Committee Minutes - Medical Oncology MEDICAL ONCOLOGY COMMITTEE (February, 2007) Corey Langer, M.D., Chair The RTOG Medical Oncology Meeting convened on 2/3/07. At least 50 individuals were in attendance. Sub-Committee Mission Dr. Corey Langer, Vice Chair RTOG, recapitulated the mission of the Medical Oncology Committee: Cross-fertilization between various disease-specific committees. Introduction of new systemic agents and radiosensitizers into the RTOG. Investigation of new therapeutic territories and venues, combining radiation and systemic treatment, e.g. the role of chemotherapy in brain metastases, or in combination with re-irradiation in head and neck cancer. Streamlining and vetting protocols, including systemic options, concomitant medications, dose modifications, eligibility, toxicity analysis, and compliance obstacles. Recruitment. Medical Oncology Quality Control In Dr. Goodyear's absence, Dr. Langer reviewed overall compliance for reviews from 2006. Over 720 cases were assessed. Compliance was only 88%, substantially lower than we have seen historically. The reasons for this decline are unclear. They were concentrated in 3 specific studies: (1) RTOG 9902, a high risk prostate trial with 102 cases analyzed (73% compliant); (2) RTOG 0420: a phase II trial of temozolomide, irinotecan, and radiation in GBM (78 cases analyzed; 60% compliant); and (3) RTOG 0247, a combined modality trial in resectable rectal carcinoma (25 cases analyzed; 46% compliance). The reasons for this drop in compliance will be investigated. This observation may have more to do with the new system of grading compliance than with true changes in protocol fidelity. Disease Site Specific Committee Reports Dr. David Ettinger of the Thoracic Surgery Committee reviewed ongoing studies, including RTOG 0212, a phase III trial of PCI in SCLC, which is nearing completion, with 210 of 264 targeted for accrual enrolled, and RTOG 0214, a phase III, prospective, randomized trial of PCI in patients with no evidence of progression after combined modality therapy for locally advanced NSCLC. Enrollment to date is just past 300; 1058 are targeted. This study remains in peril if enrollment does not improve. He also lamented the recent closure of RTOG 0241, a phase III trial testing induction chemotherapy versus concurrent induction chemotherapy and radiation in the setting of resectable stage IIIA NSCLC. Analysis of why this trial failed to accrue is underway. Finally he focused on an upcoming phase III trial, RTOG 0617, testing high dose versus standard dose radiation using 3D conformal technique, in combination with standard paclitaxel and carboplatin. This trial is asking a unique radiation question, and should open in the next quarter of 2007. Dr. Sartor, the new Medical Oncology Co-Chair of the Genitourinary Cancer Committee reviewed a phase III trial in prostate carcinoma (RTOG 0521) testing the role of docetaxel in the setting of definitive RT and androgen suppression. Of 600 targeted for accrual, 80 are enrolled. A more modest phase I/II effort (RTOG 0524) assesses paclitaxel and trastuzumab in combination with radiation as an organ preservation approach: 12 of 88 patients targeted for enrollment have been accrued. Finally, upcoming trials will focus on renal cell carcinoma testing palliative RT to bone and brain, either alone or in combination with sunitinib, a multi kinase inhibitor that has demonstrated efficacy in advanced, metastatic disease. RTOG - Specific DSMB An external Data Safety Monitoring Committee (DSMC) assesses phase III trials on a regular basis in congruence with each biannual meeting. However, to date, we have only enacted an ad hoc internal monitoring strategy for other high-risk studies, generally as dose limiting toxicities (DLT) emerge. Internally, within the group, we have decided to formalize the process, so reviews can be accomplished on a timely basis with both discipline and dispassion. In addition, the NCI has mandated such efforts be undertaken under the cooperative group mandate. This committee will convene at each biannual meeting and hold at least one interim teleconference between meetings, as well as additional ad hoc teleconferences, if significant, unexpected toxicities arise. The Chair of the Committee is Ross Abrams. The Radiation Oncology Co-Chair is Rosemary Wong. Corey J. Langer will be the Medical Oncology Co-Chair with at least one other Medical Oncology designee. The Surgical Oncology Co-Chair remains to be determined. Tom Pajak and Kathryn Winter will represent the statistics office, and