Fast Neutron Beams In Radiotherapy : influence of energy and clinical implications

Les indications cliniques de neutrons rapides, délivrés dans des conditions techniques similaires à celles des photos se sont dégagées à partir d’essais cliniques pluricentriques randomisés. Leurs résultats ont permis de conclure aux avantages de la neutronthérapie, notamment dans le traitement local du cancer avancé des glandes salivaires et de celui de la prostate. Les neutrons se différencient des photons par leur haute densité d’ionisation ou, ce qui revient au même, par leur valeur élevée de Transfert Linéique d’Energie (TEL). Si dans la gamme des faibles TEL propres aux rayonnements conventionnels (photons, électrons), on observe que peu de variation de la réponse biologique en fonction de la qualité des faisceaux, il n’en est pas de même dans la gamme des hauts TEL où la réponse est susceptible de varier significativement selon les énergies. Il en résulte que les doses de neutrons devront être pondérées par un paramètre biologique qui tient compte des différences d’efficacité en fonction de l’énergie effective des neutrons. C’est dans ce contexte que s’inscrit notre étude. En utilisant deux systèmes biologiques, l’un, Vicia faba, système végétal répondant à des faibles doses uniques, l’autre, le jéjunum de la souris, répondant à des doses uniques élevées, une différence de l’effet biologique exprimée par l’Efficacité Biologique Relative (EBR) atteint 50% dans une large gamme d’énergie de neutrons utilisées en clinique. La variation de l’accroissement de l’EBR en fonction de l’énergie décroissante des neutrons est plus importante avec le système recourant à des faibles doses uniques. Nous avons confirmé cette observation dans une longue expérience in vivo avec le poumon de la souris, tissu à haute capacité de réparation, en utilisant une procédure de multifractionnement et comparant des neutrons d’énergie voisine. Une différence de l’EBR de 20% a été objectivée pour les doses par fraction de l’ordre de celles utilisées en thérapie, alors qu’avec une dose unique pour ce même tissu pulmonaire la différence n’était que de 5%. L’Efficacité Biologique Relative d’un faisceau de qualité donnée par rapport à un faisceau de référence se définit par un rapport de doses de sorte que toute variation de l’EBR se traduit par une variation similaire des doses. Il est donc indispensable dans la conduite d’une étude pluricentrique impliquant des faisceaux de neutrons d’énergie différente de doubler les comparaisons dosimétriques avec une comparaison radiobiologiqueThe place of radiotherapy on the arsenal of cancer treatment is nowadays well established. It is based on the use of high energy photons produced by cobalt-60 units or linear accelerators and of electrons produced from the latter. Its indications and limitations have been defined during the last decades. In addition to the developments that made it possible to overcome most of the technical and physical impediments of dose delivery, other improvement sin radiotherapy have emerged. The radiobiological observations accumulated during the last three decades allowed to distinguish the different according to the type of tissues and the irradiation modalities. Neutrontherapy has been developed in this framework. Improvement of radiotherapeutic treatments is first of all based on seeking better physical and technical conditions to achieve optimal and precise dose distributions (physical precision). On the other hand it is based on searching for treatment modalities which for a same absorbed dose would enhance the radiation effects on the tumour and reduce the effects on normal tissues (differential effect). 1. Physical selectivity Physical precision results from the combination of technology and physics. For instance, a combination of new imaging techniques (i.e. nuclear magnetic resonance and computed tomography …) with a radiation therapy simulator enables a better delimitation of target volume in the patient. In addition, devices especially designed to immobilize the patient in treatment position guarantee the reproducibility of the set-up. In this respect one can take advantage of dosimetry and computerizing to innovate in planning complex treatments. So, the conformal therapy is an example of external beam radiotherapy in which the high-dose volume is made to conform closely to the target volume [ Tait, Nahum, 1990]. The ultimate development of it is the radiosurgery which using a stereotaxic frame to immobilize the patient’s head can treat very small intracranial tumours (less than 1 cm³ to 10 cm³) [Larson et al., 1990]. Another approach is the use of proton beams by which an optimum dose distribution can be achieved (Bragg peak). The proton depth dose curves can be flat at ≈ 100% over the depth of interest while the dose behind the target volume is reduced to virtually zera [Suit, 1990]. Obviously, the use of protons requires the same technical conditions as those needed for conformal radiotherapy. However, the improvement of the physical precision cannot resolve the problem of geographically mixed malignant and benign cells. Therefore, the search for other modalities aiming at destroying more selectively tumoral cells than normal cells is another approach to improve the therapeutic gain. 2. Biological selectivity It is well known that the radiation response of tissues, at doses relevant to radiotherapy, is related to cell death, defined as the irreversible loss of reproductive