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International audience; La prescription de la dose en radiothérapie est actuellement basée sur des abaques qui ne prennent pas en compte la complexité de la relation patient/dose/effet. Leurs performances prédictives tant sur l’efficacité anti-tumorale que sur la toxicité peuvent être améliorées par l’utilisation de modèles radiobiologiques. C’est dans cette optique qu’ont été développés les modèles de calculs TCP (Tumor Control Probability) et NTCP (Normal Tissue Complication Probability). Leur construction comporte plusieurs étapes importantes utiles à comprendre. La première étape est basée sur les modèles radiobiologiques permettant de définir de manière plus ou moins complexe des taux de cellules survivantes après irradiation. Deux étapes supplémentaires sont nécessaires pour convertir la dose physique en dose biologique équivalente, notamment en dose biologique équivalente à 2 Gy (EQD2) ; d’une part, pour prendre en compte l’effet du fractionnement de la dose, tant pour le volume cible que les organes à risque, et d’autre part, pour réaliser sa conversion en une dose uniforme qui permet de modéliser l’effet produit par une dose hétérogène sur un organe (dose uniforme équivalente généralisée (gEUD) de Niemierko). Enfin, les modèles radiobiologiques de prédiction des effets cliniques transforment les doses en probabilités de contrôle tumoral (TCP) ou de toxicité (NTCP) en recourant aux paramètres qui rendent compte des caractéristiques radiobiologiques des tissus en question. L’utilisation de ces modèles est encore limitée en pratique courante mais comme les logiciels de radiothérapie en propose l’utilisation, il est important d’en connaître les conditions d’application.

In radiotherapy, the dose prescription is currently based on discretized dose-effects records that do not take into fully account for the complexity of the patient-dose-response relationship. Their predictive performance on both anti-tumour efficacy and toxicity can be optimized by integrating radiobiological models. It is with this in mind that the calculation models TCP (Tumor Control Probability) and NTCP (Normal Tissue Complication Probability) have been developed. Their construction involves several important steps that are necessary and important to understand. The first step is based on radiobiological models allowing to calculate according to more or less complexity the rate of surviving cells after irradiation. Two additional steps are required to convert the physical dose into an equivalent biological dose, in particular a 2Gy equivalent biological dose (EQD2): first to take into account the effect of the fractionation of the dose for both the target volume and the organs at risk; second to convert an heterogeneous dose to an organ into an homogeneous dose having the same effect (Niemierko generalized equivalent uniform dose (gEUD)). Finally, the process of predicting clinical effects based on radiobiological models transform doses into tumour control (TCP) or toxicity (NTCP) probabilities using parameters that reflect the radiobiological characteristics of the tissues in question. The use of these models in current practice is still limited, but since the radiotherapy softwares increasingly integrate them, it is important to know the principle and limits of application of these models.

Adjuvant radiotherapy is a key treatment in early-stage breast cancer. The meta-analysis by the Early Breast Cancer Trialist's Collaborative Group (EBCTCG) has demonstrated a decreased risk of locoregional relapse and death after whole-breast radiotherapy. Prophylactic lymph nodes irradiation in breast cancer has also proven to be beneficial in several therapeutic trials. At a time when three-dimensional conformal radiotherapy has become the standard procedure and with the development of intensity-modulated radiation therapy, defining nodal volumes is essential and practices should be harmonized to assess and compare the efficiency and toxicity of radiotherapy. Furthermore, the indication of lymph nodes irradiation has to take into account the risk/benefit balance as expanding the irradiated volume can increase radio-induced toxicity. Selection of patients receiving this treatment is essential. The aim of this update is to define nodal volumes, to precise the indications of their irradiation and to present the expected benefits as well as the potential side effects.