Wilma Hoffman will sit in for RTOG Headquarters. Walter Curran, the RTOG Group Chairman, and Mitch Machtay, the RTOG Group Deputy Chairman will remain ex-officio members. The charter of this committee is evolving. It will include all phase I and II trials not covered by the established, external DSMC. Real time monitoring of toxicities, particularly DLTs as well as both acute and late effects, will be emphasized. High-risk trials, in particular, will be the major focus. It is crucial the monitors and reviewers remain as unbiased as possible, and within the group they do not include the disease site chairs or the chairs of studies under review. Triggers for analysis include: (1) all grade 5 toxicities; (2) life threatening grade 4 toxicities, as delineated on AdEERs reports; and (3) unexpected or unusual patterns of toxicity. An emphasis will be placed on combined modality trials. The goals of this group will be both safety and timely review. The group will have an advisory function, with capacity to send out directives and recommendations to the disease site and protocol chairs. In addition, if necessary, it will be empowered to suspend or terminate "toxic" trials, while amendments are reviewed or feasibility revisited. Ultimately, a priori reviews of upcoming trials will be implemented. But first, it is the intention of the committee to monitor those in progress. Potential representatives from the Medical Oncology Committee were solicited. Drs. Rogerio Lilenbaum, Vera Hirsh, and Tarek Mekhail indicated a willingness to participate. Pipeline Presentations: None Combined Modality Reviews Dr. Corey Langer, the Chair of the Medical Oncology Committee, reviewed selected combined modality trials, in both the thoracic and head and neck portfolio. Although accrual to the Lung Cancer Committee has slowly risen from 93 patients per year in 2001 to nearly 400 in 2005, this past year witnessed a downtrend to 327. The imminent opening of RTOG 0617, a phase III trial comparing standard dose RT (60 Gy) to high dose RT (74 Gy) using 3D conformal technique, should help address this lag. In this study, eligible patients will receive concurrent chemotherapy with paclitaxel 45 mg/m2 and carboplatin AUC 2 weekly during RT, followed by 2 two full cycles of adjuvant paclitaxel and carboplatin every 3 weeks. RTOG 0117, a phase I/II dose-intensification study using 3 dimensional conformal RT has laid the foundation for this approach. In this effort, 74 Gy in 37 Fx (2Gy per Fx) was established as the MTD; and early assessment of survival suggests a two-year median. The targeted accrual for the phase III effort is 512 individuals. The primary objective is survival, with hypothesized improvement in survival from a median of 17 months to 24 months, based on phase II trials both in RTOG and elsewhere employing high dose, 3D-conformal technique. Secondary objectives will include PFS; local regional control; toxicity; the prognostic and predictive effects of GTV on survival; quality of life; correlative biomarkers; and a prospective analysis of the predictive value of SUV. Eligibility will stipulate pathologically proven, unresectable or inoperable stage IIIA/IIIB NSCLC, with measurable disease, intact performance status (Zubrod PS 0-1) baseline FEV-1 of > 1.5 liters; and adequate physiologic indices. Dr. Hirsh voiced a concern about the potential inadequacy of consolidative therapy. In her institution, and in many others, 3 or 4 cycles are typically employed. The schema of RTOG 0613 was also reviewed. This is an upcoming effort evaluating the role of adjuvant RT, in combination with bevacizumab or erlotinib after standard adjuvant chemotherapy in patients with resected IIIA and hilar node (+) stage II NSCLC. There are no restrictions on the nature of chemotherapy to be used. The duration of targeted therapy is still under discussion, but will equal at least 1 year in each arm. At this point, adjuvant cytotoxic therapy is the standard approach post resection. However, the role of targeted therapy in the curative setting has not yet been explored. BR 21 has demonstrated therapeutic superiority for erlotinib compared to placebo in the second and third line setting in advanced NSCLC. In addition, ECOG 4599 has shown a statistically significant and clinically meaningful survival benefit for bevacizumab in combination with chemotherapy, compared to chemotherapy alone (paclitaxel/carboplatin) in treatment-naïve advanced NSCLC. Each of these agents will be investigated in the adjuvant setting in upcoming trials, both within the intergroup (CTSU mechanism) as well as outside the RTOG. An upcoming intergroup trial in stage IB - IIIA NSCLC will assess standard platinum-based chemotherapy either alone or in combination with bevacizumab. And the Radiant Trial will test the role of erlotinib versus placebo in the maintenance setting post-chemotherapy in an enriched population with EGFr positivity by either IHC or FISH. The role of radiation in preventing local recurrence in resected stage IIIA (N2) and stage II (hilar N1) NSCLC has not been adequately addressed in modern trials. The ANITA effort suggested an incremental benefit to radiation after vinorelbine and cisplatin, compared to chemotherapy alone in selected patients with stage IIIA resected NSCLC. In addition, a recent retrospective evaluation of the SEER data by Lally et al concluded that radiation could yield a survival benefit in patients with resected stage IIIA NSCLC. Hence, a randomized phase II trial will enable us to assess radiation in combination with the two most crucial targeted agents available in NSCLC, but introduce these agents earlier in resected patients after they complete adjuvant cytotoxic therapy. The statistical hypothesis of this randomized phase II trial is based on a projected 10% absolute improvement in local control and distant control for the addition of targeted therapy to radiation. The statistical assumption is based on RTOG 9705, a phase II trial evaluating concurrent radiation and paclitaxel/carboplatin in the adjuvant setting, which yielded a median progression-free survival of 35.6 months, and a median survival overall of 56 months, with 5-year survival rate of 46%. First site intra-thoracic failure rate was 18%, and first site brain relapse rate was 22%, an inversion of previous patterns of failure observed in ECOG 3590, which compared radiation alone to radiation in combination with etoposide and cisplatin in patients with resected stage II and IIIA NSCLC. The upcoming trial will incorporate a number of correlative markers, which should be relatively easy to obtain, since all of these patients will have undergone resection, with, presumably, abundant tissue for analysis. With 91 patients enrolled in each arm, we should be able to reject the null hypothesis that median progression-free survival is only 30 months, and conclude the alternative hypothesis (median PFS of > 40 months). Assuming 5% of patients are retrospectively ineligible, 85 will be required in each arm. RTOG 0320 is a potentially imperiled trial prospectively randomizing patients with 1-3 brain metastases to a standard approach (whole brain WBRT and SRS), or to WBRT and SRS in combination with temozolomide or erlotinib. Of 381 patients targeted for accrual, 41 have been enrolled as of 1/07; though the numbers are low, there has been a slow but steady increase in accrual over the past 6 months to 3.2 per month. To date, there have been no grade 5 toxicities. By definition all patients on this trial are RPA class 1 or 2. On initial assessment, 60% have no evidence of extra cranial disease. Over 80% have adenocarcinoma. The study, because of relatively poor accrual, has been assessed by the recruitment strategy committee. The provisional mandate to use two full cycles of temozolomide after WBRT/SRS was considered an impediment. At this point, any systemic regimen can be implemented after RT is completed, to help control extracranial progression. In addition, frequent email/fax reminders will be distributed to clinicians and their nurses. Finally, RTOG 0241, a phase III study comparing cisplatin and docetaxel alone to combination cisplatin, docetaxel and pre-op radiation in resectable IIIA NSCLC, was closed because of poor accrual. A proper post-mortem will be performed assessing why the trial failed and glean lessens that can be applied to future studies in this realm. Concerns exist within the RTOG that this organization may have intrinsic difficulty mounting studies comparing a radiation treatment arm to a no-RT treatment arm. Head and Neck studies were also reviewed. Based on the Bonner trial (NEJM 2006) which showed a statically significant, clinically meaningful local regional control advantage and survival advantage for C225, in combination with RT, versus RT alone, the RTOG has mounted two separate trials incorporating C225. RTOG 0234 is a randomized phase II assessment in high risk patients evaluating post-op radiation in combination with weekly C225 and either weekly cisplatin or weekly docetaxel. This trial recently completed accrual, with over 230 patients enrolled. The