Jean Marc Cosset

Prospective Randomized Comparison of Single-Dose Versus Hyperfractionated Total-Body Irradiation in Patients With Hematologic Malignancies

PURPOSEnFractionated total-body irradiation (HTBI) is considered to induce less toxicity to normal tissues and probably has the same efficacy as single-dose total-body irradiation (STBI) in patients with acute myeloid leukemia. We decided to determine whether this concept can be applied to a large number of patients with various hematologic malignancies using two dissimilar fractionation schedules.nnnPATIENTS AND METHODSnBetween December 1986 and October 1994, 160 patients with various hematologic malignancies were randomized to receive either a 10-Gy dose of STBI or 14.85-Gy dose of HTBI.nnnRESULTSnOne hundred forty-seven patients were assessable. The 8-year overall survival rate and cause-specific survival rate in the STBI group was 38% and 63.5%, respectively. Overall survival rate and cause-specific survival rate in the HTBI group was 45% and 77%, respectively. The incidence of interstitial pneumonitis was similar in both groups. However, the incidence of veno-occlusive disease (VOD) of the liver was significantly higher in the STBI group. In the multivariate analysis with overall survival as the end point, the female sex was an independent favorable prognostic factor. On the other hand, when cause-specific survival was considered as the end point, the multivariate analysis demonstrated that sex and TBI were independent prognostic factors.nnnCONCLUSIONnThe efficacy of HTBI is probably higher than that of STBI. Both regimens induce similar toxicity with the exception of VOD of the liver, the incidence of which is significantly more pronounced in the STBI group.

Localized Low-Dose Radiotherapy for Follicular Lymphoma: History, Clinical Results, Mechanisms of Action, and Future Outlooks

The extreme radiosensitivity of indolent lymphomas was reported in the early years of radiotherapy (RT). The efficacy of low-dose total body irradiation (1.5-2 Gy) was particularly demonstrative. Higher doses were considered appropriate for localized disease. The optimal (or conventional) dose of curative RT derived from the early studies was determined to be 30-35 Gy. Nevertheless, in older series addressing the tumoricidal radiation dose in non-Hodgkins lymphomas, investigators noted that a significant number of nodular lymphomas were controlled with a dose of <22 Gy for >3 years. The idea of reintroducing localized low-dose radiotherapy (LDRT) for indolent non-Hodgkins lymphomas came from a clinical observation. The first study showing the high efficacy of LDRT (4 Gy in two fractions of 2 Gy within 3 days) in selected patients with chemoresistant, indolent, non-Hodgkins lymphomas was published in 1994. Since this first report, at least eight series of patients treated with localized LDRT have been published, showing a 55% complete response rate in irradiated sites, with a median duration of 15-42 months. How LDRT induces lymphoma cell death remains partly unknown. However, some important advances have recently been reported. Localized LDRT induces an apoptosis of follicular lymphoma cells. This apoptotic cell death elicits an immune response mediated by macrophages and dendritic cells. Follicular lymphoma is probably an ideal model to explore these mechanisms. This review also discusses the future of LDRT for follicular lymphoma.

Radiobiological and clinical bases for total body irradiation in the leukemias and lymphomas

In spite of the recent introduction of conditioning regimens consisting of chemotherapy alone, therapeutic total body irradiation (TBI) remains a powerful antileukemic and immunosuppressive tool in preparative regimens for bone marrow transplantation. However, the question of the best TBI schedule has not been answered. Available radiobiological and clinical data show that (1) the role of fractionation (or dose rate) on leukemia cell killing may vary with the leukemia type. Acute myeloid leukemia cells have been found to be insensitive or only slightly sensitive to fractionation, whereas chronic myeloid leukemia cells appear to be sensitive. Data are still controversial for acute lymphocytic leukemia and the non-Hodgkins lymphomas; (2) the immunosuppressive effect of TBI is very fractionation sensitive; and (3) most normal tissues at risk are also highly sensitive to fractionation and dose rate. These data permit some cautious adaptations of the TBI schemes to the type of leukemia, use of T-cell-depleted donor marrow, and potential normal tissue toxicity. However, we still lack data concerning the precise intrinsic and fractionation radiosensitivity of the leukemia/lymphoma of a given patient. Recent improvements in leukemia-cell cultures allowing the generation of dose survival curves and the study of in vitro radiation-induced apoptosis (mainly for lymphomas) may soon provide radiation oncologists with the data to allow further refinement and individualization of TBI schedules.

