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Nanomedicine has undergone significant development since the 2000s and it is only very recently that two metallic nanoparticles have emerged in clinical trials. The mechanism of these radiosensitizing agents is based on the presence of atoms with a high atomic number (Z) allowing a higher dose deposition into the tumor during irradiation. The first nanoparticle used in humans is NBTXR3, composed of hafnium (Z=79), with intratumor injection for the treatment of sarcoma. Another gadolinium-based nanoparticle (Z=64), AGuIX, has been used for intravenous injection in the treatment of brain metastases. The preliminary results are promising in terms of feasibility, safety and efficacy, as evidenced by the significant number of ongoing clinical trials. The upcoming challenges for the development of nanoparticles will be the targeting of cancer cells, their biodistribution into the body, their eventual toxicity and their industrial production. In the coming years, modalities of administration and optimal combinations with radiotherapy should be defined in connection with fundamental research.

Radiation therapy is a cornerstone of head and neck cancer management. Technological improvements in recent years in radiation therapy, with intensity-modulated techniques, reinforce even more its role. However, both local and locoregional relapses are still observed. Understanding biological mechanisms of treatment resistance is a topic of major interest. From the cancer cell itself, its ability to repair and proliferate, its microenvironment and oxygenation conditions, migratory and invasive capacity, to biological parameters related to the patient, there are many mechanisms involving radiosensitivity and/or radioresistance of head and neck cancer. The present study explores the main biological mechanisms involved in radiation resistance of head and neck cancer, and describes promising therapeutic approaches.

Since twenty years, many nanoparticles based on high atomic number elements have been developed as radiosensitizers. The design of these nanoparticles is limited by the classical rules associated with the development of nanoparticles for oncology and by the specific ones associated to radiosensitizers, which aim to increase the effect of the dose in the tumor area and to spare the health tissues. For this application, systemic administration of nanodrugs is possible. This paper will discuss the development of AGuIX nanoparticles and will emphasize on this example the critical points for the development of a nanodrug for this application. AGuIX nanoparticles display hydrodynamic diameters of a few nanometers and are composed of polysiloxane and gadolinium chelates. This particle has been used in many preclinical studies and is evaluated for a further phase I clinical trial. Finally, in addition to its high radiosensitizing potential, AGuIX display MRI functionality and can be used as theranostic nanodrug for personalized medicine.

Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact.

Nanoparticles have emerged in oncology as new therapeutic agents of distinct biochemical and physical properties, and pharmacokinetics. Current rationale and clinical applications in combination with radiation therapy were analyzed.A review of the literature was conducted on nanoparticles as radiosensitizers, with a focus on metallic nanoparticles and radiosensitization mechanisms.Nanoparticles are mainly used as vectors for drugs or to potentiate dose deposit selectively in irradiated tissues. Preclinical data suggest a predominating effect in the kilovoltage range through a photoelectric effect and a potential in the megavoltage range under a combination of physical and biochemical (diameter, concentration, site of infusion etc) conditions. Several clinical trials are ongoing with metallic/crystalline nanoparticles.Nanoparticles have shown a potential for better therapeutic index with radiation therapy, which is being increasingly investigated clinically.

The overexpression of the Human Epidermal Growth Factor Receptor 2 (HER2) is observed in 15% of breast cancers and associated with poor prognosis in terms of overall survival. Trastuzumab is an anti-HER2 targeted therapy, leading to a specific inhibition of the molecular mechanisms triggered by this receptor. In an adjuvant setting, trastuzumab and radiotherapy have each proved their oncologic efficacy in the management of the breast tumours presenting this molecular profile. However, both treatments expose to an increased risk of toxicities, particularly cardiovascular ones. Moreover, the radiosensitizing effect of trastuzumab has been proved in vitro and in vivo. Hence, in clinical practice, the benefit/risk ratio of a concurrent treatment remains to be defined. This literature review has for purposes to describe the rationale making conceivable the administration of trastuzumab concurrently with locoregional breast radiotherapy, and to remind the results of the clinical studies having assessed this therapeutic association.

Brain metastases are the leading cause of intracranial malignancy and a major cause of mortality and morbidity. From 20 to 40% of cancer patients develop brain metastases. The irradiation of the whole brain remains the most commonly undertaken treatment, but should be discussed in relation to other therapeutic alternatives such as stereotactic radiotherapy or the use of new chemotherapy drugs. Its use according to pathology should be discussed. It can lead to a long-term neurocognitive toxicity that should be evaluated more precisely. This literature review aims to highlight the role of whole-brain radiotherapy used alone or in combination with other treatments.