upcoming replacement trial will likely incorporate a multitargeted TKI in combination with RT and platinum. An ongoing, phase III trial is also evaluating cetuximab in the locally advanced, unresectable or unresected setting. As background, RTOG 0129, a phase III trial comparing standard fractionated RT (70Gy/35Fx) to accelerated fractionation with concomittant boost with full dose cisplatin in each arm completed accrual ahead of schedule in July of 2005. At the first interim analysis, there was no reason to unblind the results. Overall survival, to date, appears to be better than initially anticipated, and may have an impact on the design of future trials. The current phase III effort (RTOG 0129) is accruing robustly. This trial evaluates accelerated fractionation and concomitant boost RT, with full dose cisplatin, either alone or in combination with C225. As of 2/07, 109 of 720 patients targeted have been enrolled. The average monthly accrual is 7.1 patients per month, with an average accrual over the last 6 months of 11.5 patients per month. In addition, the RTOG is initiating a phase II trial (RTOG 0615) grafting bevacizumab onto standard treatment for nasopharyngeal carcinoma. This trial features 3D conformal RT and IMRT, and employs full dose RT (70 Gy/ 35Fx) with concomitant cisplatin/bevacizumab followed by 3 cycles of adjuvant cisplatin, 5 FU and bevacizumab, then maintenance bevacizumab for an additional 8 cycles. This trial is based on a prior intergroup phase III effort published by Al Sarraf et al (JCO 1998; 1310-1317), which demonstrated a tremendous survival advantage for concurrent and sequential therapy versus RT alone, with 3-year survival rates of 70% and 47% respectively, despite poor compliance to adjuvant chemotherapy. The current trial is slated to accrue 46 patients. Finally, RTOG 0421 was shut down because of poor accrual. This study compared split course BID re-irradiation in combination with cisplatin and paclitaxel to chemotherapy alone. It was based on RTOG 9911, a phase II effort, which demonstrated a 52% 1-year and 25% 2-year survival rate for the split course, platinum- based approach. Post Mortem Analysis of RTOG 0421 Dr. Wong conducted an analysis to determine the factors responsible of the demise of this trial. Although this randomized trial was activated in April of 2005, only 15 patients were accrued, in contrast to previous RTOG re-irradiation studies which enrolled roughly 3 patients per month. A number of potentially contributing factors were analyzed. In aggregate, it did not appear to be resistance on the part of medical oncologists. The chemotherapy agents targeted for use were standard. In addition, in a survey of head and neck surgeons, the absence of any proviso for debulking did not seem to hamper accrual. Nor did site activation. The ratio of sites that activated this trial to patients accrued was 5 to 1. However, several sites were concerned about potentially restrictive entry criteria, including the need for histologic confirmation and measurable tumor. In a survey, off protocol use of re-irradiation was found in 80% of 45 respondents, although only 29% had a clear bias in favor of re-irradiation. A similar trial was conducted by the Groupe D'Etude Des Tumeurs De La Tete et Cou [GORTEC]. This study likewise closed because of poor accrual; only 46 patients were enrolled over a 4 year period. A general bias favored re-irradiation in this setting, hampering overall accrual. A proposal has been made to combine the GORTEC and RTOG data for analysis. Regardless, a number of lessons have been learned. Re-irradiation in this setting is gaining increasing acceptance, even in the absence of phase III data. Given the relative paucity of patients with localized recurrence, and given the underlying biases that exist, it is likely impossible to launch a properly mounted, prospective phase III effort in the future. Upcoming phase III studies will likely incorporate targeted agents, as well as alternative schedules and new RT technologies including 3-D conformal, IMRT, etc. RTOG 9911 has established the benchmark, with a 2-year survival rate of over 25%. Future trials will need to match these results, hopefully with less toxicity. At least one concept to date has proposed the use of cetuximab, in lieu of chemotherapy, with RT. Whether to graft this onto the established BID split course regimen or proceed with continuous RT is an outstanding question. Protocol Service Announcement (PSA) Dr. Michael Seider of Akron City Hospital reviewed RTOG 0517, a randomized prospective