[Interest of image-guided radiotherapy for brain tumors and positioning control]. / Apport du guidage par l'image pour le repositionnement au cours de la radiothérapie des tumeurs encéphaliques.

A narrow therapeutic index and more and more patients with long survival characterize primary and second brain tumors. Image-guided radiotherapy can increase accuracy of the patient's position during a course of intracranial irradiation thanks to a direct or indirect visualization of targets volumes. Treatment reproducibility and organ at risk-sparing are the primary issues, particularly with the development of stereotactic radiotherapy and protontherapy. Regarding intracranial treatments, image-guided radiotherapy seems to be a repetitive task based on skeletal structures registration. And yet, this innovation makes possible to assess the dosimetric impact of daily positioning variations avoiding invasive immobilizations. Image-guided radiotherapy offers automated tools to limit time consumption and furthers adaptive radiotherapy opportunities. Nevertheless, medical evaluation is still necessary and image processing should be strictly defined (frequency, use, performance). The purpose of this article is to describe image-guidance in brain irradiation, as repositioning tool and to focus on its recent prospects.

Osteoporosis treatment and 10 years' oestrogen receptor+ breast cancer outcome in postmenopausal women treated with aromatase inhibitors.

BACKGROUND: Risk factors for breast cancer relapse are well-known, such as large tumour size or lymph node involvement. The aim of our study was to analyse the influence of bone mineral density, fractures and bisphosphonate or vitamin D prescription on 10 years' breast cancer outcome. PATIENTS AND METHODS: This is a longitudinal and prospective cohort of 450 postmenopausal women with local oestrogen receptor (ER)+ breast cancer. For every patient, we analysed tumour characteristics, bone status at the beginning of aromatase inhibitor treatment and 10 years' cancer outcome with Cox model. RESULTS: Mean follow-up was 10.3 ± 3.0 years. Seventy nine women died, and 75 had a relapse; 30.7% had a history of fracture, 16.9% had a T-score ≤ -2.5 and 11.3% had vitamin D deficiency. Bisphosphonates were prescribed to 35.3% women for osteoporosis for a mean duration of 5 ± 1.7 years. Tumour size (hazard ratio [HR] = 1.32, P ≤ 0.01) and the number of lymph nodes involved (HR = 1.07, P = 0.03) were significantly associated with relapse. Bisphosphonate treatment was significantly associated with a decreased risk of relapse (HR = 0.51, P = 0.03). Age at cancer diagnosis (HR = 1.07, P ≤ 0.01) and vitamin D deficiency (HR = 1.85, P = 0.04) were significantly associated with an increased risk of death, whereas bisphosphonate treatment was associated with a decreased risk of death (HR = 0.46, P = 0.01). CONCLUSION: Osteoporosis treatment, including vitamin D and bisphosphonates, is associated with a 50% reduction of relapse and death in women treated with aromatase inhibitors for ER+ breast cancer.

[Recurrence sites following definitive intensity-modulated conformational radiotherapy of squamous-cell carcinomas of the upper aerodigestive tract]. / Sites de récidive après radiothérapie conformationnelle avec modulation d'intensité des carcinomes épidermoïdes des voies aérodigestives supérieures.

PURPOSE: The implementation of intensity-modulated radiotherapy (IMRT) in a centre requires regular critical review of medical practices and feedback to optimize the subsequent management of patients. PATIENTS AND METHODS: We reviewed and determined through a retrospective single-centre study recurrence sites of 167 consecutive patients treated for head and neck squamous cell carcinoma excluding skin or sinuses. Patients had mostly stage III or IV locally advanced cancer (n=123). RESULTS: Locoregional control rates at 1 and 2 years were respectively 87.9% (95% confidence interval [95%CI]: 81.6%-92.1%) and 77.6% (95%CI: 70.1%-83.5). Among 55 relapses, 20 patients (36.4%) had treatment failures. Patients treated with 70 Gy relapsed mainly in high risk volume (78%). Those treated with 66 Gy recurred regionally outside the irradiated volume (n=4) or in the irradiated high risk volume (n=3) or had isolated metastatic failure (n=3). Those irradiated with 50 Gy had regional relapse outside the irradiated volume (n=2) or isolated metastatic relapse (n=2). We noticed respectively 5.4%, 10.2% and 4.2% isolated metastatic, local, cervical lymph node relapse. CONCLUSION: Our results are consistent with data from the literature. Corrective actions were performed to enhance our practices.

Fracture incidence after 3 years of aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy. PATIENTS AND METHODS: A prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates. RESULTS: Among 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment. CONCLUSION: This real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women.

[Adjuvant treatment of keloid scars: electrons or brachytherapy?]. / Traitement postopératoire des cicatrices chéloïdes : électrons ou irradiation interstitielle ?