Cancer stem cells are a subject of increasing interest in oncology. In particular, several data suggest that cancer stem cells are involved in the mechanisms of tumor radioresistance, and may explain the therapeutic failures after radiotherapy. Because of its poor prognosis and high recurrence rate after irradiation, glioblastoma model is often studied in the search for new radiosensitizers. There are several preclinical data suggesting that cancer stem cells could be a potential therapeutic target for improving the biological effectiveness of radiation therapy. Through the example of glioblastoma, we review the main signaling pathways involved in the mechanisms of radiation resistance of cancer stem cells and for which pharmacological targeting could potentially enhance tumor radiosensitivity.

During the last decades, advances in diagnostic and therapeutic technologies have modified the management of brain metastases, which is currently tailored to the type of primary site and to prognostic factors isolated in multivariate analyses. The aim of this article is to take stock of the current state of knowledge regarding prognostic factors in the setting of brain metastases from breast cancer as well as prognostic classifications proposed in this context. An appropriate multidisciplinary treatment for each prognostic class will be then discussed in light of the results of major randomized controlled trials enrolling patients with brain metastases from breast cancer.

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.

International audience; Protracted preoperative radiochemotherapy with a 5-FU-based scheme, or a short course of preoperative radiotherapy without chemotherapy, are the standard neoadjuvant treatments for resectable stage II-III rectal cancer. Local failure rates are low and reproducible, between 6 and 15% when followed with a "Total Mesorectal Excision". Nevertheless, the therapeutic strategy needs to be improved: distant metastatic recurrence rates remain stable around 30 to 35%, while both sphincter and sexual sequels are still significant. The aim of the present paper was to analyse the ongoing trials listed on the following search engines: the Institut National du Cancer in France, the National Cancer Institute and the National Institute of Health in the United States, and the major cooperative groups. Keywords for the search were: "rectal cancer", "preoperative radiotherapy", "phase II-III", "preoperative chemotherapy", "adjuvant chemotherapy" and "surgery". Twenty-three trials were selected and classified in different groups, each of them addressing a question of strategy: (1) place of adjuvant chemotherapy; (2) optimization of preoperative radiotherapy; (3) evaluation of new radiosensitization protocols and/or neoadjuvant chemotherapy; (4) optimization of techniques and timing of surgery; (5) place of radiotherapy for non resectable or metastatic tumors.

Lung cancer is the leading cause of cancer-related death. Between 80-85% of lung cancers are non-small cell lung carcinomas. One third of the patients are diagnosed with locally advanced stage. In this condition, concomitant radio-chemotherapy is the standard treatment for patients with good performance status. Despite important improvements in the last years, non-small cell lung carcinoma prognosis remains poor, with high rates of both local recurrences and metastases. The heterogeneity of molecular characteristics of non-small cell lung carcinoma cells and a better knowledge of potential targets offer promising developments for new pharmacologic agents. Hereafter we will review the currently most studied pathways and the most promising ones for the treatment of locally advanced unresectable non-small cell lung carcinoma. Two of the most attractive pathways where new agents have been developed and assessed in combination with thoracic radiotherapy or radiochemotherapy are the EGFR pathway (either with the use of monoclonal antibodies or tyrosine kinase inhibitors) and the angiogenesis inhibition. The development of targeted agents could lead to individualized therapeutic combinations taking into account the intrinsic characteristics of tumor cells. Pharmacological modulation of tumour cells radiosensitivity by targeted therapies is only starting, but yet offers promising perspectives.

Platine-based chemotherapy agents are major drugs in oncology and are currently used in most solid malignancies. Of these, cisplatin has been the most widely used over past years. Its efficacy and toxicity have been both well documented in the literature. Carboplatin has a rather different toxicity profile and seems to be better tolerated than cisplatin. This might potentially impact on quality of life. Carboplatin has been assessed for treatment of most malignancies in which cisplatin has demonstrated its efficacy. This paper aims at reviewing and comparing the current indications in terms of efficacy and toxicity of cisplatin and carboplatin. Although cisplatin has demonstrated its superiority over carboplatin for treatment of lung cancers and germ-cell tumors, the tolerance of carboplatin is better than that of cisplatin. This might be taken into account for patients treated with non-curative attempt. Further studies should compare both chemotherapy agents for quality of life. Of course, carboplatin remains widely used for patients who are contra-indicated for cisplatin.

