phase I trials among patients aged over 75 years with that observed in younger patients.
Patients treated from 2007 to 2012 at Institut Gustave Roussy in phase I trials were included. The conditional Cox proportional hazards model was used to compare the occurrence of AE and overall survival in a subpopulation of elderly people (EP, aged > 75 years) matched with patients aged < 75 years (YP) according to the same phase I protocol and the same Royal Marsden Hospital (RMH) prognostic score.
Among the 32 EP and the 158 YP, 63% and 61% experienced grade 3-4 AEs and dose-limiting toxicities occurred in 6% and 11% in each group respectively. Age over 75 years was neither associated with a greater risk of high toxicity (HR=0.90 [CI95%, 0.47-1.70], p=0.74) nor of death (HR=0.86; CI95%: 0.38-1.93; p=0.71).
Age over 75 years had no impact on the occurrence of either high toxicity or of death. This article is protected by copyright. All rights reserved.
International Journal of Cancer 09/2015; DOI:10.1002/ijc.29849 · 5.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thyroid carcinoma is a frequent complication of childhood cancer radiotherapy. The dose-response to thyroid radiation dose is now well established, but the potential modifier effect of other factors still requires further investigation.
To investigate the role of potential modifiers of the dose-response.
We followed, over an average of 27 years, a cohort of 4338 5-year survivors of solid childhood cancer treated before 1986. The dose received by the thyroid gland and some other anatomical sites during radiotherapy was estimated after reconstruction of the actual conditions in which irradiation was delivered.
Fifty-five (55) patients developed a thyroid carcinoma. The risk of thyroid carcinoma increased with a radiation dose to the thyroid of up to two tenths of Gy, then leveled off for higher doses. When taking into account the thyroid radiation dose, a surgical or radiological splenectomy (>20 Gy to the spleen) increased thyroid cancer risk (RR=2.3, 95%CI:1.3-4.0), high radiation doses (> 5 Gy) to pituitary gland lowered this risk (RR=0.2, 95%CI:0.1-0.6). Patients who received nitrosourea chemotherapy had a 6.6-fold (95%CI: 2.5-15.7) higher risk than those who did not. The excess relative risk per Gy of radiation to the thyroid was 4.7 (95%CI: 1.7 to 22.6). It was 7.6 (95%CI: 1.6 to 33.3) if body mass index at time of interview was equal or higher than 25, and 4.1 (95%CI: 0.9-17.7) if not (p-value for interaction=0.1).
Predicting thyroid cancer risk following childhood cancer radiation therapy probably requires the assessment of more than just the radiation dose to the thyroid. Chemotherapy, splenectomy, radiation dose to pituitary gland, and obesity also play a role.
The Journal of Clinical Endocrinology and Metabolism 09/2015; DOI:10.1210/jc.2015-1690 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and purpose
The dose effect-effect relationship for cardiac diseases following radiotherapy suffers from uncertainties. Three dimensional coronary artery (CA) dose calculation after mediastinal Hodgkin lymphoma radiotherapy was performed, using the patient’s coronary CT angiography (CCTA), and the relationship between the coronary arteries’ radiation doses and the risk of stenosis was estimated.
Materials and methods
Radiotherapy simulation CT scans and CCTAs of patients treated for a mediastinal Hodgkin lymphoma were used to merge thoracic and detailed cardiovascular anatomies. Radiation treatment parameters were used to estimate CA radiation doses. Twenty-one patients without coronary stenosis (controls) were matched with twelve patients with stenosis (cases). CA segments were considered as sub-volumes of interest. Radiation doses to stenotic segments were compared with those received by normal segments (from cases and controls) using a logistic regression.
In eleven cases out of twelve, the highest of the coronary dose distribution was on a damaged segment. Logistic regression with CA segments yielded an odds ratio associated with the risk of coronary stenosis of 1.049 per additional gray with the CA segment median dose (95% confidence interval, 1.004–1.095; p-value <0.05).
