[Functional iron deficiency, inflammation and fatigue after radiotherapy]. / Carence martiale fonctionnelle, inflammation et fatigue après radiothérapie.

Radiation therapy is associated with a fatigue in the majority of patients with a relative variability according to the type of the tumour, comorbidities, associated treatments and the extent of the irradiation. Its origin is multifactorial. One explanation described is that fatigue could be related to the inflammation caused by irradiation exposure. One of the suspected mechanisms is a functional iron deficiency following pro-inflammatory cytokines synthesis, particularly the interleukins 1 and 6. This phenomenon is accompanied by a reduced availability of iron, while iron reserves are normal or increased. Thus, iron inaccessibility induces lower coefficient of transferrin saturation, which can lead to a non-regenerative normocytic or microcytic anaemia. The availability of iron is controlled by hepcidin that is synthesized in the liver as a response to radiation-induced inflammatory. The presence of hepcidin blocks iron absorption in the intestine and decreases its recycling from senescent red blood cells. A direct relationship between elevated levels of hepcidin, inflammation markers and radiation-induced side effects have been reported. The aim of the article is to review the literature related to fatigue in radiotherapy and understand the mechanisms involved or worsening its occurrence to consider better care and improve patients' quality.

Functional data analysis in NTCP modeling: a new method to explore the radiation dose-volume effects.

PURPOSE/OBJECTIVE(S): To describe a novel method to explore radiation dose-volume effects. Functional data analysis is used to investigate the information contained in differential dose-volume histograms. The method is applied to the normal tissue complication probability modeling of rectal bleeding (RB) for patients irradiated in the prostatic bed by 3-dimensional conformal radiation therapy. METHODS AND MATERIALS: Kernel density estimation was used to estimate the individual probability density functions from each of the 141 rectum differential dose-volume histograms. Functional principal component analysis was performed on the estimated probability density functions to explore the variation modes in the dose distribution. The functional principal components were then tested for association with RB using logistic regression adapted to functional covariates (FLR). For comparison, 3 other normal tissue complication probability models were considered: the Lyman-Kutcher-Burman model, logistic model based on standard dosimetric parameters (LM), and logistic model based on multivariate principal component analysis (PCA). RESULTS: The incidence rate of grade ≥2 RB was 14%. V65Gy was the most predictive factor for the LM (P=.058). The best fit for the Lyman-Kutcher-Burman model was obtained with n=0.12, m = 0.17, and TD50 = 72.6 Gy. In PCA and FLR, the components that describe the interdependence between the relative volumes exposed at intermediate and high doses were the most correlated to the complication. The FLR parameter function leads to a better understanding of the volume effect by including the treatment specificity in the delivered mechanistic information. For RB grade ≥2, patients with advanced age are significantly at risk (odds ratio, 1.123; 95% confidence interval, 1.03-1.22), and the fits of the LM, PCA, and functional principal component analysis models are significantly improved by including this clinical factor. CONCLUSION: Functional data analysis provides an attractive method for flexibly estimating the dose-volume effect for normal tissues in external radiation therapy.

Breast radiotherapy (RT) using tangential fields (TgF): a prospective evaluation of the dose distribution in the sentinel lymph node (SLN) area as determined intraoperatively by clip placement.

BACKGROUND: Randomized trials have established that patients with limited involvement of sentinel lymph node (SLN) do not require axillary lymph node dissection (ALND). The similar outcome in patients with ≤2 positive SLN with or without additional ALND is attributed, in part, to tangential fields (TgF) RT. We evaluated the dose distribution in the SLN biopsy area (SLNBa) as determined intraoperatively by clips placement for radiotherapy (RT) optimization. METHODS: This prospective study included 25 patients who had breast conservation. Titanium clips were used intraoperatively to mark the SLNBa. All patients had 3D-conformal RT using standard (STgF) or high tangential fields (HTgF). Axillary levels, SLNBa, and organs at risk were contoured on a CT scan. Dose distribution and overlap between TgF and target volumes were analyzed. RESULTS: The average doses delivered to axilla levels I-III and SLNBa were 25, 5, 2, and 33 Gy, respectively. The average dose delivered to SLNBa was higher using HTgF with better coverage of the axilla. Only 12 of 25 patients (48 %) had their SLNBa completely covered by the TgF. There was no impact of TgF size on ipsilateral lung dose. The mean heart dose delivered using STgF was lower than HTgF. CONCLUSIONS: In the era of SLNB, axilla and SNLBa RT technique has to be standardized to deliver adequate dose. We recommend the use of HTgF or direct axillary RT techniques (such as in AMAROS trial) in patients with metastases in SLN without ALND completion, when only TgF are expected to cure potential residual disease in the axilla.