Objectif de l’etude La chimioradiotherapie est le traitement de reference des cancers bronchiques non a petites cellules localement evolue, mais le resultat de ce traitement reste mediocre. L’etude RTEP5 (programme hospitalier de recherche clinique [PHRC] de 2011) propose d’augmenter la dose de radiotherapie chez les patients atteints de tumeur hypoxique d’apres la TEP-scanographie au fluoromisonidazole (F-miso). Materiel et methode Chaque patient eligible a beneficie d’une TEP-scanographie pretherapeutique au fluorodesoxyglucose (FDG) afin de definir le volume metabolique et F-miso afin de confirmer le caractere et le volume hypoxiques ; ces examens ont egalement ete realises a 42 Gy dans le cadre d’etudes ancillaires. Les patients chez qui la TEP au F-miso etaient positives et ont beneficie d’une augmentation de dose au sein du volume hypoxique sans limite de dose du boost selon les contraintes pulmonaire (V20 [volume recevant 20 Gy] inferieur a 30 %) et medullaire (dose maximale, Dmax, inferieure a 45 Gy). Resultats Sur 79 pre-inclus, 54 patients etaient definitivement inclus dans l’etude, dont 34 avec une TEP-scanographie au F-miso positive. La fixation sur la TEP au FDG et le volume metabolique etaient significativement plus importants dans le groupe hypoxique ( Standard Uptake Value maximale [SUVmax] de 14,5 ; volume fixant le FDG de 55,4 cm 3 ) que dans le groupe non hypoxique (SUVmax de 10 ; volume fixant le de FDG a 27,3 cm 3 ) ( p = 0,021 ; p = 0,026). Sur les 34 patients eligibles a une augmentation de dose, 24 ont pu en beneficier (dose moyenne de 77,1 Gy [70 a 86 Gy]). Il n’a pas ete mis en evidence de difference de toxicite tant aigue que tardive entre le bras ayant beneficie d’un boost et les patients non hypoxiques (66 Gy). Il s’agit de la plus importante etude clinique proposant de moduler la dose de radiotherapie des cancers bronchiques selon les donnees de l’hypoxie definie par TEP. Conclusion Cette etude demontre : – que les-tumeurs fixant le F-miso sont plus volumineuses et plus hypermetaboliques que les tumeurs ne fixant pas le F-miso ; – la faisabilite d’augmenter la dose de radiotherapie chez les patients traites pour un cancer bronchique non a petites cellules au sein d’une population et d’un volume selectionne par la TEP au F-miso sans augmentation de la toxicite.

National audience; no abstract

Brachytherapy is a possible treatment for localized low risk prostate cancer. Although this option is minimally invasive, some side effects may occur. Acute retention of urine (ARU) has been observed in 5% to 22% of cases and can be prevented in most cases by alpha-blocker treatment. Several alternatives have been reported in the literature for the management of ARU following brachytherapy: prolonged suprapubic catheterization, transurethral resection of the prostate and also intermittent self-catheterization. The authors report an original endoscopic approach, using urethral endoprosthesis, with a satisfactory voiding status.

The dense lymphatic network of the esophagus facilitates tumour spreading along the cephalo-caudal axis and to locoregional lymph nodes. A better understanding of microscopic invasion by tumour cells, based on histological analysis of surgical specimens and analysis of recurrence sites, has justified a reduction in radiotherapy target volumes. The delineation of the clinical target volume (CTV) depends on tumour characteristics (site, histology) and on its spread as assessed on endoscopic ultrasonography and ((18)F)-fluorodeoxyglucose positron-emission tomography (FDG-PET). We propose that positive and negative predictive values for FDG-PET should be used to adapt the CTV according to the risk of nodal involvement.

Large doses per fraction are not recommended in daily radiotherapy due to a higher risk of late normal tissue injury. The technical refinements of modern radiotherapy and suggestions that some tumors could be sensitive to dose per fraction have renewed the interest in hypofractionated schedules. The estimation of α/β ratio value requires large samples of carefully evaluated patients in whom total and fractional doses have varied independently. Tumor repopulation has to be considered when the treatment duration is altered. Without setting aside conflicting publication, the α/β ratio values for prostate and breast (after lumpectomy) cancers could be as low as 2.5 Gy and 4 Gy, respectively. While it is too early to change our routine protocols, the time has come to conduct clinical trials comparing different fractionation schedules.

