[Primary breast angiosarcoma: two case reports]. / Angiosarcome mammaire primitif: à propos de deux cas.

Primary angiosarcoma is a rare type of breast cancer, the diagnosis is difficult to establish and it has the worst prognostic of all breast malignancies. Two cases of primary breast angiosarcoma have been observed at the centre Henry Kaplan of Tours and at the hospital La Source of Orleans since 2001. Based on a literature review, we analyse the epidemiological, pathological, clinical, diagnostic and treatment aspect of this type of cancer. Mastectomy is the reference treatment and the benefit of radiotherapy and chemotherapy remains to be demonstrated.

[Standards and Options for the use of radiation therapy in the management of patients with osteosarcoma. Update 2004]. / Recommandations pour la pratique clinique: Standards et Options 2004 pour la prise en charge par radiothérapie des patients atteints d'ostéosarcome. Mise à jour.

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French regional cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVE: To update the SOR recommendations for the use of radiation therapy in the management of patients with osteosarcoma. This work was performed in collaboration with the French society against cancers in children and adolescent (SFCE). METHODS: Data have been identified by literature search using Medline (from January 1992 to October 2003). In addition several Internet sites were searched in October 2003. RESULTS: The 3 mains standards are: 1) local and exclusive curative irradiation is not indicated as primary treatment for osteosarcoma or for local and operable recurrence, except for lesion in inaccessible sites or if the patient refuses surgery; 2) local and prophylactic adjuvant irradiation is not indicated for the treatment of osteosarcoma after chemotherapy (neoadjuvant and/or adjuvant) and complete macro or microscopic surgery, except for non-operable R1 or R2 surgical resection; 3) whole-lung prophylactic irradiation is not indicated in non-metastatic osteosarcoma. Systemic metabolic radiotherapy for pain treatment, using samarium-153 ethylenediaminetetramethylene phosphonic acid (Sm-153-EDTMP) can be offered to patients with painful metastatic osteosarcoma or in case of recurrent bone sites inaccessible to local therapies (surgery, external irradiation).

[Use of fast neutrons in the treatment of tumors of the salivary glands: rationale, review of the literature and experience in Orleans]. / Utilisation des neutrons rapides dans le traitement des tumeurs des glandes salivaires: rationnel, revue de la littérature et expérience d'Orléans.

If low LET radiation therapy (photons, electrons), following radical microscopically and complete surgery can improve results in term of local control from 34 to 74% for salivary gland tumors, local control is more difficult to achieve in advanced tumors and only palliative treatment is usually attempted. In this survey, all the patient series treated worldwide were reviewed. They show an overall control rate of 31% with photon vs 64% with neutron therapy. A prospective randomised trial sponsored by the RTOG and the MRC published in 1988 and reviewed in 1993 showed an overall locoregional complete tumor clearance of 67% for neutrons and 17% for photons (P < 0.005), with 68% and 25% survival at two years for neutrons and photons respectively. This study was closed for ethical reasons. In Orleans, since 1987, 59 patients have been treated. At five years the persistent local control probability was 69.5%, the five-year crude survival probability 66% and the five-year tumor free survival probability was 64.5%. This review provides evidence that surgical treatment for salivary gland tumors should be limited to patients presenting a high likelihood of negative surgical margin and a small risk of facial nerve damage. Others patients should receive neutron radiation therapy alone as definitive treatment.

[Radiotherapy of high grade glioma: use of fast neutrons, therapy and enhancement by neutron capture]. / Radiothérapie des gliomes de haut grade. Utilisation des neutrons rapides, therapie et potentialisation par capture de neutrons.