capacity. In this regard the problem of differential effect can be analyzed through the cell survival curves which express the variation of cell lethality as a function of dose. Different mathematic models have been proposed to characterize these cell survival curves. The linear-quadratic model is nowadays the most widely used; it described easily the shape of survival curves of mammalian cells exposed to photon radiation [Tubiana et al, 1986; Thames, Hendry, 1987]. In the linear-quadratic model, the expression for the cell survival curve is S= e-(αD+βD²) where S is the fraction of cells surviving at a dose D and α and β are constants representing direct lethal events and sublethal events respectively. The ratio α/β corresponds to the dose at which the two components of cell killing are equal; it is an index of their relative importance. The ratio is high when the survival curve is almost exponential and smaller when the survival curve exhibits a shoulder in its initial part. The ration α/β is higher for normal tissues responsible for early effects and tumours than for healthy tissues responsible for late effects; which indicates that the shape (i.e. the shoulder) of the survival curves for both types of biological tissues is different. the first mean to obtain an advantages differential effect has been the fractionation of the dose. The differential effect obtained in this way results from a difference in repair capacity between some healthy and some tumoral tissues, as reflected by the difference in the shapes of the initial parts (at the level of 2 Gy) of the survival curves. Cell killings result either from direct lethal events or from accumulation of repairable sublethal damages. The repair of sublethal damages takes place immediately after irradiation and is competed within a few hours (Elkind recovery) [Elkind, Sutton, 1960]. The relative proportion of both lethal mechanisms (which determines the initial part of the curve) will depend on several factors as well related to the intrinsic radio sensitivity as to the radiation modalities (e.g. radiation quality, dose level …). Regarding photon irradiations, the classical treatment regimen (2 Gy / fraction over 5-6 weeks is justified by the fact that the survival curves in this dose range general exhibit the largest advantageous differences inc ell killing rate between tumoral and normal cell lines. On the other hand, the influence of tumour proliferation in an overall time of 5-6 weeks was assumed until now to be negligible although more recently this has been questioned. The optimization of the differential effect resulting from dose fractionation as been sought in “hyperfractionation” which provides a better sparing of some healthy tissues such as those responsible for late effects (e.g. lung, kidney, spinal cord …); which enables to increase the total dose [Thames, Hendry, 1987; Withers, Horiot, 1988]. Practically, this technique consists of larger number of smaller fractions of more or less 1.2 Gy, distributed into an overall time nearly the same as with classical fraction sizes of 2 Gy per day [Horiot et al., 1988]. As the time of proliferation onset can be some days after the start of treatment in some situations [Fowler, 1986; Peters, Ang, 1988], another modality if hyperfractionation consists of reducing the overall time in order to circumvent tumour proliferation during therapy course (“accelerated fractionation”) [Dische, 1990]. As the presence of malignant hypoxic cells has been recognized as limiting the tumour cure by radiotherapy, another way to enhance the differential effect can be found in the combination of radiation with hypoxic cell sensitizer drugs. However, the clinical use of the misonidazole leads to severe neurotoxic effects [Hall, 1987]. But analogues show reduced uptake un neural tissue and appear to less neurotoxic. Phase III studies are still in progress or data are not yet sufficiently mature for evaluation. Hyperthermia combined with radiation might be another way [Field, 1989]. The vasculature and blood supply in tumours is generally different and less well-organized than that of normal tissues. As a matter of fact, some tumours (or regions within tumour) will have poorer cooling capacity than normal tissues and may thus be more sensitive to the heating. Moreover, hyperthermia acting to poorly vascularized parts of tumours and thus to less oxygenated cells can further enhance the radiation effect. Although first results obtained for superficial tumours are encouraging, the heating of deep-seated tumours is still clinically unachievable [Tubiana et al, 1986]. A fascination research way fir improving the differential effect is the use of other radiation qualities [Raju, 1990]. In this regard, particles such as carbon, neon or argon (so called “heavy particles” by the radiation oncologist) and neutrons have specific radiobiological properties related to their ionization density. Therefore those having a high ionization density (e.g. neutron, carbon, neon, argon) are called “high LET ‘Linear Energy Transfer) radiations” in contrast with conventional “low LET radiations” (such as gamma, electron, proton, helium. Linear Energy Transfer (LET) property will be presented more extensively subsequently. Our work takes part in the radiobiological study of “high LET radiations” and more especially of clinical neutron beams having different energiesThèse d'agrégation de l'enseignement supérieur (Faculté de médecine) -- UCL, 199