Acute radiation-induced esophagitis includes all clinical symptoms (odynophagia, dysphagia) occurring within 90 days after thoracic irradiation start. Its severity can be graded using RTOG and CTCAE scales. The clinical risk factors are: age, female gender, initial performance status, pre-therapeutic body mass index, pre-therapeutic dysphagia, tumoral and nodal stage, delivered dose, accelerated hyperfractionned radiotherapy, concomitant association of chemotherapy to radiotherapy and response to the treatment. The dosimetric parameters predictive of esophagitis are: mean dose, V(20Gy), V(30Gy), V(40Gy), V(45Gy) and V(50Gy). Amifostine is the only drug to have a proven radioprotective efficacy (evidence level C, ESMO recommendation grade III). The medical management of esophagitis associates a diet excluding irritant food, medication against gastroesophageal reflux, analgesic treatment according to the WHO scale and management of dehydration and denutrition by enteral feeding.

Acute radiation-induced esophagitis includes all clinical symptoms (odynophagia, dysphagia) occurring within 90 days after thoracic irradiation start. Its severity can be graded using RTOG and CTCAE scales. The clinical risk factors are: age, female gender, initial performance status, pre-therapeutic body mass index, pre-therapeutic dysphagia, tumoral and nodal stage, delivered dose, accelerated hyperfractionned radiotherapy, concomitant association of chemotherapy to radiotherapy and response to the treatment. The dosimetric parameters predictive of esophagitis are: mean dose, V(20Gy), V(30Gy), V(40Gy), V(45Gy) and V(50Gy). Amifostine is the only drug to have a proven radioprotective efficacy (evidence level C, ESMO recommendation grade III). The medical management of esophagitis associates a diet excluding irritant food, medication against gastroesophageal reflux, analgesic treatment according to the WHO scale and management of dehydration and denutrition by enteral feeding.

Dose escalation in prostate cancer is made possible due to technological advances and to precise dose-volume constraints to limit normal tissue damage. This article is a literature review focusing on the correlations between exposure (doses and volumes) of organs at risk (OAR) and rectal, urinary, sexual and bone toxicity, as well as on mathematical models aiming at toxicity prediction. Dose-volume constraint recommendations are presented that have been shown to be associated with reduced rectal damage. Indeed, the clinical data is relatively strong for late rectal toxicity (bleeding), with constraints put on both the volume of the rectum receiving high doses (≥70 Gy) and the volume receiving intermediate doses (40 to 60 Gy). Predictive models of rectal toxicity (Normal Tissue Complication Probability) appear to accurately estimate toxicity risks. The correlations are much weaker for the bulb and the femoral heads, and nearly do not exist for the bladder. Further prospective studies are required, ideally taking into account patient-related risk factors (co-morbidities and their specific treatments), assays of normal tissue hypersensitivity to ionizing radiation and mathematical models applied on 3D images acquired under the treatment machine (e.g. Cone Beam CT).

The a priori evaluation of normal tissue complication probability is an important issue for the radiation oncologist looking for the best therapeutic index. The advances in radiobiological and technological knowledge provide a better understanding of the determinants of radiation effects. The amount of information required to optimize the treatment modalities justifies the use of mathematical models linking the treatment characteristics (dose, volume, treatment time...) to the likelihood of complications. The radiation oncologist needs a minimal understanding of the mathematical models and their limits to justify his prescriptions.