At the beginning of the 21st century, radiation biology is at a major turning point in its history. It must meet the expectations of the radiation oncologists, radiologists and the general public, but its purpose remains the same: to understand the molecular, cellular and tissue levels of lethal and carcinogenic effects of ionizing radiation in order to better protect healthy tissues and to develop treatments more effective against tumours. Four major aspects of radiobiology that marked this decade will be discussed: technological developments, the importance of signalling and repair of radiation-induced deoxyribonucleic acid (DNA) damage, the impact of individual factor in the response to radiation and the contribution of radiobiology to better choose innovative therapies such as protontherapy or stereotactic body radiation therapy (SBRT). A translational radiobiology should emerge with the help of radiotherapists and radiation physicists and by facilitating access to the new radio and/or chemotherapy modalities.

The central role of p53 after exposure to ionizing radiation has been widely demonstrated. Mdm2, the main cellular regulator of p53, is a promising target for radiosensitizing purposes. In this article, we review the most recent data on the pharmacological targeting of Mdm2, with focus on strategies of radiosensitization. Antitumor activity of Mdm2 inhibitors has been related with activation of p53-dependant apoptosis, action on DNA repair systems, and antiangiogenic activity. Preliminary data suggested a synergic interaction between Mdm2 inhibitors and ionizing radiations. However, no clinical data has been published yet on the pharmacological targeting of Mdm2. Given their new mechanisms of action, these new molecules should be subject to careful clinical assessment. Although promising, these strategies expose to unexpected toxicities.

Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a mediator in the downstream signalling pathway phosphatidylinositol 3-kinase/Akt, playing a key role in regulation of basic cellular functions including growth and cell proliferation. The inhibitor of mTOR RAD001, or everolimus (Novartis Pharma AG), is a hydroxyethyl ether rapamycin derivative administered orally. Everolimus showed an important anti-angiogenic and antiproliferative activity on cell lines derived from human tumours and on xenograft models of human tumours. This molecule appears well tolerated, with skin reactions, stomatitis, myelosupression and metabolic abnormalities transient and reversible with interruption of treatment. Clear data suggest antitumor activity, including tumour regression and prolonged stable disease, which has been reported in patients with a variety of malignancies, especially those with metastatic renal cell cancer. Here, we review the preclinical data of this compound with current clinical results and future developments.

The Oxygen effect plays a key role in cellular response to ionizing radiations. From many years, tumour hypoxia is a limiting treatment factor. Multiple ways to interact with free radicals have been developed. The increase in tissue oxygenation has a limited impact. Radiosensitizing agents as nimorazole or gadolinium have a clinical benefit. Tirapazamine or AQ4N, bioreductive agents, are not routinely used. New agents through the HIF-1 and the endothelial cell pathways are currently being developed. Studies on the expression of endogenous markers of hypoxia could be useful tools to predict tumour response to the treatment.

A hallmark of locally advanced non-small cell lung cancer is its high local and systemic recurrence rates, ranging from 60% to 80%. Radiotherapy has shown its efficacy in controlling the tumor and in increasing overall survival, especially with combined sequential or concurrent chemotherapy to allow an anti-tumoral synergy. Gemcitabine, a new generation cytotoxic agent, is a potent radiosensitizer in vitro, and thus appears as a promising molecule in these multimodal therapeutic regimens. If the initial trial with gemcitabine and radiation produced unacceptable toxicities, lessons were learned from this study, and further phase I-II trials demonstrated that in a clinical trial setting, gemcitabine and radiation can be given safely, both in sequential and concurrent chemoradiation regimens, leading to high response rates and prolonged survival. Gemcitabine-radiation combination is currently integrated in phase III trials evaluating the optimal therapeutic sequence in locally advanced non-small cell lung cancer, and appears as one of the most promising therapeutic regimen in thoracic oncology.

This work aims at describing the wide variety of questions relative to the treatment of locally advanced non-small cell lung cancer; it shows how the advent of new results induces new questions, as well as the diversity of clinical research directions. Lung cancer represents a model of organization of multimodal therapeutic algorithms, the ultimate aim being the therapeutic optimization of the most frequent cancer.

Clinical trials carried out during the last decade have shown that chemo-radiotherapeutic combinations can be used to improve the treatment of locally advanced carcinomas in a range of localisations. A small number of drugs only, among which platinum salts are the most frequently used, was selected on the basis of randomized trials. The rationale for these combinations relies on spatial cooperation for the control of metastases and on interaction at the level of the primary tumour. Such interaction may take place at the molecular level, with altered DNA repair or modification of the lesions induced by drugs or radiation; at the cellular level, notably through cytokinetic cooperation arising from differential sensitivity of the various compartments of the cell cycle to drug or radiation; and at the tissular level including reoxygenation, increased drug uptake or inhibition of repopulation or angiogenesis. Further improvements aiming at an increased therapeutic index, should come from studies on the mode of action of drugs and on the mechanisms of acute toxicity of drugs and radiation.