Morbidity after total body irradiation

High-dose chemotherapy and total body irradiation with either allogeneic or autologous bone-marrow rescue has been used successfully in the treatment of various hematologic malignancies. Total body irradiation, despite its acute and late side effects, combined with cyclophosphamide remains one of the best conditioning regimens before bone marrow transplantation. Interstitial pneumonitis and veno-occlusive disease are major and lethal complications following bone marrow transplantation. In this article, morbidity after total body irradiation will be discussed.

ESTRO Breur Gold Medal Award Lecture 2001: Irradiation accidents – lessons for oncology?

Considering the number of radioactive sources in use all over the world (both in industry and medicine) irradiation accidents are exceedingly rare, as demonstrated by the main databases registering such cases: UNSCEAR, IAEA, REAC/TS (Oak Ridge, USA), the German group in Ulm and the Paris Institut Curie. The precise causes of most accidents have been openly analyzed, allowing to reduce the risk of subsequent identical accidental exposures. In addition, a rapid retrospective overview shows that positive lessons could be drawn from such accidents: 1)Lessons for patient management: one should keep in mind that the first ever allogeneic bone marrow transplantations were performed in 1958, on scientists from Yugoslavia who had been severely irradiated in a nuclear Research laboratory. Apart from what was learned from such accidents for the management of severe aplasia, the treatment of superficial accidental exposures has also benefited radiotherapy patients in certain specific situations. 2) Lessons for technology: the efforts to improve safety in nuclear plants are well known; the (successful) efforts to reduce the once-elevated risks when changing the therapeutic Cobalt 60 sources are less well known. Today, most irradiation accidents (by far) are related to misuse or loss of radioactive sources from industrial radiography sets. However, here again, various technological improvements significantly reduced the risks. 3) Lessons for radiobiology: the need for more and more sophisticated biological dosimetry has led to studies allowing better understanding of the short- and long-term effects of radiation on human cells. Analyses of samples taken in areas which were heavily accidentally irradiated also helped to identify, in particular, the cardinal role of TGF beta and TNF alpha in the development of fibrosis and necrosis after irradiation. 4) Lessons for prevention of accidents in radiotherapy: only three large-scale accidents involving external radiotherapy have been registered in the last decade, but deciphering the cause(s) of such problems clearly participated in the setting of demanding Quality Assurance programmes and strict national and international recommendations. Such open circulation of the information about these (fortunately rare) accidents appears to be one of the ways to improve Quality Assurance in Radiotherapy.

Clinical applications of proton therapy. Experiences and ongoing studies.

Proton therapy offers potentially considerable advantages in the management of slow-growing, poorly resectable or non-resectable tumors resistant to x-rays and located close to critical radiosensitive anatomical structures, such as the brain stem of the spinal cord. Among over 13 000 irradiated patients in the USA, Europe, and Japan, two major clinical indications have been documented: 1. The conservative management of choroidal melanomas, in which 98% 5-year local control can be expected at the price of low toxicity and visual preservation in approximately half of them. 2. The curative management of low-grade chondrosarcomas and chordomas of the base of the skull and cervical spine, leading to, in combination with maximal tumor resection, 84%–94% long-term survival. Other ongoing studies concern prostate, head and neck carcinomas as well as various intracranial tumors. Radiosurgical programs are being conducted generally with single fractions and under stereotactic conditions.

New particles in radiotherapy: An introduction

Since the discovery of x-rays and radioactivity, the radiotherapeutic management of malignancy has seen numerous spectacular improvements. Beside the widely used photons and electrons, one area of particular interest is the development and refinement of what has become known as “new particles”. In this paper we give a brief outline of the properties of such particles and catalogue the impact these have made on the clinical outcome.