PURPOSE: Evaluation of perioperative treatment of keloid scars with electron beam therapy or iridium 192 low dose rate brachytherapy. PATIENTS AND METHODS: From 1994 to 2010, 95 patients with 142 keloid scars have been treated by immediate perioperative irradiation and retrospectively reviewed in our institute: 116 scars were treated by electrontherapy and 26 by brachytherapy. RESULTS: In the electrontherapy group treated locations were: earlobe (n=88, 76%), thorax (n=14, 12%), neck (n=9, 8%), limbs (n=5, 4%). The median size of lesions was 3cm (range [R]: 0.5-18cm). In 95.6% of cases, a dose of 15Gy was delivered in five fractions of 3Gy. The median follow-up was 70 months (R: 7-161 months). The 2-year and 5-year local control were respectively 69% (95% confidence interval [95% CI]: 59-76%) and 55% (95% CI: 45-64%). In the brachytherapy group treated locations were: neck (n=3, 11%), earlobe (n=8, 32%), abdomen (n=3, 11%), thorax (n=2, 8%), limbs (n=10, 38%). The median size of lesions was 6.6cm (R: 1.7-28cm). The median dose delivered at 5mm from the source was 20Gy (R: 15-20.69). The median follow-up was 113 months (R: 21-219 months). The 2-year and 5-year local control were respectively 84.6% (95% CI: 64-94%) and 73.5% (95% CI: 49-87%). So far, no radiation-induced cancer has occurred. A trend to a better local control with brachytherapy was noted (compared to electrontherapy, 2-year relapse is halved with brachytherapy) though this difference did not reach the significance (P=0.0991), probably due to the reduced number of patients in the brachytherapy group. CONCLUSION: Brachytherapy seems to provide better local control compared to electrontherapy, and should be proposed as first line treatment. However, electrontherapy is an interesting alternative in case of difficulty to realize brachytherapy. There is probably a dose effect: according to published data, 25 to 30Gy should at least be proposed.

High prevalence of vertebral fractures in women with breast cancer starting aromatase inhibitor therapy.

BACKGROUND: The purpose of this study was to describe bone status in a large cohort of postmenopausal women with nonmetastatic breast cancer, at the initiation of aromatase inhibitor therapy. PATIENTS AND METHODS: A prospective, transversal and clinical study was conducted. Each woman had an extensive medical history, a biological evaluation, a bone mineral density (BMD) measurement and spinal X-rays. RESULTS: Four hundred and ninety-seven women aged 63.8 ± 9.6 years were included in this study. Eighty-five percent of these women had a 25-OH vitamin D concentration <75 nmol/l. One hundred and fifty-six women (31.4%) had a T-score < -2 at one of the three site measurements. Ninety-five women (19.1%) had a history of nonvertebral fracture with a total of 120 fractures. Spine X-rays evaluation revealed that 20% of the women had at least one vertebral fracture. The presence of vertebral fracture was associated with nonvertebral fracture history [odds ratio (OR) 1.6, 95% confidence interval (CI) 1.1-2.4] and with spine BMD (OR 1.4, 95% CI 1.1-1.7). The prevalence of vertebral fracture reached 62.9% in women with age above 70 years and femoral T-score < -2.5. CONCLUSION: Before starting aromatase inhibitor therapy for breast cancer, a large proportion of women had a vitamin D insufficiency and vertebral fractures.

Low-level laser therapy: a standard of supportive care for cancer therapy-induced oral mucositis in head and neck cancer patients?

BACKGROUND AND AIMS: Oral mucositis (OM) is still a common and severe acute side-effect of many oncologic treatments, especially in patients treated for head and neck cancer. It may affect quality of life, require supportive care and impact treatment planning and its efficacy. Low-level laser therapy (LLLT) seems to promote pain relief and reduces OM incidence and its severity. It has been recommended for these patients as a treatment option but without any consensus in the LLLT procedure. New recommendations and perspectives for clinical trials will be discussed. Materials (Subjects) and Methods: Step by step, the efficacy of soft laser in the management of iatrogenic oral mucositis has been evaluated during the last two decades. Its effectiveness and level of recommendation got stronger with time. We will report and discuss some major results and the latest recommendations published on this topic. RESULTS: The major clinical results have been reported and analysed last year in a first meta-analysis (1)). 11 randomized placebo-controlled trials were selected with a total of 415 patients treated with chemotherapy and/or radiotherapy for head and neck cancer. The relative risk for developing OM was significantly reduced after LLLT but only for a dose between 1 to 6 Joules per point. Pain, severity and duration of OM grade ≥ 2 were also reduced without difference with placebo for possible side-effects. Nine years after the positive results published for patients treated by radiotherapy alone (2)), a new French randomized, multicentric, phase III trial for patients treated with new standard treatment, using LLLT in accordance to recent recommendations is ongoing. Seven centers are specifically established for this trial which should include a hundred patients. CONCLUSIONS: The very encouraging results of LLLT in the prevention and treatment of OM in patients treated by chemotherapy or radiotherapy for advanced head and neck cancer could soon be proposed as a new standard of care, according to the multinational Association of Supportive care in Cancer (MASCC) criteria. Modern lasers are less time consuming and extraoral applicators for a possible use by trained paramedical staff could be helpful to complete clinician practice. A preventive dose of 2 J/cm(2) and a curative dose of 4 J/cm(2) if using a red wavelength lasers are now recommended.