Growing evidence suggests that intracellular signal pathways play a significant role in radiation response. Promising results have been obtained in experimental studies assessing the combined use of specific inhibitors and radiotherapy. Based on these data, a number of clinical trials were started to enhance tumor responses and thus to decrease the rate of locoregional recurrences. Several prognostic factors on tumoral radiosensitivity have been identified including intracellular signal pathways. Nevertheless, these factors do not correlate with responses to targeted therapies. Concerning rectal cancer, promising results have recently been obtained with concurrent radiotherapy and a monoclonal antibody against VEGF (bevacizumab). Studies combining cetuximab (anti-HER1) and radiotherapy will start soon in this setting. Other specific inhibitors combined with radiotherapy are still in preclinical evaluation.

Head and neck carcinomas are rare in young patients without a history of tobacco consution, tho two classical risk factors. Our report is about 20 year-old patient without a history exosure to radiations or of alcohol / tobacco consumption, who presented with repeated episodes of dysphonia that didn't improve under medical treatment. Endoscopy showed a fungating hemilaryngeal lesion with a histology of epidermoid carcinoma stage T3N0. The patient initially 3 courses of cisplatin-5 fluorouracil resulting in a 90% objective response, followed by a loco-regional radiotherapy. 36 months after the diagnosis and 24 after the end of therapy, the patient is still alive and in complete remission.

New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neoangiogenesis promoters, TGF-beta, cyclooxygenase or the transcription factor NF-kappaB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms.

Since its discovery by Rosenberg in 1965, cisplatin and its derivatives have appeared as the most important chemotherapeutic agents, particularly for their radiosensitizing properties and their clinical use with radiation. In spite of numerous preclinical and clinical studies, optimal schedules of platin and radiotherapy combination have to be defined. The first part of this overview will describe biological mechanisms of interaction between radiation therapy and platinum derivatives. The second part will report the major clinical impact of their association.

Taxanes (paclitaxel and docetaxel) stabilized microtubules against depolymerization, and inhibit their function. Their radiosensitizing properties have been discovered more than 10 years ago; they synchronized tumor cells in G2/M phase, the most radiosensitive portion of the cell cycle. Other radiosensitizing mechanisms have been also discussed, as reoxygenation, promotion of radio-apoptosis and antiangiogenic cooperation. Many phase I and II studies have been performed, essentially in bronchus and head and neck carcinomas. In lung cancer, paclitaxel was delivered weekly at a dose of 60 mg/m2. Many studies combined cisplatin or carboplatin with paclitaxel, demonstrating that this combination is feasible and efficient. Only one phase III trial was reported; after two cycles of chemotherapy for inoperable lung cancers, radiotherapy was delivered, with or without paclitaxel radiosensitization: a benefit in disease-free survival was observed for the combination arm. In head and neck carcinomas, conomitant association of cisplatin, paclitaxel and radiation was feasible and showed promising results. Clinical trials with docetaxel are in progress.

Although the term "targeted therapy" is used to described new molecular approaches derived from the recent increase in the knowledge of cancer biology, radiation therapy is a "targeted therapy" used against cancer. Dose fractionation changes and time treatment duration modifications are used to specifically increase the anti tumor effects of ionising radiation while minimising normal tissue impact of these changes. The implementation of 3 dimensional radiation therapy and IMRT allowed specific tumor targeting and tumor radiation dose increase with normal tumor surrounding tissue relative protection. Clinical research has widely used those concepts with the development of hyper fractionation which showed positive results for head and neck tumours in clinical trials. The development of IMRT has allowed tumor dose escalation in the case of prostate cancer without significant increase in normal tissue toxicity. Beside these approaches, a better understanding of cancer biology and in particular of tumor radiation resistance mechanisms led to the identification of new molecular targets that could be used to increase the therapeutic ratio of radiation therapy. These approaches attempt to widen the therapeutic ratio of radiation, i.e. to increase specifically tumor radiation response with little impact on normal tissue response.

