Antonin Levy

Targeting a cornerstone of radiation resistance: cancer stem cell.

In radiation oncology, cancer stem cells (CSCs) have become an important research field. In fact, it appears that most cancer types contain populations of cells that exhibit stem-cell properties. CSCs have the ability to renew indefinitely, which can drive tumor development and metastatic invasion. As those cells are classically resistant to conventional chemotherapy and to radiation therapy, they may contribute to treatment failure and relapse. Over past decades, preclinical research has highlighted that variations in the CSCs content within tumor could affect their radiocurability by interfering with mechanisms of DNA repair, redistribution in the cell cycle, tumor cells repopulation, and hypoxia. It is now possible to isolate particular cells expressing specific surface markers and thus better investigating CSCs pathways. Numerous inhibitory agents targeting these specific signaling pathways, such as Notch and Wnt/B-catenin, are currently evaluated in early clinical trials. By targeting CSCs, tumor radioresistance could be potentially overcome to improve outcome for patients with solid malignancies. Radiation therapy using ion particles (proton and carbon) may be also more effective than classic photon on CSCs. This review presents the major pathophysiological mechanisms involved in CSCs radioresistance and recent developments for targeted strategies.

Phase I Trials of Molecularly Targeted Agents: Should We Pay More Attention to Late Toxicities?

PURPOSE Phase I trials traditionally aim at determining the recommended phase II dose (RP2D) using grade ≥ 3 toxicity data from cycle 1 (C1) only. This design dates from the era of conventional chemotherapy and may not be relevant for new molecularly targeted agents (MTAs) usually administered in a chronic fashion and for which late or moderate toxicities may deserve particular attention. PATIENTS AND METHODS All consecutive patients treated in phase I trials of MTAs at the Royal Marsden Hospital and Institut Gustave Roussy between January 2005 and July 2008 were included. Gastrointestinal, skin, and clinical renal toxicities of any grade and grades 3 to 4 toxic events of any type occurring at any cycle on treatment were recorded. Doses administered, treatment interruptions, dose modifications, and prescription of comedications were analyzed. RESULTS A total of 445 patients (1,566 cycles; median treatment duration, 55 days) were included in 36 eligible trials; 790 toxicities (590, grade 1; 176, grade, 2; 24 grades, 3 to 4) and 1,819 toxicities (1,521, grade 1; 265, grade 2; 33, grades 3 to 4) were recorded during and after C1, respectively; 57% of the grades 3 to 4 toxicities occurred after C1; 50% of patients presented their worst-grade toxicity after C1. The risk of grades 3 to 4 toxicity was 3% in cycles 1 to 6 and was almost null afterwards. No cumulative toxicities were observed. Median toxicity duration was 15 days, with comedication administered in 68% of events. CONCLUSION Moderate and severe toxicities occur regularly after the first cycle in phase I trials of MTAs and may deserve increased attention in the RP2D process for these agents.

Interest of diffusion-weighted echo-planar MR imaging and apparent diffusion coefficient mapping in gynecological malignancies: A review

Magnetic resonance imaging (MRI) remains the standard modality for the local staging of gynecological malignancies but it has several limitations, particularly for lymph node staging or evaluating peritoneal carcinomatosis. Consequently, there has been a growing interest in functional imaging modalities. Based on molecular diffusion, diffusion‐weighted imaging (DWI) is a unique, noninvasive modality that provides excellent tissue contrast and was shown to improve the radiological diagnosis of malignant tumors. Using quantitative apparent diffusion coefficient (ADC) measurement of DWI provides a new tool for better distinguishing malignant tissues from benign tumors. The aim of the present review is to report on the results of DWI for the assessment of patients with gynecological malignancies. An analysis of the literature suggests that DWI studies would improve the diagnosis of cervical and endometrial tumors. It may also improve the assessment of tumor extension in patients with peritoneal carcinomatosis from gynecological malignancies. However, since the signal intensity of some cancers can range from high intensity to low intensity, a degree of uncertainty was demonstrated due to the proximity of the normal uterine myometrium and ovaries. Interestingly, there is also evidence that ADC might improve the follow‐up and monitoring of patients who receive anticancer therapies, including chemotherapy or radiation therapy. J. Magn. Reson. Imaging 2011;33:1020–1027.

Radiation therapy and immunotherapy: Implications for a combined cancer treatment

Ionizing radiation (IR) is used as primary treatment for numerous localized cancers. Although it is usually described as an immunosuppressive modality, there are new preclinical evidences suggesting that IR could have also generated substantial changes in the tumor microenvironment, including triggering an inflammatory process. This finding implies that radiotherapy could both modulate tumor immunity and have out-of-field activity by recruiting biological effectors. There are numerous uncertainties regarding the true biological impact of radiation on tumor immunogenicity, but some preclinical studies established the proof of concept that combining IR with strategies modifying immunology could enhance antitumor effects. From these findings, clinical trials are now analyzing how immunotherapy and radiation work while given together, with promising preliminary results. This review aims at summarizing the recent developments regarding the impact of IR on tumor immunity, with focus on potential therapeutic targets.

Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation.

Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44+/ALDHhigh were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44+/ALDHhigh were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44+/ALDHhigh cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation.