Role of 2'-2' difluorodeoxycytidine (gemcitabine)-induced cell cycle dysregulation in radio-enhancement of human head and neck squamous cell carcinomas.

BACKGROUND AND PURPOSE: To try to get a better insight on the interaction between dFdC and ionizing radiation at the cellular level, we examined in vitro the effect of dFdC on the cell cycle of two human head and neck squamous cell carcinoma cell lines (SQD9 and SCC61). PATIENTS AND METHODS: Experimental conditions yielding radio-enhancement were used. Confluent cells were incubated with dFdC (5 microM) for different incubation times, washed, pulse-labeled with BrdUrd (10 microM), fixed and then processed for flow cytometry analysis. Alternatively, cells preincubated or not with dFdC were irradiated (5Gy) in drug-free medium, incubated at 37 degrees C for various times and then processed for flow cytometry analysis. RESULTS: In both cell lines, dFdC incubated between 1 and 6 h induced a DNA synthesis inhibition with accumulation of cells in the G1-S boundary followed, when DNA reinitiated, by a synchronous progression of cells throughout the cycle. A slightly different kinetics was observed in the two cell lines. A weak correlation between dFdC radio-enhancement and distribution of cells in the cell cycle was observed. It was also observed that for longer dFdC incubation times, DNA synthesis could reinitiate while cells were still incubated with dFdC. This reinitiation could be correlated with a decrease in the intracellular dFdCTP pool to non-inhibitory levels. Finally in both cell lines, dFdC modified neither the importance nor the kinetics of the radiation-induced G1 delay. CONCLUSIONS: This study provides evidence that gemcitabine used at radio-enhancing concentration induces alteration of cell kinetics and cell redistribution throughout the cell cycle. This effect is cell line-dependent. However, the weak correlation between dFdC radio-enhancement and cell cycle distribution suggests that the cell cycle effect does not constitute the most important mechanism of interaction with ionizing radiation. Our study also indicated that in the two cell lines studied, a modulation of the G1-S checkpoint was not implicated in enhancement of radiation response by dFdC

Effect of gemcitabine on the tolerance of the lung to single-dose irradiation in C3H mice

In an early phase II trial combining gemcitabine (dFdC) and radiotherapy for lung carcinomas, severe pulmonary toxicity was observed. In this framework, the objective of this study was to investigate the effect of dFdC on the tolerance of the lungs of C3H mice to single-dose irradiation. The thoraxes of C3H mice were irradiated with a graded single dose of 8 MV photons; dFdC (150 mg/kg) or saline (control animals) was administered i.p. 3 or 48 h prior to irradiation. Lung tolerance was assessed by the LD50 at 7-180 days after irradiation. For irradiation alone, the LD50 reached 14.45 Gy (95% CI 13.33-15.66 Gy). With a 3-h interval between administration of dFdC and irradiation, the LD50 reached 13.29 (95% CI 12.26-14.44 Gy); the corresponding value with a 48-h interval reached 13.01 Gy (95% CI 11.92-14.20 Gy). Our data also suggested a possible effect of dFdC on radiation-induced esophageal toxicity. dFdC has a minimal effect on lung tolerance after single-dose irradiation. However, a proper phase I-II trial should be designed before any routine use of combined dFdC and radiotherapy in the thoracic region