Between May 2002 and May 2004, eight French comprehensive cancer centres did a prospective nonrandomized study including 200 patients, 100 with cancer of the prostate and 100 with head and neck cancers. Half of each patient group was treated by IMRT and the others by RTC 3D. This clinical study was associated with an economic study and a physics study. We report here the first results.For the clinical study, the analysis of the data of the first 88 patients irradiated for a prostatic cancer shows that 39 received RTC and 49 IMRT with a mean dose of 78 Gy at the ICRU point at 2 Gy per fraction. For HN tumours, the preliminary analysis was done on the 87 first patients with a mean follow-up of 11.5 months (2 to 25 months) and a median of 8.4 months for the IMRT groups and 13.2 months for the RTC group. The economic study was done on the first 157 patients included during the first 18 months: 71 treated by RTC (35 for HN and 36 for prostate) and 86 treated by IMRT (38 for HN and 48 for prostate). The assessment of the direct costs was realized by a micro-costing technique. The physical study compared dose distributions for both techniques and has created quality control recommendations.Clinical studies of the acute reactions do not show any difference between groups, but we want to point out the short follow-up and the relatively high dose delivered to cancers of the prostate. The physics study demonstrates that IMRT is technically feasible in good clinical conditions with high quality assurance, a good reproducibility and precision. Dosimetric data show that IMRT could certainly spare organs at risk more than RTC for HN tumours. The direct costs of "routine" treatments for HN tumours were 4922 euros for IMRT versus 1899 euros for RTC and for the prostatic cancers 4911 euros for IMRT versus 2357 for RTC.

The aim of quality control procedures during radiation therapy is to check the consistency between actual and prescribed treatments. Given the technical complexity of modern radiotherapy, stricter policies are necessary to meet increasing requirements for quality and safety. Among the various tools available, electronic imaging systems play an increasing role in patient-beam position checking and in vivo dose measurements. Written procedures will have to be established in order to describe the control modalities and frequency, as well as the rules for error corrections according to the treatment intent. Non medical staff will be devoted to new tasks, under the radiation oncologist's responsibility. A special attention should be directed at electronic archives, since the present technology is unlikely to meet the legal requirement to keep medical records accessible for at least 30 years.

Conformal irradiation of non-small cell lung carcinoma (NSCLC) is largely based on a precise definition of the nodal clinical target volume (CTVn). The reduction of the number of nodal stations to be irradiated would render tumor dose escalation more achievable. The aim of this work was to design an mathematical tool based on documented data, that would predict the risk of metastatic involvement for each nodal station.From the large surgical series published in the literature we looked at the main pre-treatment parameters that modify the risk of nodal invasion. The probability of involvement for the 17 nodal stations described by the American Thoracic Society (ATS) was computed from all these publications and then weighted according to the French epidemiological data. Starting from the primitive location of the tumour as the main characteristic, we built a probabilistic tree for each nodal station representing the risk distribution as a function of each tumor feature. From the statistical point of view, we used the inversion of probability trees method described by Weinstein and Feinberg.Taking into account all the different parameters of the pre-treatment staging relative to each level of the ATS map brings up to 20,000 different combinations. The first chosen parameters in the tree were, depending on the tumour location, the histological classification, the metastatic stage, the nodal stage weighted in function of the sensitivity and specificity of the diagnostic examination used (PET scan, CAT scan) and the tumoral stage. A software is proposed to compute a predicted probability of involvement of each nodal station for any given clinical presentation.To better define the CTVn in NSCLC 3DRT, we propose a software that evaluates the mediastinal nodal involvement risk from easily accessible individual pre-treatment parameters.

Conformal irradiation of brain tumours is based on the three-dimensional reconstruction of the targeted volumes and at-risk organ images, the three-dimensional calculation of the dose distribution and a treatment device (immobilisation, beam energy, collimation, etc.) adapted to the high precision required by the procedure. Each step requires an appropriate methodology and a quality insurance program. Specific difficulties in brain tumour management are related to GTV and CTV definition depending upon the histological type, the quality of the surgical resection and the medical team. Clinical studies have reported dose escalation trials, mostly in high-grade gliomas and tumours at the base of the skull. Clinical data are now providing a better knowledge of the tolerance of normal tissues. As for small tumours, the implementation of beam intensity modulation is likely to narrow the gap between conformal and stereotaxic radiotherapy.