Among high linear energy transfer (LET) irradiations techniques, those using fast neutrons are able to eradicate glioblastoma cells. At least a 13 grays (Gy) irradiation dose has to be used, but high morbidity is observed in case of over 11 Gy irradiation. So, no therapeutic windows have been found despite the fact that more than 900 patients were included in clinical trials. Boron neutron capture therapy (BNCT) uses alpha emitting nuclear reactions, produced within tumoral cells by boron neutron captures. (10)B is specifically loaded inside tumoral cells via a boronated molecule, and the tissues are then irradiated with thermal or epithermal neutrons. Although this type of irradiation is yet considered as a regular method in Japan, USA and Europe have started clinical trials, currently in progress, in order to define the BNCT place in the post-operative care of high grade glioma. Non-removable tumors may benefit from boron neutron capture enhancement of fast neutron irradiation, i.e. the combination of these two methods. Preliminary studies show that a "biological" dose enhancement of 20 % could be obtained within the tumor when a concentration of 100 microg/g of (10)B is targeted into it. These concentrations are achievable by intra-arterial administration of (10)boronophenylalanine (BPA) or borosulfhydryl (BSH). Recently, some publications have also demonstrated that the thermal neutron flux yielded within the irradiated tissues could be increased. Clinical trials, using this technique, are planned in USA and Europe.

[Locoregional recurrence of adenocarcinomas of the rectum treated with irradiation combined with or without excision surgery]. / Rechutes locorégionales d'adénocarcinomes du rectum traitées par irradiation associée ou non à une chirurgie d'exérèse.

PURPOSE: Retrospective study to analyze the results of external beam radiation treatment with or without surgery for loco-regional recurrence of adenocarcinoma of the rectum following previous surgery without pre- or post-operative radiotherapy. PATIENTS AND METHODS: Between March 1973 and November 1991, 211 patients with loco-regional recurrence of rectum cancer were treated with external beam radiation treatment. Radical surgery was the only initial treatment modality. Surgical resection of local recurrence was done in 36 patients and only 17 patients could undergo complete resection. Forty-seven patients underwent radiotherapy (RT) combined with surgery and 164 received external beam radiation treatment alone to a mean total dose of 46 Gy. RESULTS: Among the 151 patients whose recurrence was revealed by pain, 64 (42%) were considered to have a complete symptomatic response after loco-regional treatment with radiosurgery or RT alone. The mean duration of response was 12 months. The 3-year overall survival rate was 16%. Five prognostic factors decreased the overall survival rate in multivariate analysis: high age, sex (male), concomitant distant metastasis, no tumor resection, and low total radiation dose with external beam radiation treatment alone. The 3-year overall survival rate for patients with completely resected recurrences was 39%. CONCLUSION: External beam RT treatment can only be considered a palliative symptomatic treatment. New techniques of early detection of local recurrence and new combined modalities approaches (radiation sensitizers or intra-operative radiotherapy) with surgical resection in some favorable cases should be studied.

Neutron therapy in malignant salivary gland tumors: results at European centers.

Malignant salivary gland tumors are relatively rare and account for only 3%-4% of all head and neck cancers. Especially in adenoid cystic carcinoma, the incidence of local recurrence and distant metastases is influenced by the perineural spread of tumor. In advanced salivary gland tumors, surgery alone has a high incidence of local failure. The results of conventional radiotherapy are suboptimal in inoperable or not completely resected salivary gland tumors and in recurrent disease. The pooled data of some international series for low linear energy transfer radiation show a local control of only 28%. Especially in advanced salivary gland tumors, neutron therapy can improve local control. In Europe at least 570 patients with salivary gland tumors have been treated with neutrons alone or with combined modalities. The clinical data of different centers in Europe and the United States result in a similar local control rate of 67% in gross disease. An analysis of different European series shows on average a complication rate of 10.6% for severe radiation-related morbidity. Modern neutron machines and the use of three-dimensional treatment planning systems are now available in a few institutions and may further reduce side effects.

Use of neutron therapy in the management of locally advanced nonresectable primary or recurrent rectal cancer.

Inoperable locally advanced or inoperable recurrent rectal cancer is a difficult problem. Tenesmus, discharge, bleeding and pelvic pain are frequently present and often are associated with infiltration of the sacral plexus. The value of radiotherapy in managing such patients is being appreciated, although up to 40% of the treated patients have no symptomatic response. Improvement in tumor response and control has been scored through efforts to overcome the radio resistance of the hypoxic tumor cells by neutron irradiation. This article is an account of the activity of neutron radiotherapy in such patients. Over 350 patients were entered in studies comparing neutrons used alone and neutrons used in a mixed-beam treatment schedule. At present no therapeutic gain for long-lasting survival has been achieved; however, local control and pain improvement seems to be better with neutrons than with photons.