Apoptotic pathways in breast cancer cells are frequently altered, reducing the efficiency of radiotherapy. Conjugated linoleic acid (CLA), known to trigger apoptosis, was tested as radiosensitizer in breast cancer cells MCF-7 and MDA-MB-231. The CLA-mix, made up of the isomers CLA-9cis 11trans and CLA-10trans 12cis, was compared to three purified isomers, i.e., the CLA-9cis 11cis, CLA-9cis 11trans, and CLA-10trans 12cis. Using the apoptotic marker YO-PRO-1, the CLA-9cis 11cis at 50 micro mol/L turned out to be the best apoptotic inducer leading to a 10-fold increase in MCF-7 cells and a 2,5-fold increase in MDA-MB-231 cells, comparatively to the CLA-mix. Contrary to previous studies on colorectal and prostate cancer cells, CLA-10trans 12cis does not lead to an apoptotic response on breast cancer cell lines MCF-7 and MDA-MB-231. Our results also suggest that the main components of the CLA-mix (CLA-9cis 11trans and CLA-10trans 12cis) are not involved in the induction of apoptosis in the breast cancer cells studied. A dose of 5 Gy did not induce apoptosis in MCF-7 and MDA-MB-231 cells. The addition of CLA-9cis 11cis or CLA-mix has allowed us to observe a radiation-induced apoptosis, with the CLA-9cis 11cis being about 8-fold better than the CLA-mix. CLA-9cis 11cis turned out to be the best radiosensitizer, although the isomers CLA-9cis 11trans and CLA-10trans 12cis have also reduced the cell survival following irradiation, but using a mechanism not related to apoptosis. In conclusion, the radiosensitizing property of CLA-9cis 11cis supports its potential as an agent to improve radiotherapy against breast carcinoma.

Recent studies have demonstrated that ionizing radiation activate existing cellular response pathways involving protein kinases. These pathways mediate the cytotoxic and cytoprotective responses of cell death and cell survival, respectively. Cytoprotective responses involve dominantly mitogen-activated protein kinase (MAPK) through radiation-induced activation of EGF receptors and may stimulate cell proliferation if radiation-induced damage is successfully repaired. Similarly, overexpression of EGF receptor family members or their activation by ligands expressed at normal levels may also confer radioresistance. Recent encouraging results indicate that EGF receptor inhibitors such as antibodies or small molecule tyrosine-kinase inhibitors may be effective radiosensitizers in tumors. Within the antibody class of EGF receptor inhibitors are monoclonal antibodies such as cetuximab and trastuzumab. These agents have a common target of the extracellular domain of the EGF receptor. Striking synergistic antitumor effects on human epidermoid and on adenocarcinoma cancer-cell xenografts have been observed when cetuximab treatment is combined with radiotherapy. Promising results have also been obtained from the first clinical trial with cetuximab and radiotherapy in squamous-cell carcinoma of the head and neck. Trastuzumab has been poorly studied in combination with radiotherapy but showed an increased radiosensitivity of HER2-overexpressing breast cancer cells as measured by in vitro colony-forming assays. The mechanism of radiosensitization appears to involve DNA repair. There are well over a dozen agents in the small molecule tyrosine-kinase inhibitor category but the preclinical studies in combination with radiotherapy exist only for ZD1839 and CI1033. Preliminary studies confirm the capacity of ZD1839 and radiotherapy to produce a highly significant increase in tumor growth inhibition when compared to treatment with either modality alone. Another member of the quinazoline class of small molecule tyrosine-kinase inhibitors (CI1033) has recently been examined for its impact in conjunction with radiation in a series of HER-overexpressing breast cancer cell lines. This molecule inhibits tyrosine-kinase activity in all four members of the HER family, and preclinical studies showed a synergistic interaction of CI1033 with ionizing radiation. Finally, EGF receptor family member inhibitors may themselves be effective radiosensitizers and their use in future clinical investigations are based on a solid radiobiological rational.

The role of oxygen as an enhancer of the biological effect of ionising radiation is crucial for radiotherapy. Most of the solid tumours have an inadequate vasculature (neo-angiogenesis) leading to hypoxic areas, favoured by anaemia. Many clinical approaches have been used to overcome this problem with oxygen breathing, radiosensitizing drugs or anaemia correction. All these parameters will be developed together with the methods available for measuring tumour oxygenation and the biological consequences of anaemia and hypoxia on tumour physiology.

Lung cancer is the most frequent form of malignant tumours. The prognosis is poor with a 5-year cure rate which increased from approximately 6% in the sixties to only 15% in the nineties. Surgery remains the reference treatment but only a small minority of patients (about 25%) present with operable disease. The post-surgical 5-year survival is only 25%, providing the rationale for the current research on adjuvant treatments for control of both local and metastatic disease. In that context, the combination of radiotherapy and chemotherapy, commonly referred to as chemo-radiotherapy, has assumed considerable importance: either exclusively in inoperable patients (inoperable tumour or patients inoperable for medical reasons), or pre-operatively. This article reviews the results of the pivotal definitive chemoradiotherapy studies in non-metastatic non-small-cell lung cancer. With exclusive chemoradiation, the concomitant scheme seems to be the most favourable, results issued from randomised studies are expected to confirm that point. An increased toxicity is observed, and the advent of conformal therapy may allow another survival gain. Optimal treatments integration will be necessary.