Most of the concepts and terms related to conformal radiotherapy were produced by English-speaking authors and eventually validated by international groups of experts, whose working language was also English. Therefore, a significant part of this literature is poorly accessible to the French-speaking radiation oncology community. The present paper gathers the 'official' definitions already published in French, along with propositions for the remaining terms which should be submitted to a more formal and representative validation process.

The significantly higher human and material costs induced by the development of conformal radiotherapy cannot be ignored. In France, the present criteria for medical reimbursements underestimate the costs related to treatment preparation and evaluation, slowing down the implementation of new equipment and therapeutic practices. To fit the legitimate concerns regarding health cost containment, conformal radiotherapy should be submitted to appropriate economic analyses. These analyses are based on rigorous methods aimed at weighing the actual costs of conformal treatment by the benefits achieved in terms of tumor control, normal tissue complication and the patients' quality of life. The conclusions from the few studies published to date are rather in favour of conformal radiotherapy when compared to alternative therapeutic procedures. These early results need to be confirmed in order to support more rational reimbursement modalities to promote innovative treatments.

A comprehensive understanding of the radiobiological bases of total body irradiation (TBI) is made difficult by the large number of normal and malignant tissues that must be taken into account. In addition, tissue responses to irradiation are also sensitive to associated treatments, type of graft and a number of patient characteristics. Experimental studies have yielded a large body of data, the clinical relevance of which still requires definite validation through randomized trials. Fractionated TBI schemes are able to reduce late normal tissue toxicity, but the ultimate consequences of the fractional dose reduction do not appear to be equivocal. Thus, leukemia and lymphoma cells are probably more radiobiologically heterogeneous than previously thought, with several cell lines displaying relatively high radioresistance and repair capability patterns. The most primitive host-type hematopoietic stem cells are likely to be at least partly protected by TBI fractionation and may hamper late engraftment. Similarly, but with possibly conflicting consequences on the probability of engraftment, the persistence of a functional marrow stroma may also be fractionation-sensitive, while higher rejection rates have been reported after T-depletion grafts and fractionated TBI. In clinical practice (as for the performance of relevant clinical trials), the influence of these results are rather limited by the heavy logistic constraints created by a sophisticated and time-consuming procedure. Lastly, clinicians are now facing an increasing incidence of second cancers, at least partly induced by irradiation, which jeopardize the long-term prospects of otherwise cured patients.

The choice of dose and fractionation for total body irradiation is made difficult by the large number of considerations to be taken into account. The outcome of bone marrow transplantation after total body irradiation can be understood in terms of tumour cell killing, engraftment, and normal tissue damage, each of these endpoints being influenced by irradiation-, disease-, transplant-, and patient-related factors. Interpretation of clinical data is further hampered by the overwhelming influence of logistic constraints, the small numbers of randomised studies, and the concomitant variations in total dose and fraction size or dose rate. So far, three cautious conclusions can be drawn in order to tentatively adapt the total body irradiation schedule to clinically-relevant situations. Firstly, the organs at risk for normal tissue damage (lung, liver, lens, kidney) are protected by delivering small doses per fraction at low dose rate. This suggests that, when toxicity is at stake (e.g., in children), fractionated irradiation should be preferred, provided that interfraction intervals are long enough. Secondly, fractionated irradiation should be avoided in case of T-cell depleted transplant, given the high risk of graft rejection in this setting. An alternative would be to increase total (or fractional) dose of fractionated total body irradiation, but this approach is likely to induce more normal tissue toxicity. Thirdly, clinical data have shown higher relapse rates in chronic myeloid leukaemia after fractionated or low dose rate total body irradiation, suggesting that fractionated irradiation should not be recommended, unless total (or fractional) dose is increased. Total body irradiation-containing regimens, primarily cyclophosphamide/total body irradiation, are either equivalent to or better than the chemotherapy-only regimens, primarily busulfan/cyclophosphamide. Busulfan/cyclophosphamide certainly represents a reasonable alternative, especially in patients who may not be eligible for total body irradiation because of prior irradiation to critical organs.