Epithelioid sarcoma: need for a multimodal approach to maximize the chances of curative conservative treatment.

OBJECTIVE: This study was designed to evaluate the impact of multimodal management on a series of epithelioid sarcoma (ES) patients treated with curative intent. METHODS: Data were collected on 69 consecutive patients treated from 1982 to 2012. Univariate and multivariate analyses were performed for tumor control and overall survival (OS). RESULTS: In total, 54 (78 %) patients had localized ES (M0 group). In the M0 group, 85 % of patients received multimodal management (surgery n = 50, radiotherapy n = 37, chemotherapy n = 30). Among 42 patients with limb ES, 9 (21 %) underwent amputation, and isolated limb perfusion (ILP) was required in 17 (40.5 %) to allow conservative management. Among the 45 patients who underwent conservative surgery, flap reconstructions were required in 13 (28.8 %). The median follow-up was 5.7 years. The 5-year actuarial OS rates were 54, 62, and 24 % in the entire group and the M0 and M1 groups, respectively. In the M0 group, the 5-year actuarial distant control, local control (LC), and locoregional control rates were 67, 75, and 66 %, respectively. Prognostic factors for poor OS in the multivariate analysis were tumors that were deep to the fascia (p = 0.04) and grade 3 (p = 0.005). In the univariate analysis, age <30 years (p = 0.04), the T2 stage (p = 0.04), and mass presentation (p = 0.03) correlated with decreased LC, whereas patients who underwent ILP had a significantly higher LC rate (hazard ratio 3; 95 % confidence interval 0.9-9.4; p = 0.05). CONCLUSIONS: Multimodal management including ILP and flap reconstruction is necessary to achieve optimal conservative LC. High rates of metastasis and lymphatic spread require innovative systemic treatments.

Role of adjuvant radiotherapy in completely resected non-small-cell lung cancer.

Most long-term survivors of non-small-cell lung cancer (NSCLC) are patients who have had a completely resected tumour. However, this is only achievable in about 30% of the patients. Even in this highly selected group of patients, there is still a high risk of both local and distant failure. Adjuvant treatments such as chemotherapy (CT) and radiotherapy (RT) have therefore been evaluated in order to improve their outcome. In patients with stage II and III, administration of adjuvant platinum-based chemotherapy is now considered the standard of care, based on level 1 evidence. The role of postoperative radiation therapy (PORT) remains controversial. In the PORT meta-analysis published in 1998, the conclusions were that if PORT was detrimental to patients with stage I and II completely resected NSCLC, the role of PORT in the treatment of tumours with N2 involvement was unclear and further research was warranted. Thus at present, after complete resection, adjuvant radiotherapy should not be administered in patients with early lung cancer. Recent retrospective and non-randomised studies, as well as subgroup analyses of recent randomised trials evaluating adjuvant chemotherapy, provide evidence of the possible benefit of PORT in patients with mediastinal nodal involvement. The role of PORT needs to be evaluated also for patients with proven N2 disease who undergo neoadjuvant chemotherapy followed by surgery. The risk of local recurrence for N2 patients varies between 20% and 60%. Based on currently available data, PORT should be discussed for fit patients with completely resected NSCLC with N2 nodal involvement, preferably after completion of adjuvant chemotherapy or after surgery if patients have had preoperative chemotherapy. There is a need for new randomised evidence to reassess PORT using modern three-dimensional conformal radiation technique, with attention to normal organ sparing, particularly lung and heart, to reduce the possible over-added toxicity. Quality assurance of radiotherapy as well as quality of surgery - and most particularly nodal exploration modality - should both be monitored. A new large multi-institutional randomised trial Lung ART evaluating PORT in this patient population is needed and is now under way.