Unexpected toxicity of cetuximab combined with conventional chemoradiotherapy in patients with locally advanced anal cancer: results of the UNICANCER ACCORD 16 phase II trial

BACKGROUND The ACCORD 16 phase II trial aimed to evaluate the objective response rate after combination of conventional chemoradiotherapy (CRT) and cetuximab in locally advanced anal canal carcinoma (LAACC). PATIENTS AND METHODS Immunocompetent patients with histologically confirmed LAACC received CRT [45 gray (Gy)] in 25 fractions over 5 weeks, fluorouracil and cisplatin during weeks 1 and 5), in combination with weekly dose of cetuximab (250 mg/m(2) with a loading dose of 400 mg/m(2) 1 week before irradiation), and a standard dose boost (20 Gy). The trial was originally designed to include 81 patients to detect a 15% of objective response increase with the new combination in comparison with CRT. RESULTS The trial was prematurely stopped after the declaration of 15 serious adverse events (SAEs) in 14 out of 16 patients. Five patients received the entire planned treatment, and the compliance was higher after amendments of the protocol. Among the 15 SAEs, 6 were unexpected. Grade (G) 3/4 acute toxic effects, observed in 88% patients, were general (n = 13, 81%), digestive (n = 9, 56%), dermatological (n = 5, 31%), infectious (n = 4, 25%), haematological (n = 3, 19%), and others (n = 9); and three patients suffered from six G3/4 late toxic effects. No treatment-related death was reported. All 11 assessable patients had an objective response consisting of six complete (55%) and five partial (45%) response 2 months after the end of the treatment. Thirteen patients were followed up with a median of 22 months [95% confidence interval (CI ): 18-27] and had a 1-year colostomy-free survival, progression-free and overall survival rate of 67% (95% CI: 40%-86%), 62% (95% CI: 36%-82%), and 92% (95% CI: 67%-99%), respectively. CONCLUSION CRT plus cetuximab was unacceptably toxic in this population of patients. Results of others phase II trials evaluating this combination are awaited to confirm these findings. EUDRA CT NO 2007-007029-38.

Radiation-enhanced cell migration/invasion process: a review.

Radiation therapy is a keystone treatment in cancer. Photon radiation has proved its benefits in overall survival in many clinical studies. However, some patients present local recurrences or metastases when cancer cells survive to treatment. Metastasis is a process which includes adhesion of the cell to the extracellular matrix, degradation of the matrix by proteases, cell motility, intravasation in blood or lymphatic vessels, extravasation in distant parenchyma and development of cell colonies. Several studies demonstrated that ionizing radiation might promote migration and invasion of tumor cells by intricate implications in the micro-environment, cell-cell junctions, extracellular matrix junctions, proteases secretion, and induction of epithelial-mesenchymal transition. This review reports various cellular pathways involved in the photon-enhanced cell invasion process for which potential therapeutic target may be employed for enhancing antitumor effectiveness. Understanding these mechanisms could lead to therapeutic strategies to counter the highly invasive cell lines via specific inhibitors or carbon-ion therapy.

External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: 5-Year Results of a Prospective Study

PURPOSE External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. METHODS AND MATERIALS From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). RESULTS Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). CONCLUSIONS Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.

Pharmacological strategies to spare normal tissues from radiation damage: useless or overlooked therapeutics?

Half of all the patients with a solid malignant tumor will receive radiation therapy (RT) with a curative or palliative intent during the course of their treatment. Deleterious effects may result in acute and chronic toxicities that reduce the long-term health-related quality of life of these patients. High-tech RT enables precise beam delivery that conforms closely to the shape of tumors yielding an improved efficacy/toxicity ratio. However, sophisticated RT will not completely prevent toxicity in the irradiated field, especially as normal tissue constraints are offset by dose escalation or concurrent chemotherapy. Pharmacological agents can be used before or after RT to reduce side effects and are classified based on the timing of RT delivery. “Radioprotectors,” used as a molecular prophylactic strategy before RT, are mostly based on antioxidant properties. Currently, amifostine is the only radioprotector approved for use in the clinic. “Mitigators,” given during or shortly after RT, reduce the action of cellular ionizing radiation on normal tissues before the emergence of symptoms. Lastly, a “treatment” is the administration of an agent once symptoms have developed in order to reverse those that are mostly due to fibrosis. This review presents the major known physiopathological mechanisms involved in radiation response and tissue damage for which potential pharmacological candidates are emerging. We discuss the potential clinical relevance of such therapeutics in the era of high-precision radiotherapy.

Accuracy of Diffusion-Weighted Echo-Planar MR Imaging and ADC Mapping in the evaluation of residual Cervical Carcinoma after radiation therapy

OBJECTIVES The impact of diffusion-weighted imaging (DWI) and apparent diffusion coefficients (ADCs) of MR imaging on the evaluation of residual Uterine Cervical Carcinoma after Radiation Therapy, in addition to conventional MR images. METHODS Fourty-nine women presenting with a uterine cervical cancer were examined with 1.5 T MRI and DWI, 8 (4-20) weeks after treatment. Treatment response was determined based on the histopathological results after therapy and was classified as a complete response (CR) or residual disease (RD). Post-treatment DWI and ADC results were compared. RESULTS Five (11%) and 44 (89%) patients were considered as having histologically-proven RD or a CR respectively. The mean ADC of cervical tissue for all patients was 1.74±0.324×10(-3) mm(2)/s and the SD was 1.94±1.11×10(-4). The mean ADC was 1.62±0.21×10(-3) mm(2)/s (SD=1.45×10(-4)) for the 5 patients with RD versus 1.76±0.33×10(-3) mm(2)/s (SD=1.99×10(-4)) for the 44 patients with a CR (p=0.09). Using 1.7×10(-3) mm(2)/s as a radiological cut-off value for the ADC, all patients classified as having histologically-proven RD had a mean ADC of ≤1.7×10(-3). In 12 (25%) cases, RD was suspected on T2-weighted MRI images alone. Eight of these cases were considered as false positives compared to the histological results. Their mean ADC was 1.98×10(-3) mm(2)/s and none of them had an ADC of <1.7×10(-3) mm(2)/s. CONCLUSION Although our results were not statistically significant, ADC values could potentially be used to predict and monitor the response of uterine cervical cancer.