Gemcitabine is a molecule presenting with major radiosensitizing or radio-potentiator capacities. This property has been extensively studied in vitro, with clinical therapeutic implications. Chemotherapy and radiation are very often used together, most of the time concurrently. This review analyses the results obtained with combined gemcitabine and radiation, for non small cell lung cancer, pancreatic adenocarcinoma, head and neck and uterine cervix carcinomas. Several therapeutic schemes are presented, for each tumor location. A description of the toxicities observed is presented, including the recall phenomenon description. Promising results justify the numerous current trials, as well as enthusiasm initiated by this therapeutic association.

Optimal treatment of non operable localized non small cell lung carcinoma (NSCLC) continues to evolve. Increasing overall survival must evolute through improving local tumoral control and eradication of probable occult metastasis. Historically, median survival varies between 7 and 10 months with a standard conventional fractionated radiotherapy (RT). Induction chemotherapy (CT) followed by RT has demonstrated its superiority over RT alone, modality which is widely utilised. Other studies revealed best results with decreasing metastatic relapses. Three independent meta-analysis confirmed benefit obtained with cisplatin based CT followed by RT that allowed to consider this association as a gold standard. Other authors demonstrated an improvement of local control and survival with concomitant RT-CT or hyperfractionated accelerated RT. Results of all of these new therapeutic modalities still poor. Implication of new CT drugs has conducted for an emergence of new studies finding to demonstrate more encouraging results. Randomized trials are conducted in this way.

Gemcitabine is a pyrimidine analog which has demonstrated antitumoral activity in a variety of solid tumors including bladder, non-small cell lung and pancreatic cancers. Gemcitabine is a potent radiosensitizer of human tumor cells. This review summarizes preclinical studies designed to elucidate the mechanism of action of gemcitabine with ionizing radiation. Phase I-II ongoing trials of combination of radiation therapy and gemcitabine are trying to determine the optimal dose and schedule which could be used in daily clinical activity. The mechanism of radiosensitization is thought to be simultaneously gemcitabine-induced dATP (deoxyadenosine triphosphate) depletion and cell cycle redistribution into the S phase. Although there are no real study which has proven supra-additive combination, the recent acute side effects in several clinical studies oblige physicists to determine with precision the maximum tolerated dose of gemcitabine in association with ionizing radiation. Radiosensitization conditions can be obtained either with a long exposition to a low concentration or a short exposition to a high concentration. Radiation sensitivity begin to be detected four hours after treatment for 48 hours. A dose about 100 mg/m2/week of gemcitabine could be used with radiation therapy according to recent phase I results. This limiting dose is approaching to a radiosensitization context where the effect of one agent is increased by another agent which is inactive or poorly active for the effect under consideration. In this type of regimen, the two modalities do interact with a frequent inhibition of recovery from potentially lethal damage and a probably increase of late side effects of radiation therapy. In contrast, radio-chemotherapy combination is used for a therapeutic advantage when the drug by itself is active against the tumor but does not enhance late side effects of radiation on the critical normal tissues within the irradiated volume. Gemcitabine surely is a strong radiosensitizer even at low doses with future extended combined modality therapeutic indications. The ultimate goal of combined treatments should be an increased therapeutic ratio.

Recent improvement in the understanding of the mechanisms involved in the response to ionizing radiation have made it possible to identify new therapeutic targets to increase the anti-tumor efficacy or, alternatively, to decrease the effect on normal tissues. These approaches included targeting genes involved in the regulation of radio-induced DNA-repair and cell death as well as genes involved in the regulation of radio-induced apoptosis. Many other molecular targets have been recently identified to potentially interfere with the response to ionizing radiation, such as some cell membrane growth factor receptors (EGFr, TGFb) or molecules involved in intra-cellular signal transduction pathways, cell cycle regulation, etc. In addition, other promising ways to modulate radiation-induced response concern extracellular or tissue factors such as hypoxia and angiogenesis.

Gliomas are moderately radiosensitive. The main prognostic factors are the anatomicopathological type and grade of glioma, the performance status, age of the patient and the extent of the surgery. According to data from the literature, high-grade gliomas should be given 60 Gy in five weekly fractions of 1.7 to 2 Gy in a volume including tumor or tumor bed, edema and a 2- to 3-cm margin. A dose of 45 Gy would be sufficient for low-grade gliomas, according to the results of a recent randomized EORTC trial. Brachytherapy and radiosurgery techniques may be indicated in selected cases.