Sacrococcygeal chordomas: potential role of high LET therapy.

Chordomas are rare malignant neoplasms representing less than 3% of all primary bone tumors. They usually have a benign histological appearance and a slow growth rate. Their locoregional progression nearly always causes suffering and eventually death. Efforts to increase local control have included aggressive surgery, radiation therapy or combined approaches but locally free survival rates remain relatively low and have not exceeded 30% at 5 years. Sacrococcygeal chordomas, which represent approximately 50% of the localizations, have been investigated less frequently than those at the base of the skull or cervical region with primary or post-operative radiation therapy. The disappointing results with photon therapy in a multimodality approach and the good results reported by Schoenthaler with charged particles in the Lawrence Berkeley laboratory led us to propose fast neutron therapy in the management of inoperable or recurrent sacrococcygeal chordomas. Preliminary results obtained from only 12 patients indicate that high linear energy transfer (LET) therapy seems to be a good alternative for radical treatment of chordomas in the case of microscopic or macroscopic residual tumor.

[Computed tomography option on simulator: a 14-month use at the Orléans hospital radiotherapy department]. / L'option scanneur sur simulateur: 14 mois d'utilisation dans le service de radiothérapie du CHR d'Orléans.

The purpose was to evaluate the use of the CT option for simulator during a 14-month period in the radiotherapy department. The CT option has been adapted on the Philips simulator SL23. The virtual tunnel diameter is 92 cm which allows slice acquisition regardless of the contention device used. This system is connected to the treatment planning system through an Ethernet link. Three fields of view are available which cover the standard radiotherapy use. Four hundred and twenty-seven patients benefited from this system over a 14-month period of use. The number of slices acquired per patient regularly increased. The use of the system was rapidly extended to all the standard treatments. Those slices were also used as additional information for these high technology treatments. The good quality of the images and the reliability of this system involved a rapid integration in the treatment preparation procedure. It will not replace the use of the scanner but will significantly improve the treatment quality.

RBE variation between fast neutron beams as a function of energy. Intercomparison involving 7 neutrontherapy facilities.

In fast neutron therapy, the relative biological effectiveness (RBE) of a given beam varies to a large extent with the neutron energy spectrum. This spectrum depends primarily on the energy of the incident particles and on the nuclear reaction used for neutron production. However, it also depends on other factors which are specific to the local facility, eg, target, collimation system, etc. Therefore direct radiobiological intercomparisons are justified. The present paper reports the results of an intercomparison performed at seven neutrontherapy centres: Orléans, France (p(34)+Be), Riyadh, Saudi Arabia (p(26)+Be), Ghent, Belgium (d(14.5)+Be), Faure, South Africa (p(66)+Be), Detroit, USA (d(48)+Be), Nice, France (p(65)+Be) and Louvain-la-Neuve, Belgium (p(65)+Be). The selected radiobiological system was intestinal crypt regeneration in mice after single fraction irradiation. The observed RBE values (ref cobalt-60 gamma-rays) were 1.79 +/- 0.10, 1.84 +/- 0.07, 2.24 +/- 0.11, 1.55 +/- 0.04, 1.51 +/- 0.03, 1.50 +/- 0.04 and 1.52 +/- 0.04, respectively. When machine availability permitted, additional factors were studied: two vs one fraction (Ghent, Louvain-la-Neuve), dose rate (Detroit), influence of depth in phantom (Faure, Detroit, Nice, Louvain-la-Neuve). In addition, at Orléans and Ghent, RBEs were also determined for LD50 at 6 days after selective abdominal irradiation and were found to be equal to the RBEs for crypt regeneration. The radiobiological intercomparisons were always combined with direct dosimetric intercomparisons and, when possible in some centres, with microdosimetric investigations.