Oral versus intramuscular high-oral medroxyprogesterone acetate (HD-MPA) in advanced breast cancer. A randomized study of the Belgian Society of Medical Oncology

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The effect of 2'-2' difluorodeoxycytidine (dFdC, gemcitabine) on radiation-induced cell lethality in two human head and neck squamous carcinoma cell lines differing in intrinsic radiosensitivity

PURPOSE: The present study investigated in vitro radio-enhancement by gemcitabine (dFdC) in two head and neck squamous cell carcinomas with different intrinsic cellular radiosensitivity. MATERIALS AND METHODS: Radiosensitive (SCC61, SF2=0.16) and radioresistant (SQD9, SF2=0.49) human head and neck squamous cell carcinomas were used. Confluent cells were incubated with dFdC and irradiated in drug-free medium with a single dose of 250 kV X-rays (0-12Gy). Cell survival curves were corrected for the toxicity of the drug alone. RESULTS: In both cell lines, radio-enhancement was observed with 5 microM dFdC incubated for 3 h prior to irradiation. Dose modification factors (DMF) at a surviving fraction level of 0.5 reached 1.3 (95% CI 1.1-1.6) and 1.5 (95% CI 1.4-1.5) for SQD9 and SCC61 cells, respectively. Radio-enhancement was associated with a modest increase in the alpha term of the linear-quadratic model. In SQD9 cells, radio-enhancement increased with dFdC incubation time. At 24h, DMF reached a value of 1.5 (95% CI 0.9-3.2). In SCC61 cells at 24h, DMF reached a value of 1.1 (95% CI 0.9-1.2). In both cell lines, radio-enhancement increased with dFdC concentration up to 5-10 microM from which values it levelled off up to 100 microM. CONCLUSIONS: The data indicated that dFdC induced a modest radio-enhancement in both cell lines. For a short incubation time, dFdC did not radio-enhance preferentially the more radio-resistant cells, whereas the opposite was observed for a longer time. In both cell lines, radio-enhancement was saturated above a dFdC concentration of 5-10 microM

A phase I-II trial of induction chemotherapy with carboplatin and fluorouracil in locally advanced head and neck squamous cell carcinoma: a report from the UCL-Oncology Group, Belgium.

Eighty-three patients (median age, 56 years and Karnofsky performance status greater than or equal to 70) were treated with carboplatin (Carbo) and fluorouracil (5Fu) for stage III and IV head and neck squamous cell carcinoma (HNSCC). 5Fu (1 g/m2/d) was administered from day 1 to 4 by continuous infusion. Carbo was given on day 1 and, in order to evaluate its maximum-tolerated dose (MTD), the dose level was progressively increased from 250 mg/m2 to 450 mg/m2. The effectiveness of this association and its potential role in local control were also evaluated. Three patients received Carbo at a dose of 250 mg/m2, 13 received 300 mg/m2, one received 330 mg/m2, 12 received 350 mg/m2, six received 375 mg/m2, 26 received 400 mg/m2, 18 received 420 mg/m2, and four received 450 mg/m2. Two (13 of 83) or three courses (64 of 83), repeated every 4 weeks, were administered. The overall (primary tumor and node) response and complete response (CR) rates were 33% and 14%, respectively. For primary tumor, the response rate (RR) was 57% with 32% CR and 18% pathologic complete response (PCR); the RR was higher for patients with oropharyngeal tumor (76%, P = .037) and for patients treated with Carbo greater than or equal to 350 mg/m2 (65%, P = .02); the tumor size (T1 + T2 v T3 + T4) was a good prognostic factor for RR (90% v 46%, P = .001), CR (65% v 20%, P less than .001), and PCR (45% v 8%, P less than .001). For nodes, the RR was 33% with 11% CR. Grade 3-4 neutropenia and thrombocytopenia were experienced by 17% and 28% of the patients treated with 420 mg/m2 of Carbo and by 50% of the patients treated with 450 mg/m2. The MTD can be fixed at 420 mg/m2 and the proposed dose at 400 mg/m2. Thirty-eight patients were treated with surgery plus radiotherapy, 33 with radiotherapy alone, and seven with surgery alone. The median follow-up is 12 months. The 18-month disease-free survival (DFS) is 78% for overall complete responders and 39% for the others (P = .04). There is no primary tumor recurrence among the 12 patients with a primary tumor PCR treated by radiotherapy alone for tumor control (median follow-up, 17.3 months). The association of Carbo-5Fu is a safe induction chemotherapy regimen for HNSCC. The proposed dose of Carbo for future treatment is 400 mg/m2.(ABSTRACT TRUNCATED AT 400 WORDS