phase III trial of Zoledronic Acid either alone or in combination with systemic radionuclides. This study had previously been endorsed by the Medical Oncology Committee and just opened to accrual. To date, nine patients have been enrolled. Grant Renewal Strategies Finally, Dr. Langer reviewed "practice slides" for the upcoming grant renewal. The leadership in Medical Oncology Committee has turned over since the last site visit. Corey Langer has assumed the chairmanship from Jaffer Ajani. In addition, Michael Goodyear has taken over for Corey Langer as Medical Oncology Quality Control Chair. Stuart Wong has assumed the mantel of Head and Neck Medical Oncology from Edward Vokes; and Oliver Sartor has taken over from Ken Pienta as Genitourinary Cancer Committee Chair. David Ettinger remains the Thoracic Medical Oncology Chair, and Al Yung, the Neuro-Oncology Medical Oncology Chair. Over 65% of current RTOG trials incorporate systemic therapy. With the exception of the Genitourinary Cancer Committee, the majority of studies in each of the site-specific committees feature systemic therapy. Over the past 5 years, we can also highlight a number of accomplishments: (1) participating in the eligibility criteria task force, deleting de facto dis-qualifiers from entry criteria and further streamlining selection criteria, etc.; (2) M5 Task Force, clarifying compliance issues, and modernizing definitions of protocol violations; (3) Ongoing ad hoc Data Safety Monitoring analyses; (4) Developing early stopping rules and strategies to spur recruitment for major studies with sluggish accrual; and (5) Helping to spearhead investigations into hitherto unexplored territory. For instance, both RTOG 9610 and 9911 have evaluated the role of re-irradiation in combination with chemotherapy in locally recurrent, previously radiated head and neck cancer; and an ongoing study evaluates WBRT and systemic therapy, either alone or in combination with temozolomide or erlotinib, for solitary and oligo- brain metastases. In addition, this committee has helped to spearhead supportive care and quality of life studies and has performed an advisory function to the Outcomes Committee with respect to feasibility and safety. RTOG 0435 is a randomized phase III effort in locally advanced SCCHN evaluating standard radiation-based therapy with or without palifermin in an attempt to lesson mucositis. RTOG 0517 is a phase III effort assessing the role of samarium or strontium in combination with zoledronic acid versus bisphosphonate alone in patients with established, symptomatic bone metastases. The committee has also featured multiple pipeline speakers over the past several years; these individuals have acted as a conduit to discuss new, potentially promising therapies within the RTOG. In addition, the Medical Oncology subcommittee has helped to troubleshoot studies in jeopardy. Strengths of this committee include the ease of collaboration between medical and radiation oncology; the ability of this committee to introduce new agents into the cooperative group; and evolving paradigms for quality control and therapeutic monitoring. Weaknesses include a somewhat challenging lack of cumulative experience in certain areas, with an obvious need to recruit new blood; and the absence of developmental therapeutics. Opportunities include the capacity to focus on new systemic agents with unique radiosensitizing properties; strategies to improve the portal of entry for new targeted agents that promise to alter the therapeutic paradigm, e.g. cetuximab, bevacizumab, small molecule TKIs (erlotinib, sorafenib, etc.); developmental therapeutic and bio-correlative sub-committees; improved collaboration with TRP; and potential implementation of "drug only" trials in venues neglected by other cooperative groups, (e.g. relapsed GBM). The only perceived threats are competing cooperative group trials and trials spearheaded by industry that target the RTOG patient population. MEDICAL ONCOLOGY COMMITTEE (January, 2006) Corey Langer, M.D., Chair Approximately 70 individuals attended the meeting. Once more, Dr. Langer reviewed the subcommittee mission. Cross fertilization of concepts and ideas between various disease-specific subcommittees. Introduction of new systemic agents and radio-sensitizers into the RTOG. Investigation of new therapeutic territories, for instance the role of chemotherapy and bisphosphonates in preventing bone metastases or combination chemotherapy and re-irradiation in locally recurrent SCCHN. Vetting protocols: reviewing systemic options, concomitant