Challenges in the implementation of trastuzumab biosimilars: an expert panel's recommendations.

Trastuzumab has transformed the treatment of HER2-positive breast cancer. Because of impending European patent expiry in 2017, numerous trastuzumab biosimilars are currently undergoing comparability exercises for marketing authorization. Although biosimilar products have been approved in Europe since 2006, many obstacles are expected for trastuzumab, resulting from its nature as a monoclonal antibody, its impact on overall survival, and its extensive biochemical complexities. Unsolved questions need to be addressed for the evaluation of biosimilars' activity in terms of appropriate clinical endpoint definitions for such anticancer drugs, specific assessment pathways and comparative testing of biosimilars, untested ensuing de facto combination of trastuzumab biosimilars with cytotoxics, and immunogenicity monitoring among immunocompromised patients. In such a context of uncertainties, the recent approval by the French parliament of biosimilar substitution, which would allow dispensing trastuzumab biosimilars in place of the originator, should interrogate the oncological community. A think tank of experts was created to delineate specificities and challenges stemming from trastuzumab biosimilars.

Methodology for quantifying interactions between perfusion evaluated by DCE-US and hypoxia throughout tumor growth.

The objective was to validate a combination of two new technologies to depict tumor physiology both temporally and spatially with dynamic contrast-enhanced sonography and an oximeter. Human cancer prostate tumors xenografted onto mice were followed for three weeks using dynamic contrast-enhanced ultrasonography (DCE-US) to detect tumor perfusion. Time intensity curves in linear data were quantified on four regions-of-interest (ROI, main tumor section and its anterior, central and posterior intra-tumoral areas) to extract three indices of perfusion. An oxygen sensor was guided by sonography to obtain accurate pO(2) measurements in the three predefined areas of tumors during their development. No impact on tumor growth of subsequent pO(2) probe insertion was detected. Among the four ROIs studied, the local central tumor showed significant perfusion and oxygenation variations throughout the experiment. A correlation was observed between local central tumor perfusion and pO(2), both of them decreasing through time (p = 0.0068; r = 0.66). The methodology which we developed demonstrated the potential of combining DCE-US with direct tissue pO(2) measurements, improving the description of complex intratumoral dynamic behavior.

Angiogenesis and tumor growth inhibition by a matrix metalloproteinase inhibitor targeting radiation-induced invasion.

In this study, we have evaluated the interactions between ionizing radiation and a matrix metalloproteinase (MMP) inhibitor. Using Matrigel invasion assays, we show that ionizing radiation induced a dose-dependent increase in the invasive phenotype of cultured B16 melanoma cells and that conditioned medium from these irradiated B16 cells promoted endothelial cell [human microvascular endothelial cells (HMEC)] invasiveness. To determine whether the radiation-induced changes in invasive phenotype could be due to changes in MMP activation, we have tested the ability of the MMP inhibitor Metastat to modulate the ionizing radiation-induced invasive phenotype using both an in vitro melanoma model and a mouse s.c. tumor model. In these studies, Metastat inhibited the ionizing radiation-induced invasive phenotype in cultured B16 cells and similarly inhibited the increase in HMEC invasion induced by conditioned medium from irradiated B16 cells. Conversely, ionizing radiation increased B16 MMP-2 activity and the conditioned medium from irradiated B16 induced HMEC MMP-2 activity. To further investigate the interaction between ionizing radiation and MMP activation, we then studied the effects of ionizing radiation on downstream effectors of the MMP system. We found that ionizing radiation induced vascular endothelial growth factor (VEGF) secretion by B16 melanoma cells and that this secretion was inhibited by Metastat. Similarly, conditioned medium from irradiated B16 was also able to increase VEGF secretion in HMECs. Moreover, ionizing radiation-induced melanoma cell invasiveness was partially inhibited by an anti-VEGF monoclonal antibody. In vivo, ionizing radiation plus concomitant Metastat yielded the greatest growth inhibition of melanoma s.c. tumors and this effect correlated with inhibition of angiogenesis as measured by both Doppler ultrasonography and platelet/endothelial cell adhesion molecule-1 staining. Finally, ionizing radiation modulated MMP-2, VEGF, and VEGF receptor expression in these tumor samples using immunohistochemistry. Taken together, these results suggest that there is an ionizing radiation-induced tumor survival pathway and a possible paracrine ionizing radiation-induced stimulatory pathway emanating from tumor cells toward the endothelial bed that is impeded when Metastat is given simultaneously. This model could provide in vivo evidence of the antitumor efficacy of combining a MMP inhibitor with ionizing radiation to target radiation-induced invasion and angiogenesis.