The use of carboplatin has become frequent in children solid tumours because of lower renal and otologic risks as compared to cisplatin. The efficacy of carboplatin has mainly been demonstrated when used in combination with other cytotoxic drugs: few phase II studies of carboplatin alone have been published in children. Because of its limiting haematologic toxicity, carboplatin has become the main platinum compound when used at high dose with hematopoietic stem cell rescue. Formula have been developed specifically in children to allow a determination of the prescribed dose using a targeted "area under the curve" rather than dose in mg/m2, which allows a better individual therapeutic adaptation. Long term follow-up after carboplatin treatment in childhood is mandatory mainly because of the mutagenic and hypofecondity potential risks.

Carboplatin differs from cisplatin by its pharmacokinetics and toxicity profile. Carboplatin is mainly eliminated by the kidneys and its dose-limiting toxicity is the bone marrow suppression. Myelosuppression of carboplatin is more closely correlated with the area under the curve (AUC) of ultrafiltrable plasma concentration versus time to which a patient is exposed, than it is with the administered dose. Similar relationships have been shown between AUC and antitumour effect, although they are in a smaller number and less close. Several methods of dosage individualisation a priori (before carboplatin administration) have been proposed. Since carboplatin is often prescribed to patients with altered renal functions, this dose optimisation is particularly justified. Dose individualisation is based on both equations allowing to predict the patient carboplatin clearance and the choice of target AUC. The different equations proposed are based on direct measurement of the renal filtration glomerular rate or on patient demographic and biological characteristics such as weight and serum creatinine. The respective advantages and limits of these equations are now well known. However, the values of optimal AUC that depend on cytotoxic drugs combined to carboplatin and the patient hematopoietic status, are not precisely determined for each protocol of chemotherapy. When carboplatin is given by reiterated administrations within each course, it is possible to adjust the last doses according to a limited number of blood samples following the first infusion and a Bayesian analysis of the observed plasma concentrations. These methodologies are more complex, but they may be useful for the intensification protocols. Carboplatin is still the only cytotoxic drug for which dose is individualised not according to the body surface area but according to pharmacokinetic parameters.

Platinum compounds primarily act by damaging cellular targets inducing direct or indirect DNA alterations, and cytoplasmic proteins modifications. Molecular and cellular mechanisms of platinum resistance include increase of DNA repair, amplification of detoxifying proteins, modification of platinum transport, and alteration of oncogenes expression. This overview will describe those preclinical constatations related to cisplatin and will focus on carboplatin specificity.

Recent data have shown that the in vitro and in vivo cytotoxicity of bioreductive drugs could be significantly increased by combination with ionising radiation or chemotherapy. Various parameters such as oxygen tension and timing of administration of the drugs could play a crucial role in the efficacy of combined treatment modalities. The aim of this study was to define the oxygen dependency of cell survival after in vitro irradiation and incubation with tirapazamine, a bioreductive drug, and cisplatin given alone or simultaneously. Two human cell lines were studied: one cell line sensitive to tirapazamine, Na11+, a pigmented melanoma with a high percentage of hypoxic cells, and a less sensitive cell line to tirapazamine, HRT18, a rectal adenocarcinoma. Gas changes were made to study cell survival at four different oxygen concentrations (pO2): air (20.9% O2), 10.2 and 0.2% O2. Cells were incubated with tirapazamine and cisplatin alone or combined for one hour at 37 degrees C, then irradiated and cultured. For Na11+, cell survival after irradiation was comparable in air and at 10% oxygen with the two drugs given alone or combined. At 2 and 0.2% oxygen, cell killing was largely increased by tirapazamine and was not modified by the addition of cisplatin. For HRT18, cell survival was not modified when cisplatin was added to radiation, whatever the oxygen partial pressure. At low pO2 (2 and 0.2%) the cytotoxic effect of tirapazamine was not significantly decreased by the addition of cisplatin. When cytotoxic and bioreductive drugs are combined to radiation, the magnitude of the observed effect is highly dependent on the partial oxygen pressure and on the sensitivity of the cell line to the individual drugs. This has very important implications for clinical strategies based on combined chemo-radiotherapy.

Much progress has been made in recent years in administration modalities for radiotherapy for lung cancer. Exposure time to external irradiation was the first parameter to be modified: hyperfractionated radiotherapy, hyperfractionated accelerated radiotherapy with or without concomitant irradiation, synchronous or asynchronous protocols, split course radiotherapy. Radiosensitizing agents have also been the subject of much research: radiosensitization of hypoxic cells, modifiers of the biological response, concomitant radiochemotherapy. The main drugs used are 5-fluorouracil, platinum salts, etoposide, hydroxyurea, taxanes, topotecan, vinorelbin, and gemcitabine. Outcome with these combinations is discussed, both for non-small-cell and small-cell lung cancer. 3D conformational radiotherapy can enable increased dosing in the tumoral target while better preserving healthy tissues. High dose endoluminal brachytherapy is used particularly as a palliative treatment for bronchial obstructions or as curative treatment for weakly infiltrative small endoluminal tumors.

