- Email: [email protected]
SP-37: Combination of Chemotherapy and Radiotherapy in NSCL Cancer?
-32-
NOVEL TAHGETING DRUGS AND RADIOTHERAPY 2012 PROGRAMME AND ABSTRACT BOOK
OC-34 INTEGRIN-LINKED-KINASE (ILK) CONTROLS GLIOMA CELL RESPONSE TO IONIZING RADIATION THROUGH HIF-1ALPHA 0. lanvin1, S. Monferran', C. Delmas', B. Couderc1 , C. Toulas 1, E. Cohen-Jonathan Moyal' 1 /nstltut Claudius Regaud, INSERM U1037, Toulouse, France 2 Unlversite Paul Saba tier, EA3035, Toulouse, France Purpose/Objective: Increasing the sensibility of gliobla'stoma cells to Irradiation is a promising approach to improve survival in patients with glioblastoma multiform. Our previous results demonstrated that inhibiting lntegrin-Linked-Kinase (ILK) in U87 cells increased their radioresistant glioblastoma radiosensitivity. The present study aimed to elucidate the mechanism Involved in ILK-induced radioresistance of these cells and to decipher the dovmstream biological pathways. To investigate the ILK-dependent Materials and Methods: biological pathways controlling radioresistance, we chose to generate U87 expressing doxycycline-inducible shRNA directed against ILK. ILK expression inhibition was obtained since 48h of shRNA expression by doxycycline. ILK, HIF-1a and survivin expression was measured by RT -QPCR and western blot analysis. MG132 was used to inhibit the proteasome. Mitotic cell death and centrosome overduplication were assayed by immunofluorescence: DAPI and y-tubulin staining. Limited dilution cloning was used to measure the fraction surviving at 2 Gy. All these experiments were done in the presence or not of doxycycline (to induce shRNA-IlK), HIF-1a siRNA or survivin inhibitor YM155. Results: In this study, we first showed that expression of an inducible shRNA directed against ILK in U87 cell line (U87shiLK) enhanced radiation-induced mitotic cell death and centrosomal overduplication: Moreover, U87shllK showed a down regulation of radiation-Induced HIF-1a expression which involves the proteasome pathway. To elucidate the role of HIF-1a in ILKdependent radioresistance we transfected cells with siRNA directed against HIF-1a. Silencing HIF-1a significantly reduced SF2 value by increasing the sensitivity of these cells to radiationinduced mitotic cell death and centrosome amplification. It is well known that survivin is involved in radioresistance and centrosome overduplication. Moreover, HIF-1a has been shown to regulate survivin expression. We hypothesized that ILK-HIF-1adependent regulation of mitotic cell death and centrosome amplification might be mediated by survivin. Our data showed a decrease of survivin mRNA and protein level in U87shiLK cells. Furthermore, Inhibiting survivin by ' the specific inhibitor of survivin, YM155 significantly increased the percentage of giant multinucleated cells and centrosomal overduplication and reduced the SF2 value of U87 cells similarly to the effect observed when ILK or HIF-1a was silenced in these cells. Conclusions: Our results strongly suggest that ILK-dependent U87 radioresistance pathway is mediated by HIF-1a and survivin. Targeting t his ILK-HIF-1a-survfvin pat hway may be crucial to optimizing radiotherapy efficiency.
