The practice and clinical implications of tablet splitting in international health.

OBJECTIVE: Tablet splitting is frequently performed to facilitate correct dosing, but the practice and implications in low-income settings have rarely been discussed. METHODS: We selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four laypersons. The mean percentage deviation from the theoretical expected weight and weight loss of divided tablets/capsules were recorded. RESULTS: Five of eight study drugs failed, on splitting, to meet European Pharmacopoeia recommendations for tablet weight deviation from the expected weight of tablet/capsule halves with 10% deviating by more than 25%. There was a significant difference in splitting accuracy between nurses and laypersons (P = 0.027). Coated and unscored tablets were less accurately split than uncoated (P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets. CONCLUSION: These findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended.

Radiotherapy of skin adnexal carcinoma.

Skin adnexal carcinomas are rare skin cancer, developing from pilosebaceous, eccrine and apocrine unit. Treatment of localised tumours usually includes surgery and radiotherapy. Indications and modalities of radiotherapy depend on the pathological subtype with a lack of consensus for some histologies. This review summarises the place of radiotherapy in terms of indication, dose and fractionation, volumes to irradiate and discuss ongoing studies.

Image-guidance triggered adaptive radiation therapy in head and neck squamous cell carcinoma: single-institution experience and implications for clinical practice.

PURPOSE: To report frequency and timing of adaptive radiotherapy (ART) and assess patient, disease, and treatment-related characteristics potentially triggering the need for such adaptive replanning in head and neck squamous cell carcinoma (HNSCC). METHODS: Medical records of HNSCC patients treated with definitive intensity modulated radiation therapy (IMRT) with or without concurrent systemic chemotherapy were reviewed retrospectively to identify patients undergoing image-guidance triggered adaptive replanning. Clinico-demographic characteristics of patients undergoing ART were compared with patients treated without adaptation using the chi-square test. RESULTS: Two hundred patients with squamous cell cancers of the oropharynx, larynx, or hypopharynx treated with definitive IMRT between 2014 to 2019 comprised the study cohort. Twenty-seven (13.5%) patients underwent adaptive replanning during treatment at a median of 17 fractions (inter-quartile range 14-24 fractions). There were no significant differences in the baseline patient (age, gender), disease (site of primary, staging/grouping), and treatment-related characteristics (dose-fractionation, chemotherapy usage) in patients undergoing ART compared to those treated without adaptation. Weight loss during IMRT emerged as a significant factor predicting the need for ART; patients having ≥10% weight loss from baseline were more likely to undergo treatment adaptation compared to patients with <10% weight loss (p = 0.0002). There was variable impact of ART on dose-volume statistics of organs-at-risk such parotid glands and spinal cord. CONCLUSION: Image-guidance triggered ART for HNSCC is not associated with significant improvement in OAR dosimetry. However, weight loss during definitive IMRT can be a potentially useful trigger for identifying patients who are most likely to benefit from such adaptive replanning.

Insights on the carbon footprint of radiotherapy in France.

The French healthcare system is responsible for 8% of the national footprint. Achieving a net zero emissions scenario will require a 4-5 fold decrease of carbon emissions in the coming years. The carbon footprint of radiation therapy has not been specifically studied to date. In this review we summarize the content of the carbon footprint dedicated session at the annual meeting of the French society of radiation oncology (SFRO). We discuss the French healthcare system carbon footprint and its major drivers and our work on the estimation of the carbon footprint of external beam radiation therapy in the French setting. We developed a dedicated methodology to estimate the carbon footprint related to radiation therapies, and describe the main drivers of emissions based on a single centre as an example, namely patient's rides, accelerators acquisition and maintenance and data storage. Based on the carbon footprint calculated in our centres, we propose mitigation strategies and an estimation of their respective potential. Our results may be extrapolated to other occidental settings by adapting emission factors (kilograms of carbon per item or euro) to other national settings. External beam radiation therapy has a major carbon footprint that may be mitigated in many ways that may impact how radiation therapy treatments are delivered, as well as the national organization of the radiotherapy sector. This needs to be taken into account when thinking about the future of radiotherapy.

Efficacy and safety of hypofractionated stereotactic radiotherapy for brain metastases using three fractions: A single-centre retrospective study.