medications; dose modification criteria; eligibility stipulations; compliance obstacles. Recruitment of new blood, including committee volunteers and replenishing the pool of principal investigators In addition, Dr. Langer reviewed the results of a task force to determine reasonable early stopping rules for ongoing clinical trials, as well as the implications of and ongoing eligibility criteria task force, whose charge is to streamline entry criteria to RTOG protocols, make them more user-friendly. In this vein, Kathryn Okrent from protocol development at RTOG headquarters, (215) 717-0856, kokrent@phila.acr.org described a CTEP initiative, focusing on standardization of adverse event forms, and implementation of "evidence-based" approaches in cooperative group trials. It is hoped, over time, that these AE and CRF forms will be standardized across all cooperative groups. Quality Control Subcommittee Dr. Michael Goodyear of Dalhousie University in Nova Scotia, the Chair of the Medical Oncology Quality Control Committee, updated the group on pertinent issues. During the period 1/1/05-12/31/05, 986 reviews were completed, compared to 1615 in 2004. The overall compliance remains 97%, stable over the past 3 years. Since the most recent meeting, a new review form has been introduced, but it is too early to determine whether this form has yielded any substantial differences in compliance. In addition, Dr. Goodyear discussed CD-based reviews, which, at this point, are felt to be the most efficient mechanism for assessment of CRFs. He encouraged principal investigators conducting reviews to provide feedback to headquarters on the process, both its utility and convenience. Pipeline Discussions Imclone Trials Dvorit Samid from Imclone discussed a number of issues. She first focused on cetuximab. She described a crucial, recently completed phase III trial in head and neck cancer comparing radiation alone to combined radiation and cetuximab, which yielded a statistically significant improvement in disease free survival and overall survival (p=0.03, HR 0.74) with no exacerbation of mucositis. The cetuximab arm featured a relatively low incidence of HSR (3%), albeit increased rate of phase III acneiform rash (18% versus 1%). The severity of rash in this effort appeared to correlate with survival. However, baseline EGFr levels did not predict response to cetuximab. The mechanism of action is believed to be related to upregulation of EGFr, with importation into the cell nucleus, subsequent inhibition of DNA repair, via DNA-dependant kinases. In early March, and FDA decision regarding approval of this agent is anticipated (it has since been approved for use in HNC in this setting). Multiple studies, both within RTOG as well as other cooperative group based efforts and investigator initiated trials, are exploring the role of this agent in thoracic and pancreatic cancers, as well as head and neck malignance. An ongoing phase III trial is evaluating gemcitabine +/- cetuximab in pancreatic cancer. Other trials are assessing the role of cetuximab in combination with chemoradiation in the neoadjuvant therapy of rectal carcinoma. Finally two separate RTOG efforts are honing in on SCCHN: (1) one [RTOG 0234] in the adjuvant setting, evaluates RT plus cetuximab and either weekly docetaxel or weekly cisplatin; (2) the other, [RTOG 0522], a flagship effort, which has just been initiated, will compare chemoradiation with cisplatin to chemoradiation plus cetuximab. The latter is crucial study, since our standard approach in fit patients with locally advanced disease remains platinum- based chemoradiation. The second topic of discussion centered on a monoclonal antibody (MAb) targeting insulin growth factor receptior (IGFR), which is undergoing phase I and phase II development in solid tumors. IGFR appears to have an anti-apoptotic effect, with the induction of pro-survival CLU proteins. A-12, an IgG1MAb, has a relatively high affinity for IGF-1R on tumor cells, but does not appear to bind to human insulin receptors. In preclinical models, it has demonstrated broad activity. In addition, in early studies, this agent has demonstrated a capacity to bind to the receptor, internalize the receptor, and trigger its degradation. There is also evidence of synergy between A12-IgG1 and cetuximab in BXPC-3 and prostate models. Finally, Dr. Samid focused on IMC-121B, an antibody targeting VEGFR-2. This antibody, unlike bevacizumab, targets the receptor, rather than the ligand. In phase I studies, it has been well tolerated. In addition, it