The potential tailoring of radiotherapy modalities to the biological characteristics of individual tumours and normal tissues appears to be an exciting way to improve the therapeutic, ratio in radiation therapy patients. Numerous assays have been proposed to provide the clinician with the biological information necessary to predict the outcome after irradiation and to guide the treatment prescription, but none of them has made its way to daily practice. Major difficulties are due to the technical burden of the procedures, the poor characterization of the assayed cells, and, moreover, the high complexity of tumour and normal tissues biology. The present paper reviews the present status of the assessment of tumour cells radiosensitivity, proliferation and oxygenation. Research remains extremely active in the field of biological predictors of response to irradiation. Future steps forwards are expected from progress in the available technologies, (re-)discovery of apoptosis and investigation of normal tissue tolerance.

The daily practice of radiation oncology is increasingly influenced by the late tolerance of normal tissues. The treatment decision must be based on detailed arguments and the physician's duty to extensively inform his patients is emphasised every day. The incidence and severity of radiation-induced sequelae and late complications can be reduced by decreasing the total dose to the normal tissues, and by decreasing the dose protraction, provided that the interval between fractions remains longer than 6 to 8 hours. This approach yields a selective protection of late responding normal tissues, since tumours are less sensitive to the effects of fractionation. Despite its own limitations, the linear- quadratic model is nowadays the standard method to compare the biological effects of different radiation treatments.

Analysis of the preliminary results of a phase I study investigating the feasibility of concomitant chemotherapy with daily doses of carboplatin (20 to 25 mg/m2/d over 45 or 10 min) and accelerated chest irradiation (60 to 64 Gy over 4 weeks, 2 Gy per fraction, using the concomitant boost technique).This combination was given alone or following three cycles of induction chemotherapy (cisplatin, 25 mg/m2 per day from d1 to d5; 5-fluorouracil, 600 mg/m2 per day from d1 to d5 and vinorelbine, 25 mg/m2 per day at d1 and d5 with a 4-week interval) in 15 patients with locally advanced unresectable non-small cell lung cancer. All patients received the planned sequence.The dose-limiting toxicity was esophagitis (5 out of 15 grade 4). No toxic deaths were observed. The tumor response rate was high: six out of 15 complete responses and 14 out of 15 tumor regressions greater than 50%. The median survival was not reached after a mean follow-up of 14 months (range, 6-28 months).We are now planning a multicenter phase II study using the following combination: 20 mg/m2 of daily carboplatin over 10 min and a 60-Gy irradiation dose over 4 weeks.

Late damages to the skin and subcutaneous tissues are almost inescapable because of the high skin doses required in the irradiation of breast tumours. While the clinical and histological descriptions date back to the first decades of the therapeutic use of ionising radiation, the recent advances in cellular and molecular biology have significantly contributed to the increased understanding of late skin injury mechanisms. In particular, sub-cutaneous fibrosis appears to be the partly reversible results of a continuous and self-maintained local process, possibly sensitive to therapeutic intervention. A second very active research avenue is the development of biologic assays potentially able to predict the probability of increased normal tissue injury after irradiation in individual patients. Such a test would allow the adaptation of the treatment modalities to the radiobiological behaviour of normal tissues. To date, these expectations have not been met. The quality of the irradiation and its modalities (total dose, fractionation, inter fraction interval) remain the main ways to achieve an optimal functional and cosmetic outcome.

Recent studies have shown that experimental tumors could be treated more efficiently with ionizing radiation if genetic material was transfered into tumor cells. Several approaches have been reported, and among them, the first one consisted of increasing the apoptotic response to radiation by modulating genes involved in the regulation of the apoptotic pathway. Indeed the modulation of p53 and bcl-2 gene expression has recently been used successfully in several experimental models to increase the apoptotic death after radiation. A second approach consisted of taking advantage of the conditional expression of some genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio-inducible promoter which can be combined to a gene, able to enhance or decrease the biological effect of radiation. The irradiation of such a transgene under the control of a radio-inducible promoter can lead to a second biological effect, concomitant to the irradiation, as reported for the TNF alpha under the control of the EGR (early growth response) promoter. A third approach consisted of enhancing the effect of radiation induced tumor cell death by the expression of a suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus thymidine kinase gene). These preliminary results obtained in experimental models appear to be very promising and might improve the efficacy and specificity of radiation therapy in a not too distant future.