PD72-09 EARLY OUTCOMES OF FOCAL BRACHYTHERAPY FOR LOCALIZED PROSTATE CANCER: COMPARISON WITH WHOLE GLAND BRACHYTHERAPY.

radical prostatectomy (RP) but does not include multiparametric pelvic MRI (mpMRI). Here, we evaluate the utility of mpMRI in predicting sXRT failure after RP. METHODS: Men undergoing RP at Mayo Clinic from 20032015 who had biochemical recurrence and received sXRT were included in a retrospective chart review. Men who underwent prostate cancer treatment prior to RP, received adjuvant XRT, or who were hormone refractory at sXRT were excluded. Patients with mpMRI within 12 months of sXRT were retained. mpMRI lesions were grouped according to location: vesicourethral, seminal vesical (SV) bed / prostate fossa, pelvic nodes, pelvic bones. If no lesion was present, the mpMRI was categorized as negative. Standard descriptive statistics and multivariable cox regression analyses were performed to assess the impact of mpMRI on PSA recurrence after sXRT. Models were adjusted for the variables in the Stephenson Nomogram: PSA at RP, PSA prior to sXRT, PSA doubling time, hormone therapy with sXRT, sXRT dosage, extracapsular extension, SV invasion, pathologic Gleason score, margin status, and pN stage. RESULTS: Overall, 473 men had mpMRI prior to sXRT (median PSA at sXRT 0.45ng/ml). Of these, 56.9% (204) had an indeterminate or suspicious lesion on MRI: 25.6% (124) vesicourethral, 27.8% (135) SV bed / prostatic fossa, 7.0% (34) pelvic node, and 0.6% (3) pelvic bone. Median PSA with a visible lesion on mpMRI was 0.45ng/ml. At a median follow up of 42 months after sXRT, 29.3% (142) had PSA recurrence and 14.0% (68) had distant metastasis. Patients without a mpMRI lesion or with a suspicious nodal/bone lesion had higher rates of PSA recurrence at 4 years compared to those with vesicourethral/SV/prostate fossa lesions alone: 39.5% vs 21.9% (p<0.001), Figure 1. On multivariable analysis, patients without a mpMRI lesion or a suspicious nodal/bone lesion were significantly more likely to have PSA recurrence (HR 2.41, 95% CI 1.52-3.83, p<0.001) after adjusting for variables in the Stephenson Nomogram. CONCLUSIONS: Pre-sXRT mpMRI is a valuable tool in risk stratifying men undergoing sXRT. The median PSA with a visible lesion on mpMRI was 0.45ng/ml, supporting the use of mpMRI in the early sXRT setting.

High incidence of secondary myelodysplastic syndromes following PROMACE-MOPP and involved field radiotherapy for localized gastric non-Hodgkin's lymphomas.

The incidence of secondary myelodysplastic syndromes (MDS) are rarely reported in an homogeneous patient population treated for non‐Hodgkins lymphoma (NHL). Less than 10 per cent of secondary MDS are usually observed in patients treated for Hodgkins disease and NHL. Data on the incidence of secondary MDS induced by modern chemotherapeutic regimens is needed. Between January 1985 and January 1989, 20 patients with localized gastric non‐Hodgkins lymphomas (stage I to IIE) were prospectively treated at the Institut Gustave‐Roussy with PROMACE‐MOPP multi‐agent chemotherapy and involved‐field irradiation. The mean age was 54 years (range 23 to 69 years). Seven patients died while on therapy or relapsed 2 to 28 months after therapy. Thirteen patients were followed up for at least 5 years. Three of the 13 long‐term survivors (23 per cent) developed a myelodysplastic syndrome (MDS) 48, 62 and 72 months after the end of therapy. Cytogenetic analysis was performed in two cases and showed −7 and 18q− in one case, t(9;21)(q13;q22), 21q+, i17q in the other case. PROMACE‐MOPP plus radiotherapy should not be recommended in patients with localized gastric non‐Hodgkins lymphoma due to the high risk of developing secondary myelodysplastic syndromes.