SYMPOSIUM: WHAT IS THE STANDARD IN ... SP-35 PLATINUM-BASED RADIO CHEMOTHERAPY IN H&Nl R. Corvo' 'lstituto Nozionale per Ia Rlcerca sui Cancro, Radio-Oncology Deportment, Genova, Italy
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Background: Each year 600.000 new cases of squamous cell carcinoma of the Head and Neck (SCCHN) are diagnosed worldwide. Concurrent chemo-radiotherapy (CRT) is the "standard-of-care treatment" In locally advanced stages and in larynx function preservation programs. Cisplatin (Cis) is the most commonly drug used with RT and the best available evidence showed clinical benefit from Cis administered at 100 mg/m2 every 3 weeks in combination with standard RT. This schedule, although effective, has reached a plateau in long-term outcome and new stategies are warranted in order to Improve therapeutic ratio In advanced SCCHN. Critical Issues: With high-dose Cis nephrotoxicity may be substantial (grade III-IV); other Cis-related toxicities are ototoxicity, leucopenia, hearing loss and tinnitus, stomatit is and severe weight loss. As a consequence, only two cycles of high
dose Cis are often administered without evidence of adverse clinica·l Impact on cytotoxic effect. However, overall survivals rates after different Cis-RT schedules do not exceed 60% at 5 years. Results: Ongoing strategies beyond standard high dose Cis and RT are in progress: 1. low-dose cisplatin (weekly 40 or 50 mg/m2, 2 cycles of 20 mg/m2 for 5 days, daily 6 mg/m2) as alternative option for frail or older patients; 2. the model "third daily Cis regimen" has been proposed to decrease normal tissue complications compared to daily Cis delivery as well as potentially increase tumor control in comparison with weekly Cis delivery; 3. the addition of cetuximab to high dose Cis-RT did not appear to show improved results; 4. the use of altered fractionation RT associated with high-dose Cis did not achieve better outcomes than standard RT; 5. induction chemotherapy including Cis followed by high-dose Cis-RT or cetuximab -RT might provide new advantages but trials are still ongoing. Conclusion: In standard high-dose Cis - RT schedule the supraddltlvity of high-dose Cis with RT (Cis synchronizes cycling clonogens cells in G2 radiosensitive phase) may be compromised by tumor stem-cells accelerated repopulation triggered after single Cis exposure. Novel strategies involving different timing of Cis with IMRT, Cis -pharmacodinamics, association of RT with targeted agents are expected to improve clinical outcome in advanced HNSCC.
SP-36 CETUXIMAB AND RADIOTHERAPY IN H&N? W. Budach', C. Matuschek', E. Bolke' 'Heinrich-Heine University DUsseldorf, DUsseldorf, Germany
Radiation
Oncology,
Radiotherapy in combination with concurrent cetuximab has been shown to improve locoreglonal tumor control and overall survival in non-surgically treated, locally advanced head and neck squamous cell carcinomas (HNC). The combined treatment induces frequently relevant but manageable skin toxicities in- and outside the radiat ion portals. In recurrent and metastatic disease, a survival benefit has also been reported for the addition of cetuximab to cisplatin and 5FU. Therefore, the expectation was that the triple combination of radiotherapy, cisplatin, and cetuximab would further improve clinical outcome. Consequently, the RTOG (110522) analysed 895 patients with unresected HNC randomized to receive either standard chemoradiation (72 Gy + 2x100 mg/m' cisplatin) or the same chemoradiation with concurrent cetuximab (400 mg/m' loading + 250 mg/m' weekly). After a median follow up of 2.4 years, the addition of cetuximab did neither improve locoreglonal control nor DFS and overall survival . Grade III-IV acute cutaneous and mucosal toxicity was significantly higher in the cetuximab arm of the study. The same approach was tested with panftumumab, a fully humanized antiEGFR-antibody, IQ a randomized phase II trial (n=150) presented on ASCO 2012 (SPECTRUM-1: Giralt et al. J Clin Oncol 30, 2012; abstr 5502). The addition of concurrent panitumumab to standard chemoradlation also failed to improve outcome and enhanced acute cutaneous and mucosal toxicity. Whereas radiotherapy and concurrent cetuximab is an alternative option to standard chemoradiatlon in unresected HNC, the combination of EFGRantibodles with concurrent chemoradiation has no role in the treatment of HNC. Radiotherapy and concurrent cetuximab is an alternative option to standard chemoradiation In unresected HNC. EFGR-antibodies in combination with concurrent chemoradiation should not be used in the treatment of HNC.