Neutrontherapy in soft tissue sarcomas: a review of European results.

The purpose of this publication is to review the data on European neutrontherapy facilities in the treatment of soft tissue sarcoma. Data on 1171 patients treated at 11 centers were analyzed. Neutrontherapy was of advantage especially for patients with primary radiotherapy of inoperable tumors, and those with macroscopic disease after surgery. Local control was about 50% in these groups. Results for postoperative neutrontherapy after R0 and R1 resection were similar to those for photon therapy. The incidence of late side effects was considerable. This was influenced by the fact that most patients were treated with first-generation machines.

European results in neutron therapy of malignant salivary gland tumors.

In Europe to date, 501 patients with salivary gland tumors have been treated with neutrons alone or with combined modalities. The most common histological types are adenoid cystic carcinomas, mucoepidermoid carcinomas and malignant mixed tumors. The results of conventional radiotherapy are suboptimal in inoperable or incompletely resected salivary gland tumors and in recurrent disease. The pooled data of some international series for low linear energy transfer radiation show a local control of 28%. Especially in advanced tumors neutron therapy can improve local control and should be the treatment of choice. The clinical data from different therapy centers in Europe show local control of 67% in gross disease.

Fast neutrons in the treatment of grade IV astrocytomas.

In 1981, the Hôpital Tenon group and the Orléans neutron therapy team initiated a collaborative study for the treatment of grade IV astrocytomas using a combination of photons and neutrons. Neutrons were used as boost in a reduced volume. Doses were progressively increased from 6 to 7 Gy and later up to 8 Gy. Since October 1994, a neutron boost of 7.5 Gy has been delivered. At the time of evaluation, 294 patients had a minimum follow-up of 12 months. Univariate analysis indicated that clinical status, tumor location and photon fractionation scheme had no significant influence on survival. In contrast, age, surgical procedure and neutron dose were found to be prognostic factors. In a multivariate analysis, the prognostic value of the surgical procedure disappeared and the only remaining independent prognostic factors up to 11 months after treatment (P = 0.001) were age and the neutron dose. As far as neutron dose was concerned, survival increased with dose from 6 to 7 Gy up to 15 months. However, after 15 months, there was no longer any benefit in survival for the patients treated with 8 Gy, and complications related to overdosage began to appear. There was a long-term survival group: 55 patients were alive 18 months after treatment (18%). The median survival was 26.7 months. The best survival was observed for patients treated with a neutron boost of 7 Gy in eight fractions over 11 days (25 vs 18%). The present study demonstrates the feasibility of a combination of photons (30 Gy total brain) followed by a neutron boost (7 Gy) in the treatment of high-grade astrocytomas. The results are in good agreement with the published data. In the literature, age and surgical procedure are currently considered as the most important prognostic factors. The prevalence of neutron dose over these two other prognostic factors, as shown in this study, is an important additional argument in favor of the use of neutrontherapy in the management of these tumors. A possible benefit when combining external fast neutrontherapy with boron neutron capture therapy (BNCT) could reasonably be expected.

Fast neutron therapy for inoperable or recurrent sacrococcygeal chordomas.

Between 1981 and 1994, 13 patients were referred to the Orleans neutrontherapy department with inoperable or recurrent pelvic chordomas. One patient who had already been irradiated refused the treatment, fearing complications. Among the 12 patients suitable for evaluation, ten had undergone one to five previous surgical operations. The time lapse between the last surgical operation and neutrontherapy was 13 months. Neutrons were used alone or as a boost depending on the tumor volume or treatment purpose. At four years, crude survival and local control probability (Kaplan-Meier) were 61 and 54% respectively. This small series suggests that fast neutrontherapy can provide a good alternative for the treatment of inoperable sacral chordomas.

[Quality assurance in protontherapy: a systematic approach in progress at Orsay].

The degree of accuracy and reliability required in proton therapy can only be guaranteed if a comprehensive quality assurance (QA) programme is established. Such a programme obviously has common features with general QA in radiotherapy, but some aspects are specific to the use of protons and particularly to the characteristics of each facility. A study is in progress at Orsay to convert a series of quality controls into a systematic quality assurance programme. It includes some basic steps on organisation, setting up a QA committee and QA task groups, organising meetings, policies, procedures, records, qualifications, and determining some examples of tolerance in controls. Among some critical and specific points identified in this process are the combined treatment with photons at different institutions, the specificity of a non-hospital-based and complex facility, the high degree of precision required for the patient setup, and the need to develop in-house basic tools such as the treatment planning system. The inclusion of all the patients in prospective well-defined clinical trials, the comparison with alternative techniques and the radiobiological studies are considered as fundamentals for the QA programme. Present dosimetric and radiobiological intercomparisons between protontherapy centres are considered as partial audits. A study is in progress to establish common dosimetric and clinical protocols, radiobiological models and dose and volume specifications. In spite of the differences between the existing facilities, it should also be possible to obtain international consensus on general guidelines for a QA programme in proton therapy.

Boron neutron capture irradiation: setting up a clinical programme in Nice.

Neutron capture irradiation aims to selectively destroy tumor cells using 10B(n,alpha)7Li nuclear reactions produced within themselves. Following the capture reaction, an alpha particle and a, 7Li ion are emitted. Carrying an energy of 2.79 MeV, they destroy all molecular structures along their path close to 10 microns. These captures, used exclusively with a 'slow' neutron irradiation, provide a neutron capture therapy (BNCT). If they are used in addition to a fast neutron beam irradiation, they provide a neutron capture potentiation (NCP). The Centre Antoine-Lacassagne in Nice is actively involved in the European Demonstration Project for BNCT of grade IV glioblastomas (GBM) after surgical excision and BSH administration. Taking into account the preliminary results obtained in Japan, work on an 'epithermal' neutron target compatible with various cyclotron beams is in progress to facilitate further developments of this technique. For NCP, thermalized neutron yield has been measured in phantoms irradiated in the fast neutron beam of the biomedical cyclotron in Nice. A thermal peak appears after 5 cm depth in the tissues, delayed after the fast neutron peak at 1.8 cm depth. Thus, a physical overdosage of 10% may be obtained if 100 ppm of 10B are assumed in the tissues. Our results using CAL 58 GBM cell line demonstrate a dose modification factor (DMF) of 1.19 when 100 ppm of boric acid are added to the growth medium. Thus for the particles, issued from neutron capture, a biological efficiency at least twice that of fast neutrons can be derived. These results, compared with historical data on fast neutron irradiation of glioblastoma, suggest that a therapeutic window may be obtained for GBM.

[Primary cutaneous neuroendocrine carcinoma (Merkel tumor). Clinical and therapeutic update apropos of 4 cases]. / Carcinome neuroendocrine cutané primitif (tumeur de Merkel). Actualités cliniques et thérapeutiques à propos de quatre cas.

The clinical and pathological features of 4 cases of cutaneous neuroendocrine carcinoma are reported. There are unusual malignancies mostly observed in elderly, the prognosis is poor by loco-regional aggressivity and disseminated metastases. They are diagnosed by a pathologist: ultrastructural studies and immunohistochemistry support the diagnosis. A combination of a wild local excision, node dissection and post-operative radiation is recommended.

Development of fast neutron therapy worldwide. Radiobiological, clinical and technical aspects.

Radiobiological data indicate that fast neutrons could bring a benefit in the treatment of some tumour types, and suggest mechanisms through which this benefit could be achieved. However, radiobiology also clearly indicates that there is a need for patient selection as well as for a high-physical selectivity. The main difficulty when interpreting the results of neutron therapy are the poor technical conditions in which the first treatments were applied. This explains why the value and the place of neutron therapy are not universally recognized, although more than 15,000 patients have been treated so far worldwide. There are, however, clinical indications of fast neutrons bringing a benefit for the following tumour sites: salivary glands, paranasal sinuses, soft tissue sarcomas, prostatic adenocarcinomas, palliative treatment of melanoma and rectum. These tumours represent about 10-15% of all patients currently referred to the radiation therapy departments.