Current approaches and recent developments in the management of head and neck paragangliomas.

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine tumors belonging to the family of pheochromocytoma/paraganglioma neoplasms. Despite advances in understanding the pathogenesis of these tumors, the growth potential and clinical outcome of individual cases remains largely unpredictable. Over several decades, surgical resection has long been the treatment of choice for HNPGLs. However, increasing experience in various forms of radiosurgery has been reported to result in curative-like outcomes, even for tumors localized in the most inaccessible anatomical areas. The emergence of such new therapies challenges the traditional paradigm for the management of HNPGLs. This review will assist and guide physicians who encounter patients with such tumors, either from a diagnostic or therapeutic standpoint. This review will also particularly emphasize current and emerging knowledge in genetics, imaging, and therapeutic options as well as the health-related quality of life for patients with HNPGLs.

[Role of radiotherapy in recurrent gliomas]. / Récidives dans les tumeurs gliales: place de la radiothérapie.

Intracranial gliomas account for less than 2% of primary solid tumors in adults, but are among the most frequent causes of death from cancer in children. Their increasing incidence and the weak impact of treatments on the prognosis justify all the efforts expended to improve results. Surgery, radiation therapy (RT) and chemotherapy are proposed as first-line therapy, according to indications and modalities that remain controversial. In this palliative setting, the only consensus is to search for an optimal efficacy/toxicity ratio. Finally, after a very variable duration of local control depending on the histologic type, recurrence is virtually inevitable, with mainly local progression. The prognosis is then generally dismal, with a median survival of less than 6 months. Although re-operation is efficient for the rapid relief of symptoms, it is often rejected. After or in the absence of surgery, different chemotherapy schedules are proposed according to the histologic type and the patient's general status and objective response rates are very limited, except in the case of oligodendrogliomas. Re-irradiation has a rather bad reputation: even as first-line therapy, total doses never exceed 60 Gy in 30 fractions of 2 Gy over six weeks (conventional fractionation). The main reasons are concerns about increasing unacceptable late neurologic complications and the absence of a demonstrated dose-effect beyond this threshold. However, some arguments have led clinicians to consider lifting the ban on re-irradiation. Among adult patients receiving focal RT for low-grade gliomas, late neurologic toxicity was recently evaluated prospectively using a battery of neurocognitive tests. Compared with the initial status, no significant deleterious effects were observed with a follow-up of at least 3 years. In addition, studies on primates demonstrated that the spinal cord was capable of repairing, at least partially, RT-induced injury. There appears to be room for further irradiation: the results of re-irradiation in more than 300 patients have been documented. The techniques used, patient selection and re-irradiation modalities reported were varied: interstitial brachytherapy or intraoperative-RT within the surgical bed, conformal 3D RT, stereotactic-RT delivered in one or several fractions. Treatment efficacy and toxicity endpoints were very heterogeneous. Nevertheless, with a clearly defined prospective assessment, re-irradiation seems possible without any unacceptable clinical neurotoxicity under the following conditions: a good general status (WHO 0-1); at least a one-year disease-free interval; an initial WHO grade 2 or 3 histology with a maximal tumor diameter not exceeding 3 cm. In this very selective setting, re-irradiation is possible at a dose of 30 to 40 Gy, if possible in stereotactic mode, with a hypofractionated schedule (less than 4 Gy/fraction). Median survival exceeding one year is expected, the main endpoint being the control of symptoms and quality of life.