A phase I study of fludarabine combined with radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Fludarabine, 9-beta-D-arabinofuranosyl-2-fluoroadenine, is an adenine nucleoside analogue that has significant activity in hematological malignancies and has shown promising activity in combination with radiation in preclinical solid tumor models. In this framework, we designed two phase I trials (one conducted at M.D. Anderson Cancer Center in Houston, and the other conducted in two Belgian hospitals) exploring concurrent fludarabine and radiotherapy in patients with intermediate to locally advanced head and neck squamous cell carcinomas (HNSCC). MATERIALS AND METHODS: Fludarabine was administered i.v. daily 3-4 h before the last 10 fractions of a standard radiation fractionation regimen (70 Gy in 7 weeks). The main objective of the trials was to determine the maximum tolerated dose (MTD) of fludarabine in this particular setting. Twenty-eight patients with stage T2-T4, any N, M0 were included in the study. Fludarabine doses started at 7.5 mg/m(2) per day (3 mg/m(2) per day in Houston) and increased by steps of 2.5 mg/m(2) per day (3 mg/m(2) per day in Houston). RESULTS: The addition of fludarabine at increasing doses to radiation did not result in increased intensity or duration of skin (18% grade 3 dermatitis) or mucosal (60% grade 3 mucositis) radiotoxicity compared to what was expected for radiation alone. At a daily dose of 17.5 mg/m(2), two patients out of five (40%) developed a grade 4 neutropenia, of whom one developed a neutropenic fever. This dose was set as the MTD. All patients developed a fludarabine dose-dependant lymphocytopenia. The plasma F-ara-A concentration peaked after the 30-min infusion in a dose-dependent fashion and reached an average peak concentration of approximately 2 microM for doses of 15 mg/m(2) and higher. CONCLUSIONS: This study demonstrates that fludarabine can be safely administered concurrently with radiation at a daily dose of 15 mg/m(2) during the final 2 weeks of radiotherapy. A phase II trial will be required to establish the potential role of concurrent fludarabine and radiotherapy in the treatment of moderately to locally advanced HNSCC

Late Intensification Chemotherapy With Autologous Bone-marrow Transplantation in Selected Small-cell Carcinoma of the Lung - a Randomized Study

A multicentric randomized prospective trial was con-ducted to test whether late intensification chemo-therapy would increase the remission rate, the re-lapse-free survival, and the survival of small-cell lung cancer patients responding to induction chemothera-py. Autologous bone marrow transplantation was used as support to reduce the duration of the aplasia induced by very high-dose chemotherapy. As induc-tion chemotherapy, 101 patients received, during a period of 5 months, a total dosage of 120 mg/m2 methotrexate, 4.5 mg/m2 vincristine, 1,800 mg/mi2 cyclophosphamide, 180 mg/m2 doxorubicin, 160 mg/m2 cisplatin, 750 mg/m 2 VP-16-213, and 30 Gy prophylactic cranial irradiation. Forty-five patients, selected for their sensitivity to this induction treat