[Radiotherapy in adult glioblastomas]. / Radiothérapie des glioblastomes de l'adulte.

Radiation therapy is a treatment of malignant gliomas in adults. It improves survival rates, whether used alone, in addition to surgery, or in combination with chemotherapy. Three-dimensional imaging techniques, image fusion, and conformational radiotherapy are optimizing treatment plans for the treatment of these tumors and are sparing healthy tissue. After a review of the physical and biological bases of ionizing radiation, we present the techniques, results, side effects, and results of irradiation of glioblastomas.

PCV chemotherapy for oligodendroglioma: response analyzed on T2 weighted-MRI.

OBJECTIVE: Because oligodendroglioma are infiltrative tumors, the Mac Donald's response criteria, usually used for solid and contrast-enhanced tumors, seem not to be adapted. To precise more relevant radiological criteria, the radiological response of oligodendroglioma to PCV chemotherapy was evaluated on T2 weighted-MRI sequences only. METHODS: 25 patients with oligodendroglioma grade A or B were retrospectively analyzed. They were treated with up to six cycles of PCV standard regimen. Tumor size was calculated before and at the end of the treatment, on T2 weighted-MRI, by two methods: volumetric reconstruction (method 1) and maximal cross-sectional area (method 2). Responses were defined according to new criteria on T2 weighted-MRI. RESULTS: According to these criteria and with the method 1, 7 of 25 patients (28%) had a partial response to the PCV, 14 patients (56%) had stabilized disease, and 4 patients (16%) had progressive disease. With the method 2, 6 had partial response (24%), 18 had stabilized disease (72%) and 1 had progressive disease. CONCLUSION: Response rate to PCV chemotherapy in this study was lower than response observed in the literature. Because of the infiltrative feature of oligodendroglioma, we think that the radiological response of these tumors should be evaluated on T2 weighted-MRI. The two methods of tumor size estimation used in this study were almost equivalent. Then, the maximal cross-sectional area measurement, more practical, could be retained.

[Bisphosphonates and bone metastases]. / Bisphosphonates et métastases osseuses.

Bisphosphonates, potent inhibitors of bone resorption have been emerging as the standard treatment of tumor-induced hypercalcemia during the 90's. All uncontrolled phase II studies up to 1992 had demonstrated efficacy in reducing morbidity in terms of bone pain, fracture and hypercalcemia. Other studies on intravenous bisphosphonates, with no other anti-tumor treatment, even demonstrated sclerosis of osteolytic breast cancer bone metastases. Randomised phase III studies only began after 1992. In multiple myeloma, one study with oral clodronate has reported a decrease in bone events and two other studies, one with intravenous pamidronate and the other with oral clodronate have both reported a decrease in skeletal events and bone pain. In breast cancer patients with bone metastases, five large studies have been reported: three with intravenous pamidronate, one with oral pamidronate and one with oral clodronate. All these studies have demonstrated the superiority of bisphosphonates over placebo on both bone pain and bone events, but have failed to show an increase in duration of survival. Bisphosphonates should therefore be considered as an important part of the palliative treatment in breast cancer patients with bone metastases. On the other hand, no definite conclusion can be drawn on the role of bisphosphonates in the treatment of prostatic carcinoma bone metastases yet. However, bisphosphonates should be considered as part of the standard therapy in managing painful lesions in patients with multiple myeloma, breast cancer and prostatic cancer. Nevertheless, further studies are needed with bisphosphonates in the adjuvant setting before bone metastases appear. Could new and more potent bisphosphonates such as zoledronate further reduce bone metastases morbidity?

Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study.

BACKGROUND: The authors have developed a new method of drug delivery into the brain using implantable biodegradable microspheres. In this study, this method was used to provide localized and sustained delivery of 5-fluorouracil (5-FU) after the surgical resection of glioblastoma. This antimetabolite and radiosensitizing drug was selected in an attempt to decrease the rate of local recurrence of the tumor. METHODS: Eight patients with newly diagnosed glioblastoma were included in the study and 2 increasing amounts of 5-FU were studied (70 mg and 132 mg). After surgical resection of the tumor, poly(D-L lactide-co-glycolide) 5-FU-loaded microspheres with an average dimension of 45 microm were implanted in the wall of the surgical bed. External beam radiation (59.4 grays) was initiated before the seventh postsurgical day. Patients were followed by clinical examination, magnetic resonance imaging, and 5-FU assays in the blood and cerebrospinal fluid (CSF). RESULTS: 5-FU assays confirmed sustained concentrations in the CSF for at least 1 month. Concentrations of 5-FU in the blood were lower and transitory. Systemic tolerance to the treatment was good; one case of recurrent brain swelling was observed at the higher dose studied. At the time of last follow-up the overall median survival time was 98 weeks from the time of implantation and 2 patients had achieved disease remission at 139 and 153 weeks, respectively. CONCLUSIONS: This study demonstrates that biodegradable microspheres are efficient systems for drug delivery into the brain and may have future application in the treatment of brain tumors. Further studies are needed to confirm the potential of 5-FU-loaded microspheres for the radiosensitization of glioblastoma. [Please see editorial on pages 197-9, this issue].