The CA segment dose significantly increased the risk of stenosis on the segment. Such personalized CA dose calculations on larger cohorts are expected to improve the understanding of the cardiovascular radiation dose–effect relationship.
Radiotherapy and Oncology 08/2015; DOI:10.1016/j.radonc.2015.07.043 · 4.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adjuvant radiotherapy, after breast conserving surgery or mastectomy for breast cancer, improves overall survival while decreasing the risk of recurrence. However, prophylactic postoperative radiotherapy of locoregional lymph nodes for breast cancer, particularly of the axillary region, is still controversial since the benefits and the risks due to axillary irradiation have not been well defined. To begin with, when performing conformal radiotherapy, volume definition is crucial for the analysis of the risk–benefit balance of any radiation treatment. Definition and contouring of the axillary lymph node region is discussed in this work, as per the recommendations of the European Society for Radiotherapy and Oncology (ESTRO). Axillary recurrences are rare, and the recent trend leads toward less aggressive surgery with regard to the axilla. In this literature review we present the data that lead us to avoid adjuvant axillary radiotherapy in pN0, pN0i+ and pN1mi patients even without axillary clearance and to perform it in some other situations. Finally, we propose an update about the potential toxicity of adjuvant axillary irradiation, which is essential for therapeutic decision-making based on current evidence, and to guide us in the evolution of our techniques and indications of axillary radiotherapy.
[Show abstract][Hide abstract] ABSTRACT: To perform a systematic review and meta-analysis of severe adverse events (SAE) reported in early trials combining molecularly targeted therapies (MTT) with radiotherapy (RT), and to compare them to standard therapy. A summary data meta-analysis was performed and compared to the historical standard. Inclusion criteria were phase I and/or II trials published between 2000 and 2011, with glioblastoma multiforme patients treated with RT and MTT. Pooled incidence rates (IR) of SAE were estimated as well as the pooled median progression-free survival (PFS) and overall survival (OS). Nineteen prospective trials (9 phase I, 1 phase I/II and 9 phase II) out of 29 initially selected were included (n = 755 patients). The exact number of patients who had experienced SAE was mentioned in 37 % of the trials, concerning only 17 % of the patients. Information such as the period during which adverse events were monitored, the planned treatment duration, and late toxicity were not reported in the trials. The pooled IR of overall SAE was 131.2 (95 % CI 88.8-193.7) per 1000 person-months compared to 74.7 (63.6-87.8) for standard therapy (p < 0.01). Significant differences were observed for gastrointestinal events (p = 0.05) and treatment-related deaths (p = 0.02), in favour of standard therapy. No significant difference was observed in PFS and OS. Reporting a summary of toxicity data in early clinical trials should be stringently standardized. The use of MTT with RT compared to standard therapy increased SAE while yielded comparable survival in glioblastoma multiforme patients.
Journal of Neuro-Oncology 05/2015; 123(2). DOI:10.1007/s11060-015-1802-5 · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to investigate the suitability of a graphics library based model for the assessment of linear accelerator radiation leakage. Transmission through the shielding elements was evaluated using the build-up factor corrected exponential attenuation law and the contribution from the electron guide was estimated using the approximation of a linear isotropic radioactive source. Model parameters were estimated by a fitting series of thermoluminescent dosimeter leakage measurements, achieved up to 100 cm from the beam central axis along three directions. The distribution of leakage data at the patient plane reflected the architecture of the shielding elements. Thus, the maximum leakage dose was found under the collimator when only one jaw shielded the primary beam and was about 0.08% of the dose at isocentre. Overall, we observe that the main contributor to leakage dose according to our model was the electron beam guide. Concerning the discrepancies between the measurements used to calibrate the model and the calculations from the model, the average difference was about 7%. Finally, graphics library modelling is a readily and suitable way to estimate leakage dose distribution on a personal computer. Such data could be useful for dosimetric evaluations in late effect studies.
Physics in Medicine and Biology 03/2015; 60(5). DOI:10.1088/0031-9155/60/5/2103 · 2.76 Impact Factor