Concomitant use of radiation therapy and chemotherapy is increasing steadily in the treatment of locally-advanced epithelial tumors. This approach has been proved effective in head and neck, esophageal, and canal and nonsmall-cell lung cancers. One of the best radiation sensitizers known to date is 5FU. In vitro cell model have demonstrated the importance of continuous exposure to the drug during 12 to 24 hours after the radiation session. These biological data have been confirmed by a randomized study in rectal cancer comparing 5FU bolus therapy versus 5FU given continuously during irradiation. Disease-free survival and overall survival were longer in the continuous infusion group. Cisplatin is being increasingly used in moderate but repeated doses, a regimen that requires central venous access. Similarly, etoposide, whose venotoxicity is well known, is an excellent radiation sensitizer that is gaining ground, most notably in the treatment of lung cancer. Nutritional support is a key component of all radiochemotherapy regimens used to treat digestive tract cancers and usually requires parenteral nutrition via a central venous access.

Cisplatin (CDDP) and radiotherapy are frequently used concomitantly in the treatment of various malignant conditions. Because of its toxicity, cisplatin tends to be replaced by carboplatin (CBDCA) in several indications. Available data regarding the combined effects of cisplatin and carboplatin with ionising radiation are contradictory.Various concentrations of cisplatin and carboplatin and various timing of association with radiation have been tested in vitro in a human ovarian cancer cell line. The parental cell line (AOvC-0) and a cisplatin-resistant stable subline (AOvC-CDDP/0) (De Pooter et al., Canc Res, 1991) were exposed to carboplatin (2.5, 5 and 10 M) and to CDDP (1, 2.5 and 5 M), 16 h and 4 h before and 4 h and 16 h after irradiation, respectively. Cell survival was evaluated by a classical clonogenic assay.Exposure of AOvC-0 to 5 M CBDCA and of AOvC-CDDP/0 to 10 M CBDCA, before or shortly after radiation exposure, increased cell lethality in a clear supra-additive way, with the highest DEF in the shoulder region of the survival curve and at radiation doses relevant to clinical radiotherapy. In the sensitive cell line, 5 M carboplatin resulted in an additional lethality equivalent to 4.5 Gy; in the resistant cells, 10 M carboplatin was equivalent to 3.6 Gy. Replacing carboplatin by cisplatin in an identical set-up demonstrated exclusively simple additivity (DEF = 1).These data suggest that carboplatin and cisplatin delivered at equitoxic doses interact with radiation in a different way and that, in the present set-up, only carboplatin enhanced the effects of radiation. Carboplatin might consequently be a better candidate than cisplatin in some concomitant combinations with radiotherapy.

Paclitaxel is an agent which stabilizes microtubules, and has been shown to block different cells in the G2/M phase of the cell cycle and thus to modulate their radioresponsiveness. We investigated the radiosensitizing potential of paclitaxel in human head and neck cancer cells.ZMK-1 cells were incubated with paclitaxel for 3, 9, or 24 h before or during 24 h after irradiation. Paclitaxel concentrations of 70 nM, 7 nM, and 0.7 nM were chosen to obtain equivalent toxicity at the different incubation times: 3 h, 9 h, and 24 h, respectively. Radiation doses ranged from 0 to 8 Gy using 60Co source. Cell survival was measured by a standard clonogenic assay after a 9-day incubation. Flow cytometry was used to measure the capacity of paclitaxel to accumulate cells in the G2/M phase.Paclitaxel alone possessed cytotoxicity dependent on time and concentration. There was a total of 40% of cells accumulated in G2/M after 24-36 h. When combined with radiation, the 9 h preincubation resulted in a radiosensitization. The 3 h pre-incubation as well as the 24 h post-incubation resulted in an infra-additive effect.In our cells a radiosensitizing effect of paclitaxel could not be demonstrated unambiguously. The blockage of the cells in the G2/M phase is not the only mechanism to explain the potential radiosensitization of paclitaxel.

Radiation therapy with concomitant chemotherapy is the standard treatment for non resectable esophageal carcinoma. For patients with operable tumors, surgery is the traditional treatment. However several data have suggested that preoperative chemo- and radiotherapy could improve therapeutic results. At the present time, no randomized trial has demonstrated, except for adenocarcinoma of the cardia, the benefit of preoperative treatment. Other randomized trials are needed to determine the role and the optimal modalities of these treatments. This is a review of the literature data in concomitant chemotherapy and radiation in the management of esophagus.