PURPOSE: Hypofractionated stereotactic radiotherapy (HFSRT) has become a standard of care for patients with a limited number of brain metastases (BM). An increasing number of linear accelerators (LA) are able to accurately perform HFSRT including VersaHD® (Elekta®) LA. The main aim of this study was to report clinical outcomes of BM treated by HFSRT using 3×7.7Gy on 70% isodose line in terms of local control (LC). PATIENTS AND METHODS: Between November 2016 and October 2018, all patients suffering from histologically-proven primary with one or several newly diagnosed BM treated by HFSRT were retrospectively included and evaluated. Patients who had received prior treatment by neurosurgery or cerebral radiotherapy were excluded. RESULTS: Among 44 patients, 61 BM were treated. With a median follow-up of 31.9 months, LC rates at 6 and 12 months were 93.2% and 90.9, respectively. Single-BM was independently predictive of LC (P=0.025) and overall survival (P=0.013). Acute toxicity rates were acceptable: 65.9% of patients had grade 1 and 2 and no acute grade 3 toxicity according to the NCI-CTCAE (version 5.0). Regarding delayed toxicity, one case (2.3%) of radionecrosis was confirmed by magnetic resonance spectroscopy. CONCLUSION: In our single-centre retrospective analysis, BM treatment by HFSRT delivered in three fractions showed a 12-month LC rate of 90.9% without major toxicities, which suggests safety and efficiency of this technique. However, longer-term follow-up and prospective studies are still needed to confirm these results.

Long-term outcome of Stereotactic Body Radiation Therapy for patient with unresectable liver metastases from colorectal cancer.

PURPOSE: To investigate clinical outcome and predicting factors of local failures in patients with colorectal cancer treated for unresectable liver metastases with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: We restrospectively reviewed the medical records of 67 patients treated with the Cyberknife SBRT system for 99 hepatic metastases between January 2007 and December 2015 in our center. In total, 37.5 to 54.0Gy in 3 to 5 fractions were prescribed to the 80% isodose line. Local control (LC), intrahepatic progression incidence, Progression-Free Survival (PFS), Overall Survival (OS) and toxicity were evaluated. RESULTS: The median follow-up was 47 months (IQR, 28-59 months). The median OS was 53 months, the 2-year OS and PFS rates were 81.4% and 54.0%. The 1- and 2-year LC rates were 86.6% and 72.4%. In the multivariate analysis, the degree of differentiation was the only prognostic factor for LC (HR 0.31, 95% CI, 0.10-0.98, P=0.046). Margin expansion>5mm was not associated with a better LC (HR 0.72, 95% CI, 0.38-1.37, P=0.317). Performans Status≥2 (HR 3.27, 95% CI, 1.07-9.98, P=0.038), chemotherapy for metastases before SBRT (HR 0.36, 95% CI, 0.18-0.75, P=0.006) and regional lymph node at diagnosis (HR 2.19, 95% CI, 1.09-4.43, P=0.029) were independent prognostic factors for OS. We report 2 cases of grade≥3 toxicity (3.0%) - one grade 3 acute nausea and one grade 3 late gastric ulcer. CONCLUSION: Stereotactic body radiation therapy is an effective and well-tolerated treatment that allow high LC for liver metastases from colorectal cancer during the first two years. A prescription dose of 45Gy in 3 fractions to the 80% isodose line with a risk adapted schedule to respect Organ At Risk constraints allows a low rate of toxicity.

The contested market of plasma.

Voluntary, anonymous free gift-giving has become the dominant norm for blood donation for transfusion purposes, in view of its established ability to satisfy the needs for labile blood products that meet satisfactory conditions of safety and cost. But the economy of blood products is also the place for one of the main exceptions to the principle of non-commercialization of body parts. I show that there exists a genuine international plasma market, which provides the raw materials to produce blood protein products by pharmaceutical industries. The recent years have seen a considerable strengthening of the massive and globalized features of this market. I briefly describe the issues that this evolution raises, and I sketch some directions for a partial resolution of these issues. I explain why the development of contract fractionation appears both possible and desirable from an economic perspective in the present context.

[Which alpha/beta ratio for prostate cancer in 2019?] / Quel rapport alpha/bêta pour le cancer prostatique en 2019 ?