appears to be compatible with cetuximab as well as antibodies targeting IGFR. The full human antibody binds VEGFR and inhibits the growth and migration of human endothelial cells. Current phase I studies are testing both weekly and every other week schedules. In mouse xenografts, it has demonstrated synergy with C225. An ongoing study is evaluating the capacity of this agent to work synergistically with radiation. Genentech Trials Dr. Robert Mass of Genentech reviewed multiple studies to date evaluating bevacizumab. This antibody which targets vascular endothelial growth factor ligand has been shown to reverse abnormalities in malignant vasculature. In xenograft models, it has demonstrated additively, if not synergy, with multiple cytotoxics, including cisplatin, doxorubicin, pemetrexed, 5FU, and gemcitabine. In the vast majority of xenografts, there is absolutely no evidence of antagonism, while potential reversal of CT resistance had been seen. In H226, the combination of bevacizumab and radiation proved superior to either modality alone, and far superior to vehicle. In SW620, a colorectal carcinoma xenograft, the combination of 5 fluorouracil, irinotecan, and bevacizumab has been shown to suppress tumor growth as well. In clinical practice, bevacizumab has altered the natural history of colorectal carcinoma, metastatic breast carcinoma, and NSCLC. In phase III studies, the addition of bevacizumab, led to statistically significant improvement in overall survival, with hazard ratios of 0.66 (colorectal carcinoma); 0.82 (breast carcinoma); and 0.9 (NSCLC). Finally in renal carcinoma, compared to placebo, bevacizumab has resulted in a significant survival advantage with HR of 0.36. As a single agent, it has demonstrated activity in breast cancer, and in particular, in ovarian cancer, with response rates approaching 18%. To date, there are no reported responses to single agent bevacizumab in lung cancer. Ongoing studies are assessing the role of this agent in the first line setting in RCC, in pancreatic carcinoma, ovarian cancer, and hormone-refractory prostate carcinoma, as well as GIST. This agent is being used in combination with other agents in recurrent GBM. In addition, recently launched studies will assess bevacizumab, in combination with cetuximab. Ongoing phase I/II studies are further defining the role of bevacizumab in combination with 5FU and radiation in metastatic colorectal carcinoma. Others are assessing combination bevacizumab and capecitabine in pancreatic cancer. In SCCHN there may be some exacerbation of stomatitis and localized bleeding, particularly in patients who have been previously radiated. Finally, in locally advanced NSCLC, SWOG has launched a three tier trial evaluating standard chemoradiation (EP/RT ' Doc) followed by bevacizumab, with subsequent cohorts receiving bevacizumab either halfway through the course of RT or, ultimately, at the very beginning. In this matter, the SWOG will determine whether this drug can be combined safely with radiation, and given to individuals with squamous carcinoma, without inducing untoward hemorrhage. Ongoing studies will also assess bevacizumab, either alone or in combination with erlotinib in maintenance phase in patients who have sustained either stable disease or response after initial cytotoxic therapy. Finally, this agent has yielded responses in GBM, in which there have been episodes of HTN, but no bleeding. RTOG looks forward to further development of this agent in combination with XRT, and in combination with chemoradiation in multiple disease sites. Protocol Service Announcements To complete the meeting, the heads of the Medical Oncology committee highlighted two separate studies: one effort, RTOG 0241, compares chemotherapy alone to chemoradiation in the induction setting in patients with potentially resectable stage III a NSCLC. This trial, for unclear reasons, is accruing poorly, with only 3 patients enrolled to date. If enrollment does not pick up, its fate remains in question. RTOG 0421 compares chemotherapy du jour, either paclitaxel or docetaxel in combination with cisplatin or 5FU infusion plus cisplatin to split course hyperfractionated XRT every other week, in combination with daily, low, radiosensitizing doses of cisplatin and paclitaxel. The later regimen has been phase II tested within the RTOG (RTOG 9911), and has yielded a 2 year survival rate of 25% compared to 17% for historic controls (RTOG 9610) with 2 year survival rate more than double the historic figures observed with chemotherapy alone in patients with locally recurrent, previously irradiated tumor. MEDICAL ONCOLOGY COMMITTEE (June, 2005) Corey J. Langer, M.D., Chair The meeting was convened at 6:00 PM on Friday evening on 6/24/05. Approximately 45 individuals attended. Dr. Langer reviewed the subcommittee mission: 1. Cross-fertilization between various disease-specific subcommittees. 