Two types of "severe accidental irradiation" can be schematically described: high dose localized irradiations and accidental total body overexposure. Actually, these two pathologies may coexist, and may be associated with external or internal radioactive contamination, and with all the "catastrophe medicine" syndromes. For high dose localized irradiation, physicians must manage as well as possible complex surgical procedures which unfortunately cannot always avoid being mutilating. For total body overexposure, haematological problems are at the forefront. In according with various situations, hematological growth factors or even allogeneic bone marrow transplantation will be discussed in specialized haematology (and transplant) units. The optimal management of severe accidental irradiation victims implies a close--and rapidly organized--cooperation between general practitioners, firemen, intensive care units, radiopathologists, specialist surgeons (hand and burns) and haematologists.

Medical radiation includes radiodiagnosis, nuclear medicine, and radiation therapy. This radiation exposure differs from occupational public exposure, since a direct benefit is conferred upon the patient. The theoretical risks include genetic mutations, carcinogenesis and teratogenesis. In radiodiagnosis and nuclear medicine, the absorbed doses are very low, and no hazardous effect has been observed. In radiation therapy however, where high doses are delivered to a small number of patients, radio-induced carcinogenesis is well documented. It is by no means sure that the nuclear risk must be taken into account, and fully justifies the accomplishments and recommendations of the French radiation protection programs. There is no question that the nuclear risk-benefit equation resulting from medical exposure is tipped heavily in favor of benefit.

The potential doubling time (Tpot) is defined as the time necessary to double the number of proliferating tumor cells in the absence of spontaneous cell loss. Tpot is thought to be a better index of tumor proliferation than clinically observed tumour volume doubling time. The in vivo measurement of Tpot is a possible way to detect fast growing tumours which would be better controlled by accelerated radiotherapy. The published data demonstrate the feasibility and the safety of the technique. Large variations in Tpot values were observed in tumors with similar histology, indicating an accelerated proliferation rate in some tumors. There are technical difficulties related to intra-tumor heterogeneity, sample contamination by normal cells, and inter-laboratory variability, which question the biological interpretation of Tpot. Further studies are ongoing to establish whether the in vivo measurement of Tpot 1) provides information that is independent of the "classical" prognostic factors, and 2) allows the early recognition of the patients likely to benefit from accelerated treatment.

In 1994, late effects of radiotherapy should be limited to an acceptable rate of benign and non-disabling complications. In almost all cases, this goal can be presently reached, owe to recent technological and radiobiological advances. The precise adaptation of irradiated volume, dose, fractionation and total duration of treatment should avoid severe post-radiotherapeutic toxicity. The identification of subgroups of patients with high susceptibility to ionizing radiations should soon allow the radiotherapists to take up the challenge of a both efficient and non-toxic irradiation.

Prognosis of esophageal cancer is very poor. Five-year survival does not exceed 20% after radical surgery, the best available treatment. Unfortunately, only 40% of the patients are amenable to surgery because of poor general status and/or locoregional extension. Adjuvant treatment did not yield survival improvement. Preoperative radiotherapy (three randomized trials) or postoperative radiotherapy (one randomized trial) showed only a decrease of regional relapses, perhaps only for the nodes negative patients. Neoadjuvant chemotherapy obtains some interesting response rate (20-60%), but there has been no evidence yet for survival improvement. Recently, promising results were presented after combination of radiotherapy and chemotherapy. In this paper, we review the present status of combined treatment for esophageal cancer. Our multicentric group (OSOF) is now completing a phase II trial, that should soon form the basis for a phase III prospective study.