In 1999, Brenner and Hall reported for prostate cancer a very low alpha/beta ratio (1.5Gy). In the following years, this value has been confirmed by a large series of papers, so that this very low alpha/beta ratio became a "dogma", on which a large number of hypofractionated schemes were being built. This was logical, since this very low value strongly suggested a beneficial advantage of hypofractionation for prostate cancer. However, more recently, several questions arose; first, a number of authors reported, from the analysis of their own data, values of alpha/beta ratio which were higher than the "dogma". Secondly, the three modern "superiority trials", aiming at demonstrating the advantages of hypofractionated schemes, actually failed to show such a superiority, in spite of high equivalent doses (calculated with an alpha/beta of 1.5Gy), reaching up to 84 - 90Gy. In 2018, three review papers/metanalyses shed a new light on what could be the value of the alpha/beta ratio for prostate cancer. In particular, those studies took into account a "time factor" (for repopulation), a parameter which had been either forgotten or underestimated before. In those three studies, the alpha/beta ratio was ranging from 2.7Gy to 4.9Gy. Those data do confirm the sensitivity to the fraction dose variation of prostate cancer, but this sensitivity could be lower than suggested by an alpha/beta ratio of 1.5Gy.

[Individualization of dose and fractionation of radiotherapy for head and neck cancers]. / Personnalisation de la dose et du fractionnement de la radiothérapie des cancers de la tête et du cou.

Head and neck cancers comprise a variety of tumours depending on the sub-site, for which target volumes and the prescribed doses need to be individualized according to each patient's history and presentation. This article aims at describing the main factors involved in decision-making regarding dose and volume, as well as ongoing research. Contouring and treatment guidelines, use of altered fractionation, major prognostic factors, the role of Human papillomavirus and of functional imaging will be presented and discussed.

[Radiation therapy in inflammatory breast cancer]. / Radiothérapie des cancers du sein inflammatoires.

BACKGROUND: Inflammatory breast cancer accounts for 1-5% of all breast cancers. It is associated with a poor prognosis, because of an increased risk to develop metastases in comparison with all breast malignancies. The treatment is multimodal. We have evaluated the role of radiotherapy: indications, techniques and impact for local control and overall survival. METHOD: The series of the literature with more than 40 patients irradiated for inflammatory breast cancer published since 1995 were analyzed. RESULTS: Chemotherapy was always delivered first. Adjuvant radiotherapy was associated with local control and overall survival at 10 years of 63-92% and 51-64 respectively. Without surgery, local control was 65% and overal survival 38% at 10years. Results of concomitant radiochemotherapy were reported: the studies were heterogenous. Modalities of radiotherapy were detailed with respect to dose and fractionation, target-volumes and technical considerations (including bolus). CONCLUSION: The multimodal strategy comprises systematically radiotherapy with an evaluation of tumor response to maximise resecability.

[Normofractionated breast irradiation in breast cancer. Indications and benefits]. / Irradiation normofractionnée des cancers du sein. Indications et bénéfices.

Whole-breast normofractionated irradiation following breast-conserving surgery is the reference treatment. It delivers a dose of 50Gy in 25 fractions of 2Gy to the reference point, and, in some patients, an additional dose of 16Gy in 8 fractions of 2Gy in the tumor bed. Long-term results and toxicity of this irradiation scheme was prospectively evaluated in several randomised trials and meta-analyses, in invasive cancers as well as in ductal carcinoma in situ. The average 10-year rate of in breast recurrences was 6 % in these trials, with limited cardiac and pulmonary toxicity and limited rate of severe fibrosis. Identification of risk factors of recurrences may help to design new irradiation schemes adapted to tumor biology. The new irradiation schemes must be rigorously evaluated in the long-term in the frame of prospective clinical trials, in order to validate them as new standards of treatment.

[Repeated radiation dose effect and DNA repair: Importance of the individual factor and the time interval between the doses]. / Effets de répétitions de doses d'irradiation et réparation de l'ADN : importance du facteur individuel et de l'intervalle de temps entre les doses.

The dose fractionation effect is a recurrent question of radiation biology research that remains unsolved since no model predicts the clinical effect only with the cumulated dose and the radiobiology of irradiated tissues. Such an important question is differentially answered in radioprotection, radiotherapy, radiology or epidemiology. A better understanding of the molecular response to radiation makes possible today a novel approach to identify the parameters that condition the fractionation effect. Particularly, the time between doses appears to be a key factor since it will permit, or not, the repair of certain radiation-induced DNA damages whose repair rates are of the order of seconds, minutes or hours: the fractionation effect will therefore vary according to the functionality of the different repair pathways, whatever for tumor or normal tissues.

[Radiotherapy of bone metastases: Which fractionations?]. / Quels fractionnements en radiothérapie des métastases osseuses ?

First-line palliative radiotherapy for painful bone metastases is an effective treatment whatever its fractionation (single or multiple fractions). It is also indicated after failure or insufficient effect of a first irradiation, or the appearance of new painful site. Other indications are spinal cord compression, either as an adjuvant to surgery or as sole treatment, and after surgery for long bone metastases. The development of high precision techniques (stereotactic conditions) widens the possibility of re-irradiation when tolerance doses to normal tissues have already been delivered. Local control and possibly overall survival could be improved in oligometastatic patients.

[Hypofractionated radiotherapy in prostate cancer]. / Hypofractionnement à visée curative dans le cancer de la prostate.

Radiotherapy plays a central role in the management of localized prostate cancer, but the total duration of treatment of nearly 2 months poses not only problems of fatigue related to repetitive transports, especially for older patients, but also increases the overall cost of treatment including linear accelerators occupancy and patient transportation. To address this problem, various teams have developed hypofractionated radiotherapy protocols seeking to maintain the same efficacy and toxicity while reducing the total duration of treatment. These hypofractionated protocols require recent techniques such as image-guided radiation therapy (IGRT) and intensity-modulated radiation therapy (IMRT). Single centre series have validated the feasibility of "light" hypofractionation schemes at doses per fraction less than 6 Gy Similarly, different teams have shown the possibility of stereotactic irradiation for delivering "severe" hypofractionation schemes at doses greater than 6 Gy per fraction. Whatever the dose per fraction, the current clinical data support the conclusion that hypofractionated radiotherapy does not increase mid-term toxicity and could even improve biochemical control. Studies with the objective of demonstrating non-inferiority are expected to definitively validate the role of hypofractionated irradiation in the treatment of prostate cancer.

[Hypofractionation and radiotherapy: "the eternal return"]. / Hypofractionnement en radiothérapie : l'éternel retour.

Hypofractionation is not a new idea in radiotherapy. The use of a few high-dose fractions has been proposed by some pioneers of our specialty in the early years of the 20th century. Hypofractionation then reappeared several times in the next decades, based on successive radiobiological concepts, a number of them having been shown to be wrong. The nominal single dose (NSD), for example, so fashionable in the 1970's, dramatically underestimated the late toxicity of the high-dose fractions. Consequently, the NSD was directly responsible for a significant increase of the incidence and of the severity of late complications in large cohorts of patients. The linear-quadratic model (LQ) unequivocally improved our understanding of fractionation sensitivity, but one has to keep in mind its limitations, both in the areas of low and high doses per fraction. For more than a decade, prostate cancer has been the subject of fierce discussions about its sensitivity to fractionation. A number of studies have suggested an unusually low (for a malignant tumor) alpha/beta ratio. However, the available data do not allow a precise evaluation of this ratio; "very low" (1.5 Gy), with an advantage of hypofractionation in terms of local control? Or simply "low" (3-4 Gy), only allowing a reduction of the total number of fractions (with a dose adequately reduced)? While waiting for complementary data, it is advised to remain very careful when modifying the classical schemes towards hypofractionation.

[IMRT and head and neck tumors: does differential fractionation have a role?]. / RCMI et voies aérodigestives supérieures : le fractionnement différentiel a-t-il un intérêt ?

For head and neck cancer, intensity-modulated radiation therapy (IMRT) provides benefits in terms of coverage of the target tumour volume and reduction of the dose to organs at risk. Altered fractionation called SMART (simultaneous modulated accelerated radiation therapy) or SIB (simultaneous integrated boost), equivalent to the "concomitant boost" of conventional techniques, provides additional theoretical gain in the therapeutic index and simplifies the practical implementation of the treatment. The impact on tumour control and acute and late toxicities is encouraging but needs to be confirmed by prospective clinical studies with sufficient follow-up. A lot of different protocols have been tested without really bringing out a "gold standard". However, the current results tend to suggest a SIB/SMART-IMRT moderately accelerated without combined chemotherapy for limited stages (I and II), and SIB-IMRT slightly accelerated with induction and/or concomitant chemotherapy for more advanced stages (III and IV).