SP-37 COMBINATION OF CHEMOTHERAPY AND RADIOTHERAPY IN NSCL CANCER? C. Le Pechoux' 1 /nstltut Gustave Roussy, Radiation Oncology, Vlltejuif, France lung cancer remains a major cause of death worldwide with more than 1.1 million deaths per year. Non-small-cell lung cancer (NSCLC) represents now more than 80% of all lung tumours, and approximately 35% of patients with NSCLC present with locally advanced nonmetastatic disease for whom the standard treatment has become combined radiochemotherapy. Concerning locally advanced NSCLC, two meta-analyses based on individual patient data have compared chemotherapy plus radiotherapy to ~ radiotherapy alone. These meta-analyses were recently updated and demonstrated that sequential or concomitant chemoradiation improved survival compared to radiotherapy alone with an
NOVEL TARGETING DRUGS AND RADIOTIIERAPY 2012 PROGRAMME AND ABSTRACT BOOK
absolute modest benefit of 4% at 2 years and 2% at 5 years. In 1990's and 2000's several randomized trials have compared sequential to concomitant chemoradiation. A meta-analysis of these trials was performed using individual patient data. (Auperin, 2010]. Data from six trials could be collected (1,205 patients, 92% of all randomly assigned patients). Median foll~w:up was 6 years. A significant benefit of concomitant chemorad1allon on overall survival (HR, 0.84; P=0.004) was observed, with an absolute benefit of 4.5% (from 10.6% to 15.1%) at 5 years. As compared to sequential chemotherapy, concomitant treatment decreased locoregional pragression but had no significant differential effect on distant progression. As expected, concomitant radiochemotherapy increased grade 3·4 acute esophageal toxicity from 4% to 18% with a relative risk of 4.9 (p• 0.001). As in other solid tumors, concomitant radlochemotherapy Is now considered as the standard treatment for locally advanced NSCLC patients with good performance status. However it should be outlined that most of these trials used 2-D radiotherapy. Ongoing trials integrate the recent developments In three-dimensional conformal radiotherapy to optimize concomitant combinations. Promising preliminary results have also been obtained in combining ·chemoradiotherapy with targeted agents such as cetuximab. Further studies are needed in lung cancer to optimize concomitant combinations
SP-38 THE RATIONAL FOR CONCOMITANT RADIO· AND CHEMOTHERAPY IN MALIGNANT GLIOMA. STATE OF THE ART AND FUTURE PERSPECTIVES
.!l.....it!m.Q\ K. Homiscko2,
1
1
R.O. Mirimanoff , L. Negretti , A.F. Hottinger<, M. Levivier', AI.E. Hegi 1 'centre Hospltoller Univ. Vaudois, Department of Neurosurgery Ei Clinical Neurosciences, Lausanne, Switzerland 2 Centre Hospltaller Univ. Vaudois, Department af Oncology, Lausanne, Switzerland JCentre Hospitaller Unlv. Vaudois, Department of Radiotherapy, Lausanne, Switzerland 'Cen tre Hospltaller Unlv. Vaudois, Department of Neurology Ei Clinical Neurosciences, Lausanne, Switzerland Radiation therapy remains the mainstay of treatment of malignant glioma. While alkylating agent chemotherapy using older drugs failed to demonstrate an improved survival repeatedly, the paradigm changed in 2004 when temozolomlde (TMZ) given concomitantly (TMZIRT) and as adjuvant/maintenance ( .. , TA\Z) t herapy · in glioblastoma demonstrated a statistically significant and clinically meaningful survival benefit. This randomized trial formally compared Initial treatment with standard radiotherapy (30 x 2 Gy) with the association of TA\2/RTiiTMZ, overall survival was the primary endpoint. However, In reality the trial was evaluating early upfront chemotherapy with delayed introduction of chemotherapy, as 75% of all patients in t he control arm received chemotherapy at progression (and 60% of the patients In the experimental). Importantly, MGMT gene promoter methylation silencing of expression of an important repair protein - was shown to be an excellent predictor for benefit of the addit ion of TMZ chemotherapy. Pragresslon-free survival was prolonged onl y in patients with a methylated MGhiT promoter and treated with TMZ/RT..>TMZ. Recently, the 10·year follow data from 2 randomized trials of (neo-) adjuvant PCV·chemotherapy in anaplastic glioma were reported. A survival benefit was shown exclusively for the subgroup of patients with a chromosomal 1p/ 19q co-deletion (a balanced translocation t1; 19), a molecularly defined subgroup of oligodendroglal tumors that have a strong correlation with AIGAIT promoter methylation. In these trials chemotherapy was prescribed before or after, but not during irradiation. Thus the questions remains, whether the benefits seen with TMZ are due to the concomitant chemoradiotherapy, or whether early introduction of chemotherapy would suffice. Nevertheless, there is a body of preclinical data demonstrating additive or synergistic effects when TMZ is given as a radiosensitizer. It Induces cell· cycle arrest, and may sensitize in particularly cells that are repair-protein deficient or depleted. Ongoing trials evaluate more specifically the value of concomitant chemoradlotherapy. The CATNON Intergroup trial (EORTC 26053·22054) compares concomitant versus adjuvant chemotherapy in a 2x2 design. Novel agents are being evaluated in conjunction with TMZI RT In newly diagnosed glioblastoma. Preclinical data In support of the use of antlanglogenlc therapy in conjunction with radiotherapy
- 33 -
are controversial; while it may enhance the cytotoxic effects of ionizing radiation, data suggest that It will also Increase tumor invasiveness. Cilengitide, a novel lntegrin Inhibitor may be well suited to counterbalance this phenotypic switch, as demonstrated in preclinical models. Large and definitive phase Ill trials evaluating bevacizumab and cilengitide in addition to TMZ/RT.. >TMZ have completed accrual, results are expected In 2013/2014. Conclusions: Molecularly defined treatments In combination with chemotherapy and radiation hold promise In the treatment of malignant glioma. Molecular marker determination are now a standard requirement for patient selection In clinical trials, and for rational decision-making.
PLENARY SESSION: STEM CELL SP-39 STEM CELL
J. Seoane1 'Hospital Universitario Vamm De Hebron, Barcelona, Spoln
Abstract not received.
POSTER: COMBINED CHEMO MOLECULAR TARGETED AGENTS AND RADIOTHERAPY: PRECLINCIAL STUDIES P0-40 COMBINATION TREATMENT OF HYDROGEN PEROXIDE AND X-RAYS INDUCES APOPTOSIS IN HYPOXIC PC-3 HUMAN PROSTATE CANCER CELLS S. Kariya 1, S. Tokuhiro', R. Akima 1, Y. Ogawa' 'Koehl Medical School, Department of Diagnostic Radiology and Radiation Oncology, Nankoku, Japan Purpose/Objective: We previously reported that hydrogen peroxide (H 20 1 ) strongly enhanced radiation-Induced apoptosis in PC·3 human prostate cancer cell line, that this apoptosls was lysosome dependent, and that mitochondria existed dovmstream of lysosomes in the apoptotic pathway (IJROBP75: 449·454, 2009). In this study, we studied how H20 2 affected radiation-Induced apoptosis in the PC-3 human prostate cancer cell line under hypoxic conditions. PC-3 cells were maintained in a Materials and Methods: humidified incubator at 37 degrees C under either hypoxic conditions (1% 0 2) or normoxic conditions (21% Oz), Subsequently, the PC-3 cells were exposed to 0.1 mM HzOz just before the irradiation of 10 Gy, which were administered with 10-MY X-rays. The percentage of apoptotic cells was determined by flow cytometry. Detection of apoptotic cells, ROS production, and morphemic changes of lysosomes and mitochondria was examined using a CCD camera-equipped fluorescence microscope. Results: Also under hypoxic conditions, H20 1 enhanced radiation· induced apoptosis in the PC-3 human prostate cancer cell line. In addition, the proportions of apoptotlc cells with X-rays of 10 Gy and 0.1 mM HzOz under hypoxic conditions were higher than the proportions of apoptotic cells only wit h X-rays of 10 Gy under normoxic conditions. As is the case with combination treatment of X-rays and H20 1 under normoxlc conditions, long term production of ROS, lysosomal rupturing, and mitochondrial fragmentation were observed under hypoxic conditions. Immediately after administration of HzOz Into the medium, o, partial pressure of the medium In which PC-3 cells were cultured under hypoxic conditions increased. However, the average Oz partial pressure increase in the medium after 7 minutes of the administration of 0.1 mM H20 2 was a mere 3.6 mmHg. Meanwhile, the activation of glutathione peroxidase In the PC-3 cells under hypoxic conditions decreased. Conclusions: H20 2 decreased the activation of glutathione peroxidase in the hypoxic PC-3 cells and may have led to prevent the removal of the hydroxyradical generated by Irradiation, ruptured lysosome, etc.. In conclusion, It was suggested that these phenomena were some of the reasons why HzOz enhanced radiation-induced apoptosis in the PC-3 human prostate cancer cell line under hypoxic conditions.
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NOVEL TAHGETING DRUGS AND RADIOTHERAPY 2012 PROGRAMME AND ABSTRACT BOOK
OC-34 INTEGRIN-LINKED-KINASE (ILK) CONTROLS GLIOMA CELL RESPONSE TO IONIZING RADIATION THROUGH HIF-1ALPHA 0. lanvin1, S. Monferran', C. Delmas', B. Couderc1 , C. Toulas 1, E. Cohen-Jonathan Moyal' 1 /nstltut Claudius Regaud, INSERM U1037, Toulouse, France 2 Unlversite Paul Saba tier, EA3035, Toulouse, France Purpose/Objective: Increasing the sensibility of gliobla'stoma cells to Irradiation is a promising approach to improve survival in patients with glioblastoma multiform. Our previous results demonstrated that inhibiting lntegrin-Linked-Kinase (ILK) in U87 cells increased their radioresistant glioblastoma radiosensitivity. The present study aimed to elucidate the mechanism Involved in ILK-induced radioresistance of these cells and to decipher the dovmstream biological pathways. To investigate the ILK-dependent Materials and Methods: biological pathways controlling radioresistance, we chose to generate U87 expressing doxycycline-inducible shRNA directed against ILK. ILK expression inhibition was obtained since 48h of shRNA expression by doxycycline. ILK, HIF-1a and survivin expression was measured by RT -QPCR and western blot analysis. MG132 was used to inhibit the proteasome. Mitotic cell death and centrosome overduplication were assayed by immunofluorescence: DAPI and y-tubulin staining. Limited dilution cloning was used to measure the fraction surviving at 2 Gy. All these experiments were done in the presence or not of doxycycline (to induce shRNA-IlK), HIF-1a siRNA or survivin inhibitor YM155. Results: In this study, we first showed that expression of an inducible shRNA directed against ILK in U87 cell line (U87shiLK) enhanced radiation-induced mitotic cell death and centrosomal overduplication: Moreover, U87shllK showed a down regulation of radiation-Induced HIF-1a expression which involves the proteasome pathway. To elucidate the role of HIF-1a in ILKdependent radioresistance we transfected cells with siRNA directed against HIF-1a. Silencing HIF-1a significantly reduced SF2 value by increasing the sensitivity of these cells to radiationinduced mitotic cell death and centrosome amplification. It is well known that survivin is involved in radioresistance and centrosome overduplication. Moreover, HIF-1a has been shown to regulate survivin expression. We hypothesized that ILK-HIF-1adependent regulation of mitotic cell death and centrosome amplification might be mediated by survivin. Our data showed a decrease of survivin mRNA and protein level in U87shiLK cells. Furthermore, Inhibiting survivin by ' the specific inhibitor of survivin, YM155 significantly increased the percentage of giant multinucleated cells and centrosomal overduplication and reduced the SF2 value of U87 cells similarly to the effect observed when ILK or HIF-1a was silenced in these cells. Conclusions: Our results strongly suggest that ILK-dependent U87 radioresistance pathway is mediated by HIF-1a and survivin. Targeting t his ILK-HIF-1a-survfvin pat hway may be crucial to optimizing radiotherapy efficiency.
SYMPOSIUM: WHAT IS THE STANDARD IN ... SP-35 PLATINUM-BASED RADIO CHEMOTHERAPY IN H&Nl R. Corvo' 'lstituto Nozionale per Ia Rlcerca sui Cancro, Radio-Oncology Deportment, Genova, Italy
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Background: Each year 600.000 new cases of squamous cell carcinoma of the Head and Neck (SCCHN) are diagnosed worldwide. Concurrent chemo-radiotherapy (CRT) is the "standard-of-care treatment" In locally advanced stages and in larynx function preservation programs. Cisplatin (Cis) is the most commonly drug used with RT and the best available evidence showed clinical benefit from Cis administered at 100 mg/m2 every 3 weeks in combination with standard RT. This schedule, although effective, has reached a plateau in long-term outcome and new stategies are warranted in order to Improve therapeutic ratio In advanced SCCHN. Critical Issues: With high-dose Cis nephrotoxicity may be substantial (grade III-IV); other Cis-related toxicities are ototoxicity, leucopenia, hearing loss and tinnitus, stomatit is and severe weight loss. As a consequence, only two cycles of high
dose Cis are often administered without evidence of adverse clinica·l Impact on cytotoxic effect. However, overall survivals rates after different Cis-RT schedules do not exceed 60% at 5 years. Results: Ongoing strategies beyond standard high dose Cis and RT are in progress: 1. low-dose cisplatin (weekly 40 or 50 mg/m2, 2 cycles of 20 mg/m2 for 5 days, daily 6 mg/m2) as alternative option for frail or older patients; 2. the model "third daily Cis regimen" has been proposed to decrease normal tissue complications compared to daily Cis delivery as well as potentially increase tumor control in comparison with weekly Cis delivery; 3. the addition of cetuximab to high dose Cis-RT did not appear to show improved results; 4. the use of altered fractionation RT associated with high-dose Cis did not achieve better outcomes than standard RT; 5. induction chemotherapy including Cis followed by high-dose Cis-RT or cetuximab -RT might provide new advantages but trials are still ongoing. Conclusion: In standard high-dose Cis - RT schedule the supraddltlvity of high-dose Cis with RT (Cis synchronizes cycling clonogens cells in G2 radiosensitive phase) may be compromised by tumor stem-cells accelerated repopulation triggered after single Cis exposure. Novel strategies involving different timing of Cis with IMRT, Cis -pharmacodinamics, association of RT with targeted agents are expected to improve clinical outcome in advanced HNSCC.
SP-36 CETUXIMAB AND RADIOTHERAPY IN H&N? W. Budach', C. Matuschek', E. Bolke' 'Heinrich-Heine University DUsseldorf, DUsseldorf, Germany
Radiation
Oncology,
Radiotherapy in combination with concurrent cetuximab has been shown to improve locoreglonal tumor control and overall survival in non-surgically treated, locally advanced head and neck squamous cell carcinomas (HNC). The combined treatment induces frequently relevant but manageable skin toxicities in- and outside the radiat ion portals. In recurrent and metastatic disease, a survival benefit has also been reported for the addition of cetuximab to cisplatin and 5FU. Therefore, the expectation was that the triple combination of radiotherapy, cisplatin, and cetuximab would further improve clinical outcome. Consequently, the RTOG (110522) analysed 895 patients with unresected HNC randomized to receive either standard chemoradiation (72 Gy + 2x100 mg/m' cisplatin) or the same chemoradiation with concurrent cetuximab (400 mg/m' loading + 250 mg/m' weekly). After a median follow up of 2.4 years, the addition of cetuximab did neither improve locoreglonal control nor DFS and overall survival . Grade III-IV acute cutaneous and mucosal toxicity was significantly higher in the cetuximab arm of the study. The same approach was tested with panftumumab, a fully humanized antiEGFR-antibody, IQ a randomized phase II trial (n=150) presented on ASCO 2012 (SPECTRUM-1: Giralt et al. J Clin Oncol 30, 2012; abstr 5502). The addition of concurrent panitumumab to standard chemoradlation also failed to improve outcome and enhanced acute cutaneous and mucosal toxicity. Whereas radiotherapy and concurrent cetuximab is an alternative option to standard chemoradiatlon in unresected HNC, the combination of EFGRantibodles with concurrent chemoradiation has no role in the treatment of HNC. Radiotherapy and concurrent cetuximab is an alternative option to standard chemoradiation In unresected HNC. EFGR-antibodies in combination with concurrent chemoradiation should not be used in the treatment of HNC.
SP-37 COMBINATION OF CHEMOTHERAPY AND RADIOTHERAPY IN NSCL CANCER? C. Le Pechoux' 1 /nstltut Gustave Roussy, Radiation Oncology, Vlltejuif, France lung cancer remains a major cause of death worldwide with more than 1.1 million deaths per year. Non-small-cell lung cancer (NSCLC) represents now more than 80% of all lung tumours, and approximately 35% of patients with NSCLC present with locally advanced nonmetastatic disease for whom the standard treatment has become combined radiochemotherapy. Concerning locally advanced NSCLC, two meta-analyses based on individual patient data have compared chemotherapy plus radiotherapy to ~ radiotherapy alone. These meta-analyses were recently updated and demonstrated that sequential or concomitant chemoradiation improved survival compared to radiotherapy alone with an
NOVEL TARGETING DRUGS AND RADIOTIIERAPY 2012 PROGRAMME AND ABSTRACT BOOK
absolute modest benefit of 4% at 2 years and 2% at 5 years. In 1990's and 2000's several randomized trials have compared sequential to concomitant chemoradiation. A meta-analysis of these trials was performed using individual patient data. (Auperin, 2010]. Data from six trials could be collected (1,205 patients, 92% of all randomly assigned patients). Median foll~w:up was 6 years. A significant benefit of concomitant chemorad1allon on overall survival (HR, 0.84; P=0.004) was observed, with an absolute benefit of 4.5% (from 10.6% to 15.1%) at 5 years. As compared to sequential chemotherapy, concomitant treatment decreased locoregional pragression but had no significant differential effect on distant progression. As expected, concomitant radiochemotherapy increased grade 3·4 acute esophageal toxicity from 4% to 18% with a relative risk of 4.9 (p• 0.001). As in other solid tumors, concomitant radlochemotherapy Is now considered as the standard treatment for locally advanced NSCLC patients with good performance status. However it should be outlined that most of these trials used 2-D radiotherapy. Ongoing trials integrate the recent developments In three-dimensional conformal radiotherapy to optimize concomitant combinations. Promising preliminary results have also been obtained in combining ·chemoradiotherapy with targeted agents such as cetuximab. Further studies are needed in lung cancer to optimize concomitant combinations
SP-38 THE RATIONAL FOR CONCOMITANT RADIO· AND CHEMOTHERAPY IN MALIGNANT GLIOMA. STATE OF THE ART AND FUTURE PERSPECTIVES
.!l.....it!m.Q\ K. Homiscko2,
1
1
R.O. Mirimanoff , L. Negretti , A.F. Hottinger<, M. Levivier', AI.E. Hegi 1 'centre Hospltoller Univ. Vaudois, Department of Neurosurgery Ei Clinical Neurosciences, Lausanne, Switzerland 2 Centre Hospltaller Univ. Vaudois, Department af Oncology, Lausanne, Switzerland JCentre Hospitaller Unlv. Vaudois, Department of Radiotherapy, Lausanne, Switzerland 'Cen tre Hospltaller Unlv. Vaudois, Department of Neurology Ei Clinical Neurosciences, Lausanne, Switzerland Radiation therapy remains the mainstay of treatment of malignant glioma. While alkylating agent chemotherapy using older drugs failed to demonstrate an improved survival repeatedly, the paradigm changed in 2004 when temozolomlde (TMZ) given concomitantly (TMZIRT) and as adjuvant/maintenance ( .. , TA\Z) t herapy · in glioblastoma demonstrated a statistically significant and clinically meaningful survival benefit. This randomized trial formally compared Initial treatment with standard radiotherapy (30 x 2 Gy) with the association of TA\2/RTiiTMZ, overall survival was the primary endpoint. However, In reality the trial was evaluating early upfront chemotherapy with delayed introduction of chemotherapy, as 75% of all patients in t he control arm received chemotherapy at progression (and 60% of the patients In the experimental). Importantly, MGMT gene promoter methylation silencing of expression of an important repair protein - was shown to be an excellent predictor for benefit of the addit ion of TMZ chemotherapy. Pragresslon-free survival was prolonged onl y in patients with a methylated MGhiT promoter and treated with TMZ/RT..>TMZ. Recently, the 10·year follow data from 2 randomized trials of (neo-) adjuvant PCV·chemotherapy in anaplastic glioma were reported. A survival benefit was shown exclusively for the subgroup of patients with a chromosomal 1p/ 19q co-deletion (a balanced translocation t1; 19), a molecularly defined subgroup of oligodendroglal tumors that have a strong correlation with AIGAIT promoter methylation. In these trials chemotherapy was prescribed before or after, but not during irradiation. Thus the questions remains, whether the benefits seen with TMZ are due to the concomitant chemoradiotherapy, or whether early introduction of chemotherapy would suffice. Nevertheless, there is a body of preclinical data demonstrating additive or synergistic effects when TMZ is given as a radiosensitizer. It Induces cell· cycle arrest, and may sensitize in particularly cells that are repair-protein deficient or depleted. Ongoing trials evaluate more specifically the value of concomitant chemoradlotherapy. The CATNON Intergroup trial (EORTC 26053·22054) compares concomitant versus adjuvant chemotherapy in a 2x2 design. Novel agents are being evaluated in conjunction with TMZI RT In newly diagnosed glioblastoma. Preclinical data In support of the use of antlanglogenlc therapy in conjunction with radiotherapy
- 33 -
are controversial; while it may enhance the cytotoxic effects of ionizing radiation, data suggest that It will also Increase tumor invasiveness. Cilengitide, a novel lntegrin Inhibitor may be well suited to counterbalance this phenotypic switch, as demonstrated in preclinical models. Large and definitive phase Ill trials evaluating bevacizumab and cilengitide in addition to TMZ/RT.. >TMZ have completed accrual, results are expected In 2013/2014. Conclusions: Molecularly defined treatments In combination with chemotherapy and radiation hold promise In the treatment of malignant glioma. Molecular marker determination are now a standard requirement for patient selection In clinical trials, and for rational decision-making.
PLENARY SESSION: STEM CELL SP-39 STEM CELL
J. Seoane1 'Hospital Universitario Vamm De Hebron, Barcelona, Spoln
Abstract not received.
POSTER: COMBINED CHEMO MOLECULAR TARGETED AGENTS AND RADIOTHERAPY: PRECLINCIAL STUDIES P0-40 COMBINATION TREATMENT OF HYDROGEN PEROXIDE AND X-RAYS INDUCES APOPTOSIS IN HYPOXIC PC-3 HUMAN PROSTATE CANCER CELLS S. Kariya 1, S. Tokuhiro', R. Akima 1, Y. Ogawa' 'Koehl Medical School, Department of Diagnostic Radiology and Radiation Oncology, Nankoku, Japan Purpose/Objective: We previously reported that hydrogen peroxide (H 20 1 ) strongly enhanced radiation-Induced apoptosis in PC·3 human prostate cancer cell line, that this apoptosls was lysosome dependent, and that mitochondria existed dovmstream of lysosomes in the apoptotic pathway (IJROBP75: 449·454, 2009). In this study, we studied how H20 2 affected radiation-Induced apoptosis in the PC-3 human prostate cancer cell line under hypoxic conditions. PC-3 cells were maintained in a Materials and Methods: humidified incubator at 37 degrees C under either hypoxic conditions (1% 0 2) or normoxic conditions (21% Oz), Subsequently, the PC-3 cells were exposed to 0.1 mM HzOz just before the irradiation of 10 Gy, which were administered with 10-MY X-rays. The percentage of apoptotic cells was determined by flow cytometry. Detection of apoptotic cells, ROS production, and morphemic changes of lysosomes and mitochondria was examined using a CCD camera-equipped fluorescence microscope. Results: Also under hypoxic conditions, H20 1 enhanced radiation· induced apoptosis in the PC-3 human prostate cancer cell line. In addition, the proportions of apoptotlc cells with X-rays of 10 Gy and 0.1 mM HzOz under hypoxic conditions were higher than the proportions of apoptotic cells only wit h X-rays of 10 Gy under normoxic conditions. As is the case with combination treatment of X-rays and H20 1 under normoxlc conditions, long term production of ROS, lysosomal rupturing, and mitochondrial fragmentation were observed under hypoxic conditions. Immediately after administration of HzOz Into the medium, o, partial pressure of the medium In which PC-3 cells were cultured under hypoxic conditions increased. However, the average Oz partial pressure increase in the medium after 7 minutes of the administration of 0.1 mM H20 2 was a mere 3.6 mmHg. Meanwhile, the activation of glutathione peroxidase In the PC-3 cells under hypoxic conditions decreased. Conclusions: H20 2 decreased the activation of glutathione peroxidase in the hypoxic PC-3 cells and may have led to prevent the removal of the hydroxyradical generated by Irradiation, ruptured lysosome, etc.. In conclusion, It was suggested that these phenomena were some of the reasons why HzOz enhanced radiation-induced apoptosis in the PC-3 human prostate cancer cell line under hypoxic conditions.
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