2. The introduction of new systemic agents and radio sensitizers into the RTOG. 3. Investigation of new therapeutic territories and venues, e.g. the role of chemotherapy in patients with bone and brain metastases, or combined with re-irradiation in recurrent head and neck cancer. 4. Vetting protocols, including appropriate systemic options, supportive care strategies, dose modifications, eligibility, and obstacles to compliance. 5. On-going recruitment of “new blood,” to help revitalize both the committee and the cooperative group. To this end, Joanne Ley reviewed a new scoring system to gauge quality control, which should prove simpler and more comprehensive than our prior strategies. The first step will be to determine if treatment has been given per protocol; this will categorize treatment accordingly: a) no modifications; b) dose modification and or delays according to protocol specifications; c) recognized reasons for early discontinuation of treatment, including death, disease progression or untoward toxicity. The second designation will be “not per protocol,” including: a) Modifications or delays that exceed protocol parameters and in which doses administered are less than 80% of the target dose for one or more agents. b) Discontinuation of treatment for non protocol reasons, including patient refusal, non-compliance, MD discretion, co-morbidities, with reasons specified. This new format will be piloted during upcoming trials, and revamped as necessary. Quality Control Subcommittee Dr. Michael Goodyear of Dalhousie University in Nova Scotia, the Chair of the Medical Oncology Quality Control Committee, updated the group on patient issues for the period 1/05 through 6/05. 310 reviews were completed during this period, with a compliance rate of 99%, the best in recent memory. Case backlog remains an obstacle, though some headway has been made with directed efforts to have individual investigators complete CRFs on a timely schedule. In addition, revisions of the prior format for medical oncology reviews are being implemented; and a more pro-active strategy to deal with reviews that are behind schedule has been initiated, incorporating a series of warning letters, with a policy to re-assign authorship to other committee oncologists if the primary reviewer is unable to complete reviews in a timely fashion. This approach will be codified proactively, and untoward delays dispatched quickly. Tribute was paid to Elaine Motyka, Director of Data Management, who has been a key individual in implementing these changes, but who is leaving Philadelphia for Seattle, Washington. Joanne Ley and others will help spearhead the program from this point on. Pipeline Discussions Michael Hamilton of GSK reviewed the potential role of SB-497115, an oral platelet growth factor. This agent, a thrombopoietin receptor agonist, has been shown to stimulate megakaryocyte proliferation and differentiation. It is orally bioavailable, given once daily, and non-immunogenic. Dose dependent activity has been shown in human bone marrow cells. Its access to megakaryocyte has been mediated by TPO transmembrane receptor. In chimpanzees, daily dosing has led to sustained elevations of platelet counts. Similar responses have been observed in humans. Toxicities are minimal, although there are reports of headache. There do not appear to be any dose dependent toxicities or dose limiting effects. Nor is there CYP 450 interaction. In humans, this agent has an indication in the treatment of ITP, and, ultimately it is hoped, in solid tumors. Study 003 paired this agent with standard doses of paclitaxel and carboplatin to test feasibility. SB-497115 was given continuously, days two through eleven, with no overt toxicity. Future efforts will assess this agent in combination with more myelosuppressive regimens, e.g. gemcitabine and carboplatin, as well as marrow ablative approaches. Jeannie Hou from Astra Zeneca explored the potential role of ZD6474 a new targeted agent with proven activity in NSCLC. This agent, a dual kinase inhibitor, targets VEGFr, and EGFr with relatively low IC50s for KDR, FLT-4, and EGFr, and some cross-reactivity with PDGFr. In-vivo, this agent has demonstrated broad, dose-dependent activity in