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Hak Choy, M.D., Chair
RTOG has one phase III trial for prophylactic cranial irradiation trials. RTOG 0212 is a phase II/III trial addressing two different dose schedules of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. We completed a phase II trial in limited stage small cell lung cancer with accelerated hyper fractionation (RTOG 0239). Based on our phase II trial, intergroup phase III trial for limited SCLC RTOG 0538 is open for accrual. RTOG 0229 is a phase II trial with high dose chemo/RT pre-op and preliminary data are encouraging. We are in the process of developing a follow up trial with HD RT plus chemo/Targeted agent. With encouraging preliminary data from RTOG 0623, we opened RTOG 0618. SBRT for operable stage I NSCLC and planning to open RTOG 0812, SBRT for central located tumor. We are conducting two trials with molecular imaging technique (PET/CT scan). The objectives of RTOG 0235/ACRIN 6668 are to evaluate the ability of peak SUV obtained at each institution shortly after definitive chemoradiation (post-treatment) to predict local control, to evaluate the ability of peak SUV obtained at each institution prior to definitive chemoradiation (pre-treatment) to predict long-term survival. RTOG 0515 is a recently activated trial to determine the impact of PET/CT fusion for each patient by comparing gross tumor volume (GTV) contours and 3DCRT treatment plans using two separate data sets (PET/CT and CT only); to determine the impact of PET on the following endpoints: GTV (cm3), number of involved nodes, location of involved nodes, and dosimetric measures of normal tissue toxicity (mean lung dose and mean esophageal dose).
We also activated a phase III trial randomizing high dose (74Gy) versus standard dose (60Gy) with chemoradiation therapy in stage III NSCLC (RTOG 0617).
In RTOG 0617, we will also investigate the association of DNA damage repair genes (ERCC1 and XRCC1), microtubule-related proteins (TUBB-III and MAP4), and shed tumor DNA with patient responses and outcomes to the platinum/taxane/radiation therapy in this trial.
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Hak Choy, M.D., Chair
1. ACHIEVEMENTS
The primary research goal of the Lung Cancer Committee is to conduct clinical trials that improve the survival rate of patients with lung cancer, non small cell(NSCLC) and small cell lung cancer (SCLC) without increasing treatment-related morbidity. In order to accomplish these goals, we developed several research hypotheses. The first hypothesis is that optimizing radiation therapy (e.g., 3D CRT, fractionation, SBRT, etc.) which will permit improved outcome with acceptable or reduced toxicity. For this hypothesis we are accruing patients in three trials. We completed a phase II trial (RTOG 0117) combining High Dose 3-D RT with chemotherapy. This trial lead to an intergroup phase III trial comparing standard dose versus high dose RT in locally advanced stage III NSCLC. RTOG 0236 is another phase II trial to determine whether radiotherapy involving high biological dose with limited treatment volume using Stereotactic Body Radiation Techniques (SBRT) achieves acceptable local control patients with medically inoperable early stage non-small cell lung cancer. Success of this trial is leading several phase I/II trials in early stage NSCLC. The third trial is an other phase II trial (RTOG 0229) to determine the feasibility, the mediastinal nodal clearance rates with the pre-operative regimen and the rate of complete pathological response of surgical resection following induction therapy with concurrent chemotherapy with high dose radiation therapy (60 Gy) in Stage IIIa (N2)or IIIb (N3) NSCLC (non-Pancoast). The second hypothesis is optimal integration of systemic therapy, using molecular targeted agent with effective chemoradiation therapy (CHRT) will improve survival with no increase in late toxicity. For this hypothesis we completed RTOG 0324 which is a phase II trial to determine the feasibility of concurrent cetuximab and chemoradiation as measured by safety and compliance. In this trial we will also estimate the treatment response rate of patients on the study regimen, overall survival as well as investigate associations between EGFR expression and toxicity, response, overall survival, and progression. The third hypothesis is integrating molecular imaging technique in chemoradiation will better characterize patient prognostic factors and better guide RT delivery. For this hypothesis we initiated two trials with PET scan. (RTOG 0235 and 0515)
2. REVIEW OF STUDIES
RTOG has one phase III trial for prophylactic cranial irradiation trials. RTOG 0212 is a phase II/III trial addressing two different dose schedule of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. We completed a phase II trial in limited stage small cell lung cancer with accelerated hyper fractionation (RTOG 0239). Based on our phase II trial, intergroup phase III trial for limited SCLC will open early next year. We have two trials for pre-operative stage III NSCLC patients. RTOG 0229 is a phase II trial with high dose chemo/RT pre-op and preliminary data are encouraging. We completed the first phase II cooperative group SBRT trial in the US (RTOG 0236) with over 50 patients entered. With encouraging preliminary data we are pursuing SBRT in several different lung cancer populations (RTOG 0618 and 0812). We are conducting two trials with molecular imaging technique (PET/CT scan). The objectives of RTOG 0235/ACRIN 66668 are to evaluate the ability of peak SUV obtained at each institution shortly after definitive chemoradiation (post-treatment) to predict local control, to evaluate the ability of peak SUV obtained at each institution prior to definitive chemoradiation (pre-treatment) to predict long-term survival. RTOG 0515 is a recently activated trial to determine the impact of PET/CT fusion for each patient by comparing gross tumor volume (GTV) contours and 3DCRT treatment plans using two separate data sets (PET/CT and CT only); to determine the impact of PET on the following endpoints: GTV (cm3), number of involved nodes, location of involved nodes, and dosimetric measures of normal tissue toxicity (mean lung dose and mean esophageal dose).
3. FUTURE PLANS
We will continue to test the hypothesis optimizing radiation therapy (e.g., 3D CRT, fractionation, SBRT, etc.) with or without systemic cytotoxic or biologic agents, will permit improved outcome with acceptable or reduced toxicity. For this effort we created SBRT working group to initiate several trials. We are also in the process of activating a phase III trial randomizing high dose (74Gy) versus standard dose (60Gy) with chemoradiation therapy in stage III NSCLC (RTOG 0617). In 0617, we will also investigate the association of DNA damage repair genes (ERCC1 and XRCC1), microtubule-related proteins (TUBB-III and MAP4), and shed tumor DNA with patient responses and outcomes to the platinum/taxane/radiation therapy in this trial.
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Hak Choy, M.D., Chair
1. ACHIEVEMENTS
The primary research goal of the Lung Cancer Committee is to conduct clinical trials that improve upon the survival rate of patients with locally advanced non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) without increasing treatment-related morbidity. In order to accomplish these goals, we developed several research hypotheses. The first hypothesis is optimizing radiation therapy (e.g., 3D CRT, fractionation, SBRT, etc.) with or without systemic cytotoxic or biologic agents, will permit improved outcome with acceptable or reduced toxicity. For this hypothesis we are accruing patients in three trials. RTOG 0117 is a phase II trial combining High Dose 3D RT with chemotherapy. As a follow up trial from RTOG 0117, we developed a phase III trial comparing standard dose RT versus high dose RT in locally advanced NSCLC (RTOG 0617). LOI for this study was submitted to the CTEP and anticipate approval this spring for us to launch the trial summer of 2007. RTOG 0236 is a phase II trial to determine whether radiotherapy involving high biological dose with limited treatment volume using Stereotactic Body Radiation Techniques (SBRT) achieves acceptable local control patients with medically inoperable early stage non-small cell lung cancer. This trial completed accrual last year and we will be submitting several phase I and II trials on SBRT for NSCLS. RTOG 0618 is a phase II trial in which we will explore SBRT concept with potentially operable early stage NSCLC patient population. RTOG 0624 is another phase II trial where we will add molecular targeted agents in medically inoperable early stage NSCLC with SBRT. RTOG 0633 is the third SBRT protocol in phase I setting where we will determine MTD and DLT of SBRT in centrally located early stage NSCLC. In addition to that we are in the process of developing a 4th SBRT protocol that will target patients with lung mets.
For medically operable stage IIIA patient population, we launched an intergroup phase III trial comparing preoperative chemotherapy versus chemoradiation therapy (RTOG 0412), however the trial was closed last year due to the lack of accrual. Meanwhile we are continuing with other phase II trial (RTOG 0229) to determine the feasibility, the mediastinal nodal clearance rates with the pre-operative regimen and the rate of complete pathological response of surgical resection following induction therapy with concurrent chemotherapy with high dose radiation therapy (60 Gy) in Stage IIIa (N2)or IIIb (N3) NSCLC (non-Pancoast). The second hypothesis is that optimal integration of systemic therapy, using molecular targeted agent with effective chemoradiation therapy (CHRT) will improve survival with no increase in late toxicity. For this hypothesis we completed RTOG 0324 which is a phase II trial to determine the feasibility of concurrent cetuximab and chemoradiation as measured by safety and compliance. In this trial we will also estimate the treatment response rate of patients on the study regimen, overall survival as well as investigate associations between EGFR expression and toxicity, response, overall survival, and progression. In this trial we attempted to collect tissue material from patients which are often difficult task in locally advanced NSCLS. However we were able to collect 62 out of 93 patients' tissue material. We are in the process of analyzing this tissue material to correlate EGFR expression to patient's outcome. This trial completed planned accrual and preliminary data was presented at ASTRO in last October in Denver and anticipate the final data analysis will be available late this year. The third hypothesis is optimal integration of systemic therapy, using cytotoxic agent with effective locoregional therapy (surgery and/or RT) will improve survival with no increase in late toxicity. RTOG Lung Cancer Committee designed a follow-up study of RTOG 9309 in collaboration with SWOG which will compare chemotherapy followed by surgery with or without radiation. The hypothesis of this trial is preoperative chemotherapy and radiotherapy will improve survival of patients with stage IIIA N2 resectable NSCLC over preoperative chemotherapy alone. This study was activated this year. Despite the slow accrual in some trials, the overall accrual within Lung Cancer Committee is nearly doubled this year compared to same time period from last year. The fourth hypothesis is integrating molecular imaging technique in chemoradiation will better characterize patient prognostic factors and better guide RT delivery. For this hypothesis we initiated two trials with PET scan. The objectives of RTOG 0235/ACRIN 6668 are to evaluate the ability of peak SUV obtained at each institution shortly after definitive chemoradiation (post-treatment) to predict local control, to evaluate the ability of peak SUV obtained at each institution prior to definitive chemoradiation (pre-treatment) to predict long-term survival, to estimate the reliability of measuring post-treatment peak SUV between the institution and a central review facility, to estimate the reliability of measuring pre-treatment peak SUV between the institution and a central review facility, to estimate the percentage of patients with inoperable stage II/III NSCLC by conventional (non-PET) imaging who are upstaged, especially to Stage IV, after PET (+confirmatory studies), to estimate the reliability of qualitative interpretation of post-treatment PET (i.e., PET defined response to therapy) between the institution and a central review facility, to estimate the prognostic value of qualitative interpretations of post-treatment PET (i.e., PET-defined response to therapy) made at the institution and made at a central review facility, to explore key differences between stages IIB/IIIA and stage IIIB with respect to peak SUV, local control, and survival, to collect tissue samples from patients treated in this study and estimate the correlation between immunohistochemical expression of Ki-67 (oncoprotein marker of cellular proliferation) and the peak pre-treatment PET-SUV measurement and to explore the association between Ki-67 expression and overall survival. RTOG 0515 is a recently activated trial to determine the impact of PET/CT fusion for each patient by comparing gross tumor volume (GTV) contours and 3DCRT treatment plans using two separate data sets (PET/CT and CT only); to determine the impact of PET on the following endpoints: GTV (cm3), number of involved nodes, location of involved nodes, and dosimetric measures of normal tissue toxicity (mean lung dose and mean esophageal dose).
2. REVIEW OF OTHERS STUDIES
RTOG has two very large phase III trial for prophylactic cranial irradiation trials. RTOG 0214 is a phase III trial comparing prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The endpoint of this trial is to determine whether prophylactic cranial irradiation (PCI) improves survival after effective local regional/systemic therapy for patients with LA-NSCLC. It will require over 1000 patients to complete the trial. Because of the very large sample size requirements, this study is opened to all the cooperative groups in North America, which includes, ECOG, CALGB, SWOG, NCCTG and NCIC. Despite the Intergroup effort the accrual rate is below the targeted goal, 260 patients as of 8/06. RTOG 0212 is another phase II/III trial addressing two different dose schedule of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. We completed a phase II trial in limited stage small cell lung cancer with accelerated hyper fractionation (RTOG 0239). Based on our phase II trial, intergroup phase III trial is planned for limited SCLC.
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Hak Choy, M.D., Chair
1. ACTIVE STUDIES
RTOG 0117 - A phase II trial combining High Dose 3D RT with chemotherapy.
RTOG 0229 - A phase II trial to determine the feasibility, the mediastinal nodal clearance rates with the pre-operative regimen and the rate of complete pathological response of surgical resection following induction therapy with concurrent chemotherapy with high dose radiation therapy (60 Gy) in Stage IIIa (N2)or IIIb (N3) NSCLC (non-Pancoast). The second hypothesis is that optimal integration of systemic therapy, using molecular targeted agent with effective chemoradiation therapy (CHRT) will improve survival with no increase in late toxicity.
RTOG 0235 - The lung cancer committee designed a follow-up study of RTOG 9309 in collaboration with SWOG which will compare chemotherapy followed by surgery with or without radiation. This study was activated this year.
RTOG 0236 - A phase II trial to determine whether radiotherapy involving high biological dose with limited treatment volume using Stereotatic Body Radiation Techniques (SBRT) achieves acceptable local control patients with medically inoperable early stage non-small cell lung cancer. In this trial we will also determine if radiotherapy involving high biological dose with limited treatment volume (using SBRT techniques) achieves acceptable treatment-related toxicity.
RTOG 0324 - A phase II trial to determine the feasibility of concurrent cetuximab and chemoradiation as measured by safety and compliance. In this trial we will also estimate the treatment response rate of patients on the study regimen, overall survival as well as investigate associations between EGFR expression and toxicity, response, overall survival, and progression. In this trial we attempted to collect tissue material from patients which is often difficult task in locally advanced NSCLS. However we were able to collect 62 out of 93 patients' tissue material. We are in the process of analyzing these tissue materials to correlate EGFR expression to patient's outcome. This trial completed planned accrual and preliminary data was presented at ASTRO in last October in Denver and anticipate the final data analysis in late this year.
RTOG 0515 - Is a recently activated trial to determine the impact of PET/CT fusion for each patient by comparing gross tumor volume (GTV) contours and 3DCRT treatment plans using two separate data sets (PET/CT and CT only); to determine the impact of PET on the following endpoints: GTV (cm3), number of involved nodes, location of involved nodes, and dosimetric measures of normal tissue toxicity (mean lung dose and mean esophageal dose).
2. REVIEW OF STUDIES
RTOG has two very large phase III trial for prophylactic cranial irradiation trials.
RTOG 0212 - A phase II/III trial addressing two different dose schedule of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. We completed a phase II trial in limited stage small cell lung cancer with accelerated hyper fractionation (RTOG 0239). Based on our phase II trial, intergroup phase III trial is planned for limited SCLC. We have two trials for pre-operative stage III NSCLC patients. RTOG 0229 is a phase II trial with high dose chemo/RT pre-op and preliminary data are encouraging. The other pre-operative trial is a RTOG lead intergroup phase III trial, mentioned previously. We completed the first phase II cooperative group SBRT trial in the US (RTOG 0236) with over 50 patients entered. With encouraging preliminary data we are pursuing SBRT in several different ling cancer populations (see below).
RTOG 0214 - A phase III trial comparing prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The endpoint of this trial is to determine whether prophylactic cranial irradiation (PCI) improves survival after effective locoregional/systemic therapy for patients with LA-NSCLC. It will require over 1000 patients to complete the trial. Because of the very large sample size requirements, this study is opened to all the cooperative groups in North America, which includes, ECOG, CALGB, SWOG, NCCTG and NCIC. Despite the Intergroup effort the accrual rate is below the targeted goal, 260 patients as of 8/06.
3. FUTURE STUDIES
We will continue to test the hypothesis that optimizing radiation therapy (e.g., 3D CRT, fractionation, SBRT, etc.) with or without systemic cytotoxic or biologic agents, will permit improved outcome with acceptable or reduced toxicity. For this effort we created SBRT working group to initiate several trials.
We also submitted a letter of intent (LOI) to CTEP for approval of phase III trial randomizing high dose (74Gy) versus standard dose (64Gy) with chemoradiation therapy in stage III NSCLC (RTOG 0617). We anticipate activating this trial late this year. In RTOG 0617, we will also investigate the association of DNA damage repair genes (ERCC1 and XRCC1), microtubule- related proteins (TUBB-III and MAP4), and shed tumor DNA with patient responses and outcomes to the platinum/taxane/radiation therapy in this trial.
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Hak Choy, M.D., Chair
ACTIVE STUDIES
RTOG 0117 - A Phase II trial combing high dose 3D-CRT with chemotherapy. RTOG has accrued 32 of the 73 patients needed to meet its accrual goal.
RTOG 0212 - A Phase II/III trial addressing two different dose schedules of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. RTOG has entered 134 patients since January, 2004.
RTOG 0214 - A Phase III trial comparing prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The endpoint of this trial is to determine whether prophylactic cranial irradiation (PCI) improves survival after effective locoregional/systemic therapy for patients with LA-NSCLC. It will require over 1,000 patients to complete the study.
RTOG 0229 - A Phase II trial to determine the feasibility, the mediastinal nodal clearance rates with the pre-operative regimen and the rate of complete pathological response of surgical resection following induction therapy with concurrent chemotherapy with high dose radiation (60 Gy) in Stage IIIA (N2) or IIIb (N3) NSCLC (non-Pancoast). RTOG has accrued 20 cases to this study.
RTOG 0236 - A Phase II trial to determine whether radiotherapy involving high biological dose with limited treatment volume using Stereotactic Body Radiation Techniques (SBRT) achieves capable local control patients with medically inoperable early stage non-small cell lung cancer. The study has accrued 24 cases.
CLOSED STUDIES
RTOG 0017 - A Phase I trial with concurrent chemotherapy with Gemcitabine. The final data will be presented at ASTRO in October. The study closed on April 12, 2005.
RTOG 0324 - A Phase II trial to determine the feasibility of concurrent cetuuximabe and chemoradiation as measured by safety and compliance. This trial has completed planned accrual and closed on June 3, 2005. The preliminary data will be presented at ASTRO in October.
RTOG 9309 - This was a NCI high priority study conducted as an intergroup trial. Preliminary results of this study demonstrate a modest but statistically significant improvement in median DFS (13.4 vs 11.8 months) favoring the surgery arm, but no difference in survival (MST 22 months for each group).
FUTURE PLANS
We will continue to test the hypothesis that optimal integration of systemic therapy, using cytotoxic or biologic agents, with locoregional therapy (surgery or RT) will improve survival with no increase in late toxicity. We submitted a phase III concept comparing standard chemoradiation therapy with or without Cetuximab. This is a follow up trial from completed phase II study RTOG 0234. We will continue to test the hypothesis, in collaboration with the RTOG Outcomes and Health Services Research Committee, that optimized RT (e.g., SBRT and fractionation), with or without systemic cytotoxic or biologic agents, will permit improved outcome with acceptable or reduced toxicity. In this trial we will add significant amount of translational research.
In RTOG 0412 which is a phase III trial comparing chemotherapy followed by surgery with or without radiation, we will also investigate the association of DNA damage repair genes (ERCC1 and XRCC1), microtubule-related proteins (TUBB-III and MAP4), and shed tumor DNA with patient responses and outcomes to the platinum/taxane/radiation therapy in this trial. We will also employ MALDI-TOF proteomic analysis of tumor and serum to identify protein profiles associated with response to therapy and prognosis. We need to evaluate the role of FDG-PET post-therapy in predicting long-term outcome. This study opened this year in collaboration with ACRIN.
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Hak Choy, M.D., Chair
RTOG Lung Cancer Committee’s Annual Report
1. Achievements
The RTOG Lung Cancer Committee activated several key trials last year and reported the outcomes from our previous trials at national and international meetings. RTOG 0212 is a phase II/III trial to participate in the International Prophylactic Cranial Irradiation Trial (PCI 01-EULINT1). In this study we hope to determine the impact of an increase in the total PCI dose on the incidence of brain metastases at a minimum of 2 years of patient follow up; Thus, two PCI dose levels will be compared: 25 Gy (standard dose PCI) versus 36 Gy (high dose PCI) in limited disease small cell lung cancer (LD SCLC) patients in complete remission, whatever the initial treatment. In addition to the international study objectives, we will determine the impact of PCI dose and schedule on the incidence of chronic neurotoxicity and impact of PCI dose and schedule on quality of life by the this RTOG study. We also activated two trials for limited stage small cell lung populations. RTOG completed a 6-arm phase I trials (RTOG 9712) to determine the MTD of accerlated hyperfractionatd radiotherapy in patients with small cell lung caner. As a follow up trial, we activated phase II trial (RTOG 0239), to determine the response rate and progression-free and overall survival in patients with limited small cell lung cancer treated with Cisplatin and oral etoposide and combined with concurrent higher dose of thoracic radiotherapy (TRT) followed by etoposide and Cisplatin to determine the qualitative and quantitative toxicity and reversibility of toxicity of daily TRT followed by hyperfractionated TRT as a boost. In addition, to this study we also activated a phase I trial (RTOG 0241) to determine the maximum tolerated dose of Irinotecan in combination with Cisplatin and either twice daily RT (45 Gy) or single daily RT (70 Gy) and to monitor the qualitative and quantitative toxicity non-dose limiting toxicity and assess the reversibility of all toxicities from this approach.
Three pivotal RTOG trials were reported at national and international meetings last year. The first trial is RTOG 9309 titled “A Phase III Comparison Between Concurrent Chemotherapy Plus Radiotherapy, and Concurrent Chemotherapy plus Radiotherapy followed by Surgical Resection for Stage IIIA (N2) Non-Small Cell Lung Cancer”. This was a NCI high priority study conducted as an intergroup trial. This trial was designed to assess whether concurrent chemotherapy and radiotherapy followed by surgical resection results in a significant improvement in progression-free, median, and long-term (2-year, 5-year) survival compared to the same chemotherapy plus standard radiotherapy alone for patients with stage IIIa (N2-positive) non-small cell lung cancer. This is a very important trial finally met its targeted accrual last year. The 2nd phase III trial is RTOG 9801, titled “A Phase III Study of Amifostine Mucosal Protection For Patients With Favorable Prognosis Inoperable Stage III-IIIA/B Non-Small Cell Lung Cancer Receiving Sequential Induction and Concurrent Hyperfractionated Radiotherapy with Paclitaxel and Carboplatin” The primary objective of the study was to evaluate whether the addition of the radioprotector Amifostine can reduce the incidence and severity of non-hematologic toxicity, specifically esophagitis and pneumonitis during concurrent hyperfractionated RT and chemotherapy. This trial also met the targeted accrual during the last year. The initial data from these two phase III trials will be submitted for next year ASCO meeting. The outcome of these two-phase III trials may affect the treatment pattern of stage III NSCLC in the US and perhaps in the World.
We also completed two very important phase I trials within the RTOG Lung Cancer Committee. RTOG 9311 was a Phase I/II dose escalation trial using 3-D conformal radiation therapy for locally advanced NSCLC. The endpoints of this study were to establish the maximum tolerable dose of radiation that can be delivered to patients with non-small cell lung cancer using three dimensional conformal radiation therapy (3D-CRT) techniques treatment related morbidity as well as assessing tumor response and morbidity of high dose 3D-CRT in carcinoma of the lung. This study accrued 62 patients before it reached the objectives of the trial. This study leads to current phase I/II trial of RTOG 0117: A Phase I/II dose intensification using 3D-CRT and concurrent chemotherapy for patients for patients with inoperable NSCLC. RTOG 9712 is another large phase I trial for limited stage small cell lung cancer to find the maximum tolerated dose of thoracic radiation using an accelerated boost with concurrent chemotherapy to increase local control by increased radiation dose in thorax and to improve survival. This trial determined MTD with XX patients. Follow up phase II study will be submitted to NCI very near future.
2. Review of Studies
One very large Phase III trial (RTOG 0214) was recently opened by the RTOG Lung Cancer Committee. RTOG 0214 is a Phase III trial comparing prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The endpoint of this trial is to determine whether prophylactic cranial irradiation (PCI) improves survival after effective locoregional/systemic therapy for patients with LA-NSCLC. It will require over 1,000 patients to complete the trial. Because of the very large sample size requirements, this study is opened to all the cooperative groups in North America, which includes, ECOG, CALGB, SWOG, NCCTG and NCIC. This study will be also opened to EORTC and other groups in Europe as well as in Asia. Another Phase II/III trial addressing two different dose schedule of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. This is a modified Phase II/III trial to help accrual for on-going international phase III study and also to answer the optimal and schedule question. This trial was recently approved by CTSU.
We also opened a Phase II study titled “A Phase II Trial of a Cox-2 Inhibitor with Limited Field Radiation for Intermediate Prognosis Patients with Locally Advanced Non-small Cell Lung Cancer with Analysis of Prognostic Significance of Comorbidity, Functional and Psychological Status”. This study is expected to accrue 122 patients to determine the toxicity and efficacy of concurrent celecoxib and thoracic irradiation for locally advanced non-small cell lung cancer in intermediate prognosis patients.
3. Membership
As we recognized the importance of multimodality approach in locally advanced NSCLC, we needed to change our committee’s leadership and overall membership to reflect our important goal. For example Dr. Roy Herbst from MD Anderson joined the RTOG Lung Cancer Committee as a Non Small Cell co-chair of the committee. He will be a key player in developing future strategy with molecular targeted combined modality therapy. In addition to Dr. Herbst, we added several prominent medical oncologists in the Lung Cancer Committee. These include, Drs. Alan Sandler from Vanderbilt University, Julie R. Brahmer from Johns Hopkins, Marty Edelman from University of Maryland, and Ramaswamy Govindan from Washington University. We also add significant number of young radiation oncologists to our committee to provide opportunities for clinical research and academic career advancement. These includes, Drs. Yuhchyau Chen from University of Rochester, Beth Gore from University of Wisconsin, Robert MacRae from Ottawa Cancer Center, Craig Stevens from MD Anderson, Maria Werner Wasik from Thomas Jefferson University and Aaron Wolfson from University of Miami.
4. Future Plans-“ Targeted Combined Modality Therapy”
Radiation affects the ability of cells to divide and proliferate and triggers the expression of genes involved in the signaling pathways that promote survival, growth, or proliferation, or trigger cell death. Future advances in lung cancer with radiation therapy will hinge on understanding mechanisms of radiation-induced transcription of genes governing cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. Preclinical results demonstrating the enhancement of molecular therapeutics when combined with radiotherapy have generated a surge of interest in developing clinical trials combining radiation and several molecular therapeutics. We will pursue early clinical trials with several molecular agents with radiation in lung cancer and results of these early-phase studies in NSCLC will determine whether targeted combination therapy with radiation will enter randomized comparative studies.
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Hak Choy, M.D., Chair
1. ACHIEVEMENTS:
RTOG Lung Cancer Committee activated several key trials last year and reported the outcomes from our previous trials at the national and international meetings. RTOG 0212 is a phase II/III trial to participate in the International Prophylactic Cranial Irradiation Trial (PCI 01-EULINT1). In this study we hope to determine the impact of an increase in the total PCI dose on the incidence of brain metastases at a minimum of 2 years of patient follow up; Thus, two PCI dose levels will be compared: 25 Gy (standard dose PCI) versus 36 Gy (high dose PCI) in limited disease small cell lung cancer (LD SCLC) patients in complete remission, whatever the initial treatment. In addition to the international study objectives, we will determine the impact of PCI dose and schedule on the incidence of chronic neurotoxicity and impact of PCI dose and schedule on quality of life by the this RTOG study. We also activated two trials for limited stage small cell lung populations. RTOG completed a 6-arm phase I trials (RTOG 9712) to determine the MTD of accerlated hyperfractionated radiotherapy in patients with small cell lung caner. As a follow up trial, we activated phase II trial (RTOG 0239), to determine the response rate and progression-free and overall survival in patients with limited small cell lung cancer treated with Cisplatin and oral Etoposide and combined with concurrent higher dose of thoracic radiotherapy (TRT) followed by Etoposide and Cisplatin and to determine the qualitative and quantitative toxicity and reversibility of toxicity of daily TRT followed by hyperfractionated TRT as a boost. In addition to this study we also activated a phase I trial (RTOG 0241) to determine the maximum tolerated dose of Irinotecan in combination with Cisplatin and either twice daily RT (45 Gy) or single daily RT (70 Gy) and to monitor the qualitative and quantitative toxicity non-dose limiting toxicity and assess the reversibility of all toxicities from this approach.
Three pivotal RTOG trials were reported at the national and international meeting last year. The first trial is RTOG 9309 titled “A Phase III Comparison Between Concurrent Chemotherapy Plus Radiotherapy, and Concurrent Chemotherapy plus Radiotherapy followed by Surgical Resection for Stage IIIA (N2) Non-Small Cell Lung Cancer”. This was a NCI high priority study conducted as an intergroup trial. This trial was designed to assess whether concurrent chemotherapy and radiotherapy followed by surgical resection results in a significant improvement in progression-free, median, and long-term (2-year, 5-year) survival compared to the same chemotherapy plus standard radiotherapy alone for patients with stage IIIa (N2-positive) non-small cell lung cancer. This is a very important trial finally met targeted accrual last year. The 2nd phase III trial is RTOG 9801, titled “A Phase III Study of Amifostine Mucosal Protection For Patients With Favorable Prognosis Inoperable Stage III-IIIA/B Non-Small Cell Lung Cancer Receiving Sequential Induction and Concurrent Hyperfractionated Radiotherapy with Paclitaxel and Carboplatin” The primary objective of the study was to evaluate whether the addition of the radioprotector Amifostine can reduce the incidence and severity of non-hematologic toxicity, specifically esophagitis and pneumonitis during concurrent hyperfractionated RT and chemotherapy. This trial also met the targeted accrual during the last year. The initial data from these two phase III trials will be submitted for next year ASCO meeting. The outcome of these two-phase III trials may affect the treatment pattern of stage III NSCLC in the US and perhaps in the World.
We also completed two very important phase I trials within RTOG Lung Cancer Committee. RTOG 9311 was a phase I/II dose escalation trial using 3-D conformal radiation therapy for locally advanced NSCLC. The endpoints of this study were to establish the maximum tolerable dose of radiation that can be delivered to patients with non-small cell lung cancer using three dimensional conformal radiation therapy (3D-CRT) techniques treatment related morbidity as well as assessing tumor response and morbidity of high dose 3D-CRT in carcinoma of the lung. This study accrued 62 patients before it reached the objectives of the trial. This study leads to current phase I/II trial of RTOG 0117: A Phase I/II dose intensification using 3D-CRT and concurrent chemotherapy for patients for patients with inoperable NSCLC. RTOG 9712 is another large phase I trail for limited stage small cell lung cancer to find the maximum tolerated dose of thoracic radiation using an accelerated boost with concurrent chemotherapy to increase local control by increased radiation dose in thorax and to improve survival. This trial determined MTD with an unknown number of patients. Follow up phase II study will be submitted to NCI very near future.
2. REVIEW OF STUDIES:
One very large phase III trial (RTOG 0214) was recently opened by RTOG Lung Cancer Committee. RTOG 0214 is a phase III trial comparing prophylactic cranial irradiation versus observation in patients with locally advanced non-small cell lung cancer (LA-NSCLC). The endpoint of this trial is to determine whether prophylactic cranial irradiation (PCI) improves survival after effective locoregional/systemic therapy for patients with LA-NSCLC. It will require over 1000 patients to complete the trial. Because of the very large sample size requirements, this study is opened to all the cooperative groups in North America, which includes, ECOG, CALGB, SWOG, NCCTG and NCIC. This study will be also opened to EORTC and other groups in Europe as well as in Asia. Another phase II/III trial addressing two different dose schedule of radiation for prophylactic cranial irradiation (PCI) with limited stage small cell lung cancer. This is a modified phase II/III trial to help accrual for on-going international phase III study and also to answer the optimal and schedule question. This trial was recently approved by CTSU.
We also opened a phase II study titled “A Phase II Trial of a Cox-2 Inhibitor with Limited Field Radiation for Intermediate Prognosis Patients with Locally Advanced Non-small Cell Lung Cancer with Analysis of Prognostic Significance of Comorbidity, Functional and Psychological Status”. This study is expected to accrue 122 patients to determine the toxicity and efficacy of concurrent celecoxib and thoracic irradiation for locally advanced non-small cell lung cancer in intermediate prognosis patients.
3. MEMBERSHIP:
As we recognized the importance of multimodality approach in locally advanced NSCLC, we needed to change our committee’s leadership and overall membership to reflect our important goal. For example Dr. Roy Herbst from MD Anderson Cancer Center joined RTOG Lung Cancer Committee as a Non Small Cell Co-Chair of the Committee. He will be a key player in developing future strategy with molecular targeted combined modality therapy. In addition to Dr. Herbst, we added several prominent medical oncologists in the Lung Cancer Committee. These include, Drs. Alan Sandler from Vanderbilt University, Julie R. Brahmer from Johns Hopkins, Marty Edelman from University of Maryland, and Ramaswamy Govindan from Washington University. We also add significant number of young radiation oncologists to our committee to provide opportunities for clinical research and academic career advancement. These includes, Drs. Yuhchyau Chen from University of Rochester, Beth Gore from University of Wisconsin, Robert MacRae from Ottawa Cancer Center, Craig Stevens from MD Anderson Cancer Center, Maria Werner Wasik from Thomas Jefferson University Hospital and Aaron Wolfson from University of Miami.
4. FUTURE PLANS-“TARGETED COMBINED MODALITY THERAPY”:
Radiation affects the ability of cells to divide and proliferate and triggers the expression of genes involved in the signaling pathways that promote survival, growth, or proliferation, or trigger cell death. Future advances in lung cancer with radiation therapy will hinge on understanding mechanisms of radiation-induced transcription of genes governing cell death and survival, the selective control of this process, and the optimal approaches to combining this knowledge with existing therapeutic modalities. Preclinical results demonstrating the enhancement of molecular therapeutics when combined with radiotherapy have generated a surge of interest in developing clinical trials combining radiation and several molecular therapeutics. We will pursue early clinical trials with several molecular agents with radiation in lung cancer and results of these early-phase studies in NSCLC will determine whether targeted combination therapy with radiation will enter randomized comparative studies.
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Hak Choy, M.D., Chair
RTOG 0117: Phase I/II 3-D RT and concurrent chemotherapy trial PI: Bradley. This study was revised for radiation dose de-escalation. It was recently re-opened in arm 2, 74 Gy in 37 Fractions. We will accrue 7 patients in this arm. If 74 Gy turns out to be feasible, we will extend this trial as a Phase II study. Those institutions that participated in the previous 3-D conformal trial, RTOG 9311, need to continue to participate in this trial. We must finish the phase II study prior to launching any Phase III trial with 3-D conformal therapy.
RTOG 0017: Phase I Gem/Carbo/RT & Gem/Taxol/RT (ping-pong trial), PI: Choy. As we discussed in Montreal, sequence B, Gemcitabine/Paclitaxel arm is closed due to excessive toxicity. We're currently accruing patients in sequence A only. This is study will be referred as a Ping trial with Pong. Currently there are 3 patients in Arm 5 - Gem 450mg/Carbo AUC2. We need to add 3 more patients before the next dose escalation.
RTOG 0213: [Phase II]; RT + COX-2 intermediate-risk patients trial, PI: Gore. This study is on hold till the end of August for planned toxicity assessment. We'll let you know when we re-open.
RTOG 0270: Neovastat Trial, PI's: Charles Lu/Komaki/Herbst/ Choi. This study was initiated by MD Anderson/CCOP a few years ago and we (RTOG) decided to participate last year. As of now, more than 15 patients are entered from RTOG institutions. Those institutions participating in this trial will receive double credit.
RTOG 0239: [Phase II]; P/E/dose escalation RT, PI: Komaki. This phase II study for limited stage SCLC trial was recently opened by RTOG. This is an extension of RTOG 9712, Dr. Komaki's Phase I study. We expect a robust accrual in this study.
RTOG 0241: [Phase I/II]; Irinotecan + EP/bid RT for LD SCLC (pca-wp), PI: Langer. This is another limited stage SCLC trial open to limited institutions. We're currently finishing arm 1, cis 60 + irinotecan 40 mg with radiation. We hope to further dose escalate in this study and need your participation.
RTOG 0214: [Phase III]; PCI vs. no PCI for NSCLC (ca-pnci), PI: Gore. This is one of the most important trials for the RTOG Lung Cancer Committee asking simple but important questions for lung cancer patients, "Is there a need for PCI for NSCLC patients?" As you all know, this is a very large study requiring over 1000 patients to be randomized between PCI vs observation. We need approximately 30 patients a month to complete the trial within reasonable time. However, only 4 per month are being entered at the moment. We'll closely monitor the accrual rate and if it doesn't increase late this year we may have to re-think our strategy in this trial. I strongly encourage your participation! Keep in mind that even if patients get randomized to the observation arm, you'll still receive credit from RTOG.
RTOG 0212: [Phase IIr vs III]; "higher" dose PCI pca-rp), PI's: Wolfson and Komaki. This is another phase III asking PCI dose for SCLC and there are no competing trials in any group in North America. I anticipate each of you will accrue a fair number of patients for this study.
RTOG 0229: High dose trimodality trial: PI's: Mohan/Edeleman. This protocol will go forward to NCI for approval sometime this year.
RTOG 0236: Stereotactic Radiosurgery for Early Stage. NSCLC: PI: Bob Timmerman.
This trial is almost ready for submission to NCI. This is another trial that's been on the waiting list a long time due to the complexity of this trial. I think we ironed out all the bugs in this study and I anticipate its submission to NCI sometime this year.
RTOG 0238: PET in combined Modality, PI: Bradley. This trial still needs some work on QA. Jeff
Bradley will work closely with RTOG HQ to find a way to centralize radiation QA.
RTOG 0324: A Phase II Study with C225/RT: PI: George Blumenschein. This is a unique phase II study using targeted combined modality therapy in NSCLC. The protocol is nearly completed and expected to be submitted to NCI by the end of August.
RTOG 0333: Neoadjuvant trial for stage III NSCLC: This will be one of the most important trials for RTOG lung group for the next 5 to 6 years. After a long discussion with SWOG and the other groups, RTOG will lead this intergroup phase III study. The key objective of the study is comparing pre-op chemo vs. chemo RT in NSCLC. The concept should be revised soon. NCI submission expected at end of August.
RTOG XXXX: Avastin and concurrent Chemoradiation Therapy (Proposed) O'Reily. This is another phase II study in targeted combined modality therapy in NSCLC. We are trying to put together the protocol with Avastin and chemoradiation. This protocol will follow RTOG 0324.
We decided not to proceed with the extended stage small cell consolidative radiation trial (proposed by Ben Movsas and Alan Sandler), chemoradiation for surgically relapsed patients (by Ron McGarry and Wally Ackerley) and Brain mets in NSCLC (proposed by Bob Timmerman). These phase II study discussed last year are high risk trials that we decided to put on hold at this time.
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Hak Choy, M.D., Chair
RTOG 0117 - A Phase I/II Dose Intensification Study Using Three Dimensional Conformal Radiation. This study’s radiation dose has been de-escalated to 74 Gy in 37 fractions in Arm 2 (instead of 80.5 Gy in 35 fractions) and 70 Gy in 35 fractions in Arm 3, if necessary. Arm 1, 75.25 Gy in 35 fractions, was completed 9-26-02. The sample size has changed from 64 to a maximum of 73; 27 patients for the Phase I component; 46 patients for the Phase II component. An amendment was submitted to CTEP in 1/03. Once the CTEP approves, this study will be re-activated.
RTOG 0017- A Phase I Gem/Carbo/RT & Gem/Taxol/RT (ping-pong trial). This study is also on hold due to toxicity assessment in arms 2 and 3. There were two asymptomatic G4 neutropenia during the consolidation period. Therefore the definition of dose limiting toxicity (DLT) will be re-defined as: 1) Acute Grade 3 or 4 nonhematologic and grade 4 hematologic toxicities occurring during concurrent chemoradiation therapy; 2) grade 4 hematologic toxicities occurring during the consolidation phase that are symptomatic (i.e. neutropenic sepsis, thrombocytopenic bleeding. This recommendation was made by Drs. Langer, Abraham and Machtay who reviewed the toxicity data for 6 patients in arm 2. We also discovered one patient with Hypersensitivity reaction from Paclitaxel in arm 2. The study will be re-activated for one additional patient in arm 2 (to replace one Hypersensitivity patient).
RTOG 0213- A Phase II RT + COX-2 intermediate-risk patients trial. This study was activated in late July. Only 3 patients were entered as of 1/1/03. We encourage all members to open this study and accrue patients. This is a simple phase II study in which patients will receive radiation therapy plus Celecoxib. Again, we need patients for this study!
RTOG 0214- A Phase III PCI vs. no PCI for NSCLC. This protocol was activated late last year and three patients have been entered to date, leaving only 1,055 patients to go! I encourage ALL of you to open the study as soon as possible and hunt for patients. Meanwhile, Beth Gore and Stuart Wong will design a newsletter that can be distributed via e-mail on a regular basis to the whole group.
RTOG 0236- A Stereotactic Radiosurgery study for Early Stage NSCLC. This trial is almost ready for submission to NCI
RTOG 0238- A PET and combined Modality study. This trial still needs some work regarding QA. Otherwise, it is closed to submission to NCI.
RTOG 0239 – A Phase II P/E/dose escalation RT study. This protocol was also submitted to NCI for final approval. I anticipate it will be open within two months. This trial will run parallel to the 0241 phase I study. Stay tuned for the study activation announcement.
RTOG 0241- A Phase I/II Irinotecan + EP/bid RT for LD SCLC. This protocol has been resubmitted to NCI for final approval and I anticipate that this study will open within two months. Considering intergroup effort of comparing BID vs. Daily RT in small cell, the effort has been bogged down by NCI. This trial is important to answer chemotherapy questions and radiation dose questions. Stay tuned for the study activation announcement.
RTOG 0270- A Neovastat Trial. This study was activated last year by RTOG. I believe about a dozen RTOG sites are participating as of January 1. Those sites participating in this study will receive double credit.
RTOG 0212- A Phase IIr vs III "higher" dose PCI. This trial is very close to activation, but still waiting for an educational video tape for neuropsych testing. I anticipate activation will be within a month.
RTOG 0229- A high dose trimodality trial. This protocol is ready for submission to the NCI and waiting for the final touches from RTOG HQ.
RTOG 0324- A Phase II Study with C225/RT. This is a top priority protocol which we expect to submit to the NCI by the end of February.
RTOG dev- Neoadjuvant trial for stage III NSCLC: PI’s. This will be a large random phase II study for stage III A patients. We discussed a possible III arm PHASE II trial, chemo/RT followed by surgery vs. chemo/RT plus celebrex followed by surgery vs. chemo/RT plus Iressa. However, we may end up doing a two arm study. I expect to have several conference calls in the next few months to finalize plans.
RTOG 0230- Adjuvant trial for stage III NSCLC. We discussed a two arm random phase II trial during the meeting, however, we may wait for the European adjuvant study data before we finalize our study design.
RTOG dev- ES Small Cell Consolidative RT Trial. As we discussed in the meeting, this will be done as a single arm phase II study. Patients with extensive SCLC who achieved CR or near CR from chemotherapy will enter this trial to receive RT alone as a consolidative treatment. Dr. Movsas and Dr. Sandler will write a protocol for submission.
RTOG dev- Chemo/RT for Surgical relapsed patients. This will be another single arm phase II study for those patients who relapsed in the chest from surgery or chemo/surgery. Patients will receive concurrent docetaxel and RT as of definitive salvage therapy.
RTOG dev- Brain Mets in NSCLC. As we discussed in the meeting, this should be done as a single arm phase II study. Patients with synchronous brain only metastatic disease will receive whole brain radiation therapy followed by stereotactic followed by chest RT.
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Hak Choy, M.D., Chair
1. RTOG 01-17: [Phase I/II]; T/Cbo + 3 D HDIF CRT dose escalation - The overall accrual is slow with 8 patients to date. There was one DLT in the first 8 patients with grade 5 lung toxicity. We recommended this study to the RTOG HQ for re-opening to accrue one more patient (9 total) and then to await an adequate follow up period prior to escalation. We also discussed problems classifying AE versus DLT (i.e. nausea and vomiting) in two other patients. Dr. Jeff Bradley will submit an amendment to improve the DLT definition and dose escalation schedule. The dose escalation schedule will be modified to have only two dose levels based on the BED. If the regimen appears to be tolerable, we will proceed to the Phase II portion of the study.
2. RTOG 02-39: [Phase II]; P/E/ RT for Limited Stage Small Cell Lung Cancer - RTOG 9712 was closed with 64 pts accrued across 6 treatment arms. The MTD was 61.2 Gy with Large field 28.8 Gy; 1.8 Gy/fx/5 days x 16 fx, and boost just in pm @ 1.8 Gy/fx on days 17-20 (use ap/pa fields in am @ 1.8 then boost 1.8 Gy BID x last 5 days. Dr. Komaki will submit a phase II study protocol using the MTD dose.
3. RTOG 02-14: [Phase III]; PCI vs. no PCI for NSCLC - We expect this trial will be activated very soon within RTOG, ECOG, SWOG, CALGB, NCCTG and NCIC. Dr. Gore and I will develop a plan to export this trial to other cooperative groups in the world. We will not seek MMSE, ADLS, and HVLT from non-north American participants.
4. RTOG 02-13: [Phase II]; RT + COX-2 intermediate-risk patients - This study was designed to evaluate toxicity and efficacy of concurrent celecoxib and thoracic RT for intermediate risk patients. We will evaluate prognostic value, such as co-morbid conditions, functional status, quality of life, psychological status as well as circulating VEGF, bFGF, and IL-8 to correlate with response and to determine if circulating pro-angiogenic and pro-inflammatory cytokines are altered. We are looking forward to successful patient accrual and data collection.
5. RTOG 02-12: [Phase IIr vs III]; "higher" dose PCI - The primary objective of this trial is to participate in the International Prophylactic Cranial Irradiation Trial (PCI 01-EULINT1) to determine the impact of an increase in the total PCI dose on the incidence of brain metastases and to determine incidence of chronic neurotoxicity and quality of life with new RT dose and schedule. We will seek collaboration from ECOG, SWOG, CALGB, NCCTG and NCIC.
6. Neovastat Trial: This is an on-going phase III trial via MD Anderson CCOP. The RTOG lung cancer steering committee endorsed this trial to be available to our member institution. This study also received very favorable response during the general lung meeting. I will work closely with RTOG HQ for speedy activation of this study.
7. DEV 1001: [Phase I/II]; Irinotecan + EP/bid RT for LD SCLC - This is a two-arm phase I study awaiting submission to CTEP. It’s in RTOG HQ's high priority list.
8. RTOG 02-30: [Phase II]; Post-op RT+Celebrex - The protocol is in near final format. Dr. Langer needs to identify the funding source for QOL, tissue and serum analysis. Once these issues are resolved, the protocol will be submitted to CTEP. This protocol will follow Dr. Movsas’ RTOG 99-09.
9. RTOG 02-29: [Phase II]; High Dose Trimodality Pre-op Trial - This is a phase II limited institution trial that is in near final format. Dr. Suntha will put together a list for participation and will circulate the protocol soon. Once the final protocol is available, we will proceed with CTEP submission, which will hopefully be long before the next meeting.
10. RTOG 02-36: [Phase II]; Proposed: Stereotactic radiosurgery - This is another limited institution pilot trial. We will utilize special techniques including stereotactic targeting, special dosimetry with rapid fall-off gradient and body frame for higher repositioning accuracy. In this trial 20 Gy per fraction (60-90% line) for 3 fractions (total 60 Gy) over 1-2 weeks will be delivered to stage I/II NSCLC patients. The protocol still needs fine tuning before its submission to CTEP. Again, once the final protocol is available, we will proceed with CTEP submission, which will hopefully be long before the next meeting.
11. THE SUPERIOR SULCUS Trial: - The lung cancer steering committee decided to participate in the planned SWOGS0220:PE/RT SurgeryTaxotere when it becomes available.
12. RTOG 02-35/02-37: [Phase II]; PET in combined Modality for NSCLC and SCLC - The overall study concepts have been approved by the committee. These trials are in need of a clear hypothesis and trial plan. Drs. Machtay and Govindan will continuously fine tune the protocol. They will also discuss with ACRIN, Dr. Barry Siegel, for their collaboration.
13. RTOG 02-37: [Phase II]; Proposed: PET in combined Modality II - This is a pilot project to compare TNM stage, GTV values, location of involved nodes, and dosimetric parameters (MLD, MED, V20) for each patient and to follow each patient for failure patterns, including “elective nodal failures” in regions not contoured as tumor. This study will be done as a limited institution trial. Dr. Bradley will put together a list for participation and will circulate the protocol soon. Once the final protocol is available, we will proceed with CTEP submission.
14. RTOG 00-17: Ping-Pong trial - We now have 8 patients in this trial. I believe that this is an important trial and we need your support.
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Hak Choy, M.D., Chair
Active Trials
RTOG 01-17 - [Phase I/II]; T/Cbo + 3 D HDIF CRT dose escalation
As we discussed, we need to figure out a way/or ways to simplify the registration process in order to prevent the loss of potential patients. I will ask Mary and Jeff to review the protocol and provide us with their recommendations by the end of the February. Once I have their comments, I will forward it to all of you.
RTOG 00-17 - [Phase I]; MTD Gem/Cbo/RT & Gem/Taxol/RT
As you heard, there are only 5 patients in this study. As far as I know, the first 3 patients are doing fine. I will find out how many sites are participating in this study. I strongly encourage your participation. We are also in discussion with Eli-Lilly for potential increase in case reimbursement per patient to stimulate patient accrual.
RTOG 97-12 - Phase I CisP/Etop Accreted RT in LSSCLC
This study is very close to MTD level. We will roll this study into a phase II study. I will ask Ritsuko to communicate with Chuck for protocol amendment.
Pending Trials
RTOG 02-13 - [Phase II]; RT + COX-2
Waiting Final approval from CTEP.
RTOG 10-09 - [Phase I/II]; Irinotecan + EP/bid RT for LD SCLC
The final protocol is in RTOG HQ, we hope it will be sent to CTEP soon.
RTOG 01-25 - [Phase III]; PCI vs. no PCI for NSCLC
This study is in our highest priority list. I will work closely with PI’s, Chuck, and HQ to finalize the protocol and submit a final copy to NCI.
RTOG 02-12 - [Phase IIr vs. III]; "higher" dose PCI (pca-rp)
Will discuss with the PI’s of the International PCI study for potential RTOG participation.
RTOG 01-23; [Cancer Control; Phase IIr]; RT ± Captopril
This study needs to be activated. Will discuss with PI’s and HQ for final touch.
Proposed Trials
Proposed: Stereotactic Radiosurgery
This proposal received favorable response by the committee.
But it needs lots of work. First, we need to find out which institution has stereotatic radiosurgery capability in order to form a Stereotactic Radiosurgery Working Group for Lung Cancer.
This group will consist of Bob Timmerman, Jeff Michalski, a physicist, and a representative from each participating institution.
Once we organize the working group for stereotatic, we will proceed with the initial conference call.
I hope we will have a final protocol long before the summer group meeting.
Proposed Post-op Trial: Chemo +RT
The original proposal from Cory was a two arm phase II trial. However, it is clear that we do not have any data/experience with concurrent tarceva, Iressa, C-225 with RT in adjuvant setting for Lung Ca. Therefore, we will proceed with a single arm phase II trial of adjuvant RT+Celebrex with RTOG. Cory will contact Genentech, Astra Zeneca and BMS for the possible pilot trial of RT+ their biological agents.
Proposed Pre-op Trial: Chemo/RT
Marty Edelman’s proposed pre-op tri-modality therapy with high dose RT received a favorable response by the committee. This trial will be conducted by limited institutions where their surgeons are comfortable in operating patients after high dose RT tri-modality.
Marty will discuss this protocol with our surgical chair, David Johnston, and a surgeon from University of Maryland for identifying other surgical colleagues in RTOG who may want to participate in this trial.
Intergroup Proposal 45 Gy BID vs. 70 QD
We will re-discuss this protocol when it is approved by CTEP.
Proposed: PET in combined Modality I
We need to find out whether this protocol is overlapping with ACOSOC’s proposed study. If so, we may need to work with them. Otherwise, Mitch will discuss this protocol with ACRIN for their support.
Proposed: PET in Combined Modality II
This proposal also received favorable response by the committee, but it also needs lots of work. First, we need to find out which institution has PET/CT planning capability in order to form a PET/CT treatment Planning Working Group. This group will be lead by Jeff Bradley and R. Munden, and a representative from each participating institution.
Once we organize the working group for PET/CT treatment planning group, we will proceed with the initial conference call. I hope we will have a viable protocol before the summer group meeting.
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Roger W. Byhardt, M.D., Chair
RESECTABLE NON-SMALL CELL LUNG CANCER
Dr. David Johnstone chaired this session. The hypotheses that drive resectable non-small cell lung cancer research are:
1. Pre-operative chemotherapy will reduce the risk of systemic failure and will improve survival for patients with early stage lung cancer.
2. Post operative radiation therapy plus immunotherapy with anti-idiotype
antibodies targeting tumor antigens will reduce the risk of local relapse for resected stage II and III A disease.
3. Radiation and chemotherapy is equivalent to radiation chemotherapy plus
surgery for resectable III A (N2) disease.
RTOG 96-16 has accrued about 120 patients, 25 of whom are from RTOG institutions. RTOG 0015, which is a phase III intergroup trial with SWOG has just recently opened and is early in its accrual time frame. It may run through May of 2004. RTOG 99-09 is nearing activation and evaluates post-operative RT + bivalent anti-idiotype antibody for resected IIA and IIIA disease.
A number of adjuvant agents are being considered for addition to radiation in the postoperative setting. Several are not ready for a clinical trial, including the BMS antiangiogenesis agent and the low molecular heparin Lovenox. An LOI has been sent to NCI regarding the Sugen compound SU6668. A final decision on which agent to pursue will depend on NCI response to the LOI. We also need to define clear biologic endpoints that relate to local control and survival indicating whether the target activity for the agent has been affected. It was also concluded that any postoperative trial should be confined to resected N2 patients. RTOG 93-09 will close about 2002. Plans are in place for a pilot study that could replace RTOG 93-09. It will also require surgical markers for tumor response and may employ antiangiogenesis inhibitors.
The upcoming meeting will explore management of early-detected lung cancer (MEDLUC) with non-surgical approaches.
Dr. Stuart Wong then presented a science session on R2 expression and tumor response specifically related to Gemcitabine radio sensitization.
INOPERABLE NON-SMALL CELL LUNG CANCER
The hypotheses applicable to inoperable non-small cell lung cancer were discussed by Dr. Byhardt and examples of developing protocols were given for each hypothesis.
The first hypothesis is that high dose RT using 3D conformal RT (3D-CRT) to involved sites only, with or without chemotherapy (ChT), will increase local control and survival. The currently open phase II dose escalation trial of 3D-CRT is nearing completion and the highest dose level has been reached in-group one (<25% of normal lung > 20 Gy) without reaching the maximally tolerated dose (MTD). In group two (25-37% of lung > 20 Gy) the second dose level has been reached without reaching the MTD. The replacement trial 1051 will add ChT (Taxol and Carboplatin). Rather than progressive increases in total RT dose using the same 2.15 Gy fraction size from 93-11, which would increase the duration of RT beyond 8-9 weeks, the fraction size will increase and the duration of treatment will be shortened. This is essentially accelerated fractionation (Afx) and is a unique exploitation of dose intensification. The data will ultimately be used in a phase III trial (1049) comparing the MTD of involved field high dose Afx 3D CRT/Taxol/Carboplatin to standard fractionation and dose extended field RT, using 3 D CRT techniques, plus Taxol/Carboplatin.
The second hypothesis is that radiation protectors will decrease the toxicity of chemo-radiation. RTOG 98?01 tests whether Amifostine can reduce the risk of severe acute toxicity (e.g., esophagitis, pneumonitis) when added to Afx RT (69.6 Gy) concurrent with Taxol/Carboplatin. It is accruing at rate of 7-8 patients per month and has an estimated closure of June 2002. If Amifostine is found to be effective, it may become a standard part of RTOG combined modality treatment. It was decided not to pursue RTOG 98?07, a phase II trial intended to evaluate accelerated fractionation RT and Taxol/Carboplatin. It was felt that concurrent Afx RT and Taxol/Carboplatin would be more safely evaluated using 3 D CRT techniques as designed in RTOG 1051.
The third hypothesis is that optimized sequencing along with chemo-radiation will improve local control and survival. The early results from RTOG study 94?10, a phase III trial of sequential versus concurrent chemo-radiation, show improvement in survival with the concurrent arm that is of borderline significant. There is also a decreased rate of in-field failure with concurrent Afx RT plus Cisplatin/Etoposide. As these results continue to mature, other ChT/RT timing and scheduling issues will be explored in pilot and Phase I/II trials. For example, based on pre-clinical data and a pilot clinical trial conducted by Y. Chen (University of Rochester) pulsed, low-dose Taxol and RT may hold promise as a well-tolerated and effective regimen. An RTOG trial of this approach is in development.
The fourth hypothesis is that radio-sensitizing ChT will increase the ability of radiation therapy to provide local control. RTOG L-0017 is a phase I dose escalation trial of two Gemcitabine doublets (Gemcitabine/Carboplatin and Gemcitabine/Taxol) concurrent with radiation for good performance patients. This trial is in the final stages of approval by NCI.
The fifth hypothesis is that hypoxic cell cytotoxics (e.g., Tirapazamine) will enhance the effectiveness of chemoradiation by overcoming the negative influence of hypoxic tumor cells. The activation of a previously designed trial to investigate this approach, RTOG 98-10, was held in order to avoid competition for accrual to RTOG 98-01. Although current accrual rates to 98-01 would allow activation of 98-10, substantial changes to 98-10 have been proposed that will require withdrawal of 98-10. A replacement trial will be designed that allows a broader range of ChT and adds radioisotope imaging of tumor hypoxia verified by Eppendorf catheter measurement.
SPECIAL POPULATIONS
Secondary analyses of completed RTOG studies have identified several special patient populations that will be the subject of focused study.
Two of these special populations are poor risk and elderly patients. The hypothesis is that de-intensified chemo-radiation for poor risk and elderly patients will have an equivalent quality adjusted survival to good performance patients. RTOG 1004 will evaluate moderate dose weekly Taxol with short course RT for elderly patients. The study includes assessment of Quality of Life, comorbidity scales, and will conduct pK analysis of Taxol levels to see if elderly patients process the drug differently than younger patients. Submitted to the National Institute of Aging in 1999, the trial was not approved for funding but has been recently resubmitted. Pending approval, the strategy is testing split course RT and weekly Taxol for poor risk patients. If the two strategies appear promising they may be tested in a phase III comparison of the two approaches combining the elderly and poor risk patients in one group. Correlation with comorbidity scales may help define patient eligibility and selection for a phase III trial.
A third special population is medically inoperable early stage suitable for non-surgical treatment. A proposed trial exploits the hypotheses that intralesional Adp53 may safely enhance RT alone for medically inoperable early stage disease. In this trial, intralesional injections of Adp53 are given three times during the course of RT. At the time of injection repeat needle biopsies are done to test for viable tumor and biological markers. The target population for the trial will need to be redefined, since medically unresectable early stage patients make up a small patient group in the RTOG patient base. Financial support will also be mandatory to cover the costs of the intralesional injections. These design issues will be explored further before the trial will be given a development number.
The fourth special population group identified from secondary analysis is patients at a high risk for CNS metastasis. The proposed hypothesis is that prophylactic cranial irradiation (PCI) will reduce the high rate of CNS failure in patients receiving definitive chemo-radiation with or without surgery for non-squamous non-small cell. RTOG study 1058 is a proposal for a phase III trial comparing PCI versus no PCI in CNS metastasis high-risk patients. Activation of 1058 as a phase III trial will be temporarily deferred and, instead, it will be opened as a phase II trial to evaluate accrual potential in this patient group and allow time to validate the neurocognitive instrument in the RTOG brain metastases trial. It also will allow time to complete a secondary analysis correlating the timing of maximal response to chemo-radiation to outcome for inoperable NSCLC patient that received chemo-radiation in prior RTOG studies. This data will assist patient selection and will help determine the timing of PCI after completion of treatment of the primary disease.
SMALL CELL LUNG CANCER (SCLC)
Dr. Ettinger led the SCLC discussion and outlined the research goals, which include 1) improvement of local control and survival with chemo-radiation through evaluation of new chemotherapy and optimizing accelerated fractionation radiation and 2) improvement of the therapeutic ratio of PCI. The two previous RTOG phase II trials attempted to improve on standard Cisplatin/Etoposide/RT by the addition of Ifosfamide (93-12) and Taxol (96-09). Neither trial has suggested a clear benefit over Cisplatin/Etoposide/RT, however, more follow up is needed for assessment of long-term survival in 96-09. The hypothesis that a higher biologically effective dose (BED) of Afx RT will enhance local control and, in turn, survival is being tested in RTOG 97?12. This trial seeks the MTD dose of RT accelerated by progressively adding additional bid treatments as boost fields near the end of RT. Complete is expected about January 2001. The MTD dose may be further tested in a phase II trial before considering it for inclusion in a future phase III trial.
A higher dose of PCI given as twice-daily RT will be tested in the phase II trial RTOG 1033 in an attempt to reduce the rate of CNS failure in limited stage small cell. The bid schedule was tested in an RTOG institutional trial and 1033 will expand the evaluation of toxicity and freedom from brain failure rate. The trial will also test whether SCLC patients can be accrued to trial of PCI in the group-wide setting. Future plans are to test the bid PCI against standard dose PCI in a phase III trial using a validated neuropsychology testing system and evaluation of neurotropic growth factor as a marker of CNS RT toxicity.
The hypothesis that treatment directed at hypoxic tumor cells, which make up a significant proportion of most SCLC tumors, will be tested in a phase I/II proposal using the hypoxic cell cytotoxic Tirapazimine along with chemo-radiation. The study includes radionuclide imaging of hypoxic tumor cells using technesium-labeled misonidazole to validate their presence and response. The proposal is in concept form now, but will be further developed.
PATIENTS AT HIGH RISK FOR LUNG CANCER
Patients at high risk for lung cancer, such as smokers with a prior history of resected early stage upper aero-digestive tract cancer, are also a potential target patient group for RTOG studies. The intergroup trial RTOG 91-01, tested 13 Cis-retinoic acid as a chemopreventive agent in this patient group, but the results on long-term follow-up were negative for prevention of new second primary cancers. An intergroup trial of Selenium as a chemopreventive agent has been proposed by ECOG, which RTOG would join if it is activated (RTOG 1034), but RTOG will not likely design or launch a chemoprevention trial of its own.
IMPACT OF SMOKING
There is a new RTOG proposal to evaluate the behavioral, demographic, and medical factors associated with continued smoking during and after RT in lung cancer patients. The study would also examine the quality of life impact of smoking and the effect of continued smoking on toxicities and outcome of chemo-radiation for lung cancer,
CORRELATIVE AND TRANSLATIONAL RESEARCH
A number of correlative and translational research questions are being pursued in RTOG studies. These include an evaluation of serum markers (surfactant, procollagen III, IL1a, IL1b, IL6, and TNFa, M1P, TGFb, ITGF) for radiation lung injury as part of the RTOG 1061 study evaluating Captopril intervention to prevent RT pulmonary toxicity. RTOG 1016 will evaluate the value of the mutagen sensitivity assay (MSA) in predicting the risk of RT toxicity and treatment outcome. Other translational studies include assessment of the role Neurotropic Growth Factor (NGF) in predicting RT CNS toxicity from PCI in RTOG 1058. In RTOG 99-09 immune response to the anti-idiotype antibodies will be assessed along with CYP1A1 polymorphism in females and its relationship to outcome. RTOG 1004 includes pK analysis of the weekly Taxol in the elderly. A serum bank is in development that would be available for all RTOG lung protocol patients. Using the collected serum, correlation of prognostic markers to outcome could be made using currently known markers and markers yet to be identified in the future.
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Roger W. Byhardt, M.D., Chair
RESECTABLE NON-SMALL CELL LUNG CANCER
Dr. Johnstone opened the session by noting the accrual to RTOG 96-16, the observation versus neo-adjuvant chemotherapy trial for T2N0, intergroup with CALGB. He also noted that RTOG 93-09, the phase III trial intergroup with SWOG for N2 disease, is closing in on its accrual target.
Developing trial RTOG 99-09 is a phase II trial of radiation therapy plus an anti-idiotype antibody post-operatively. It was noted that the Lung Steering Committee has recommended that this trial be activated as soon as possible to take advantage of the availability of resected patients for post-operative treatment. The Titan drug company is now willing to release the bivalent antibody for our use.
Three developing phase II trials will explore anti-growth agents as possible replacements for RTOG 99-09 when it closes. They will include the BMS agent, Lovenox, and SU6668. Activation of any one of these will depend on the availability of the agents, phase I data, and the emergence of other promising agents. RTOG 1012, a phase III trial of observation versus neo-adjuvant Taxol/Carboplatin followed by surgery, was approved by the Research Strategy Committee. This is an intergroup study with SWOG.
This session was followed by two five-minute science presentations, the first by Reggie Munden, M.D., the new diagnostic radiology (ACRIN) liaison to the Lung Cancer Committee. He talked about radiological imaging and screening for lung cancer. This led to some discussion about development of a program to address treatment of early stage endobronchial lesions identified by spiral CT scanning and bronchial lavage marker studies. The treatment options could include endobronchial brachytherapy, stereotactic radiosurgery procedures, 3D conformal radiation therapy, and/or photodynamic therapy. Dr. Ginsberg suggested that at the next meeting a special several hour session be set up including pulmonologists, radiation oncologists, medical oncologists and surgical oncologists interested in pursuing this type of investigation. Dr. Laurie Gaspar and Reggie Munden will assist in setting up this special session.
The second five-minute session was chaired by the new Translational Research Liaison to the Lung Committee, Alan Franko, Ph.D., who briefly described some of his laboratory research into the genetic component of pulmonary fibrosis. He believes this work might have a future link to a clinical trial exploring prevention of lung fibrosis. The lung committee welcomed both Dr. Munden and Dr. Franko as new members.
INOPERABLE NON-SMALL CELL LUNG CANCER
Dr. Byhardt chaired this portion of the session. He introduced Jeff Bradley, M.D., from Washington University, who will be in charge of a subcommittee that will oversee evaluation of existing lung protocol content. The purpose will be to assure that all protocol sections are updated. The subcommittee would be part of the protocol review mechanism. The subcommittee will examine each new protocol to make certain each section is current.
It was noted that the survival results from RTOG 94-10 are not yet available for group wide presentation. Toxicity data is available and is in the meeting book. Preliminary survival results might be available in several months.
For RTOG 93-11, the 3D total dose in group one has now reached 90.3 Gy. It was decided to stop the trial after accruing the necessary number of patients at this dose level to determine toxicity. There was some discussion about whether to write another dose escalation. However, it was felt that it was not a goal of the trial to find the highest tolerable dose of 3D radiation, but to find a tolerable dose about 30% higher than what can be given with standard radiation therapy. As the protocol is written, it takes nine weeks to deliver 90.3 Gy. To go to a higher total dose would require treatment to extend beyond 9 weeks. To keep the same treatment duration or to shorten treatment accelerated fractionation would have to be used which would change the nature of the study. Developing trial 1051 will replace 93-11 when it closes. As written, 1051 will examine Taxol/Carboplatin concurrent with dose escalated 3D conformal radiation therapy. There are two ways 1051 could be designed. One could fix the radiation therapy dose and escalate the chemotherapy dose or vice versa. A future conference call will decide the final study design. In the meantime, RTOG 1049, a phase III trial that will replace 1051, is being put into electronic format for submittal as a concept to NCI. Arm 1 of RTOG 1049 will be concurrent chemotherapy and 3 D radiation therapy to a standard radiation dose (60 Gy) covering both involved and prophylactic sites. Arm 2 will be concurrent chemotherapy and 3 D radiation therapy to the maximum tolerated dose identified from 1051 covering only involved sites with a 3-D defined margin. Taxol/Carboplatin will likely be the choice for chemotherapy. There was some question about whether Taxol/Carboplatin should be piloted with 3D radiation to the primary and elective nodal irradiation as in arm 1, however it was felt that Choy’s pilot data from Vanderbilt was probably sufficient to establish the safety of this regimen. The alternative would be to use the Cisplatin/Vinblastine or Cisplatin/Etoposide chemotherapy from RTOG 94-10, but these agents would not be embraced by most medical oncologists today.
RTOG 98-01, a phase III trial evaluating the possible role of Amifostine in reducing acute esophagitis and pneumonitis in patients receiving chemoradiation, was discussed. Its accrual has now reached the goal of nine patients per month and it was again reemphasized what an important trial it is. The Data Monitoring Committee reviewed the sample size and felt it was still necessary to keep the sample size the same to be certain that there is no survival decrement related to the radio-protector. The sample size will be reviewed in the near future and it is possible that the sample could be reduced from 300 to 230 patients so that the trial could close in a more timely fashion. Because of the better accrual to RTOG 98-01 the Lung Steering Committee has decided that another phase II trial can open if RTOG 98-01 accrual maintains nine per month over the next two months. At that time RTOG 98-07 may be limited to those institutions that have never accrued any patients to RTOG 98-01 because of logistics reasons. The radiation therapy section of RTOG 98-07 will be rewritten to incorporate 3D terminology for field designation using fields designed to treat involved sites only.
Dr. Byhardt presented a new proposal for a phase II trial of 3D conformal radiation to the primary tumor plus involved nodes concurrent with Taxol/Carboplatin plus the antigrowth low molecular weight heparin (LMWH) Lovenox, which has some significant anti-angiogenesis properties. This was followed by a ten-minute mini science session presented by Dr. Majed Abu-Hajir, medical oncologist from the Medical College of Wisconsin. He talked to the group about the role of anticoagulants such as LMWH's as potential anti-angiogenesis agents. The discussion was well received and raised a lot of interesting questions suggesting some significant group enthusiasm for this approach.
RTOG 1004, a phase II trial of radiation and weekly single agent Taxol for the elderly, was then discussed. It was noted that this proposal had been submitted to the NIA a year ago and received a reasonably good score but not a level for funding. One of the reviewers concerns was the proposed radiation schedule was felt to be “too weak”. After several conference calls and meetings the group working on the trial has recommended 45 Gy and 15 fractions over three weeks with weekly Taxol. While there was some concern about the risk of esophagitis, it was noted that there is other experience with concurrent radiation chemotherapy in the elderly. In the Italian ELVIS trial for elderly patients the toxicity of chemoradiation was acceptable and survival was somewhat increased. The drugs used were slightly different than the Taxol proposed in 1004, but close enough that the ELVIS experience is applicable. There are currently stopping roles for toxicity built into the design of 1004 so that if unacceptable toxicity is noted in the first several patients, the doses can be de-escalated as necessary. 1004 will be resubmitted to NIA when the revisions are complete and it will also be submitted to CTEP for approval at the same time.
Developing trial 1035 will explore dose limitations for Gemcitabine/Carboplatin and Gemcitabine/Taxol. The best of these two regimens will be inserted into developing trial 1010 as either a fourth or third arm along with several other chemotherapy doublets that have been selected for their ability to radiosensitize. It was noted that the thematic approach for choice of chemotherapy in RTOG lung trials will be to focus attention on chemotherapy agents that are radiosensitizing.
SMALL CELL LUNG CANCER
Dr. Ettinger chaired this session and described the current status of the dose escalation trial RTOG 97-12. He noted that it has now escalated to the next dose level. He noted that the NCI review committee has rejected our proposed RTOG 99-12 trial, a phase III comparison of Taxol/Etoposide/Cisplatin/Hyperfractionated RT (45 Gy/3 wks [96-09]) to the Etoposide/Cisplatin/Hyperfractionated RT (45 Gy/3 wks [88-15]. The reasons given for the rejection were that the one year survival data was too premature to serve as the basis for a phase III trial and that the drug regimen was altered from that previously given in RTOG 88-15. We noted that the drug dosage change was a typographical error in the electronic submission form. Also, RTOG had acted on the recommendation of NCI's prior review of RTOG 96-09, which recommended that if there were favorable one year data for 96-09 it could form the basis for a phase III trial. Apparently, these NCI recommendations did not apply with the new review committee system. The rejection does not allow the opportunity for resubmission unless more mature data continues to show a survival benefit.
RTOG 1032 is a phase III proposal to compare chemotherapy versus chemoradiation to the chest in so called "favorable" small cell patients with extensive disease. These are patients with a small amount of disease outside the thorax who have a complete response to chemotherapy. It was thought this trial that might engender significant interest amongst other groups and it might be the basis for collaboration. Further development will go forward on this trial.
RTOG 1033 is a phase III comparison of Prophylactic Cranial Irradiation (PCI) to 25 Gy/10 fractions or 36 Gy and 24 fractions bid over three weeks. There were some concerns over the sample size necessary and whether the trial could be conducted with RTOG resources alone. It was noted that the answer was probably "no" and that it would probably have to have the cooperation of some of the other cooperative groups. There were also concerns expressed that not all institutions would be interested in or willing to do PCI bid. It was clear there will have to be further discussions of the design and rationale for this trial before it is submitted through the NCI review committee process.
MISCELLANEOUS AND CORRELATIVE TRIALS
It was noted that RTOG 1061, a developing trial of Captopril intervention to prevent pneumonitis, will be submitted for R01 funding. RTOG 1023, a smoking cessation trial from SWOG, was not discussed since there was no up to date information RTOG will join. RTOG 1034, the phase III selenium chemoprevention trial, with ECOG as the lead institution. Fadlo Khuri will pursue further development of 1034 working through the Cancer Control Committee and Chemoprevention Committee. Dr. Komaki then presented proposal 1016 to evaluate the role of mutagen sensitivity assays in predicting outcome and toxicity in irradiated lung patients. This protocol would be a correlative trial companioned with other trials.
Dr. Okunieff described some laboratory research being done at his institution by Dr. Chen evaluating Taxol and Taxotere with radiation therapy. This laboratory work has shown effectiveness of pulsed low dose chemotherapy administration against non-small cell lung. Dr. Chen will be invited to present more details of her interesting work at the next meeting. Her means of administering these two agents might have application in the elderly age group as a low toxicity means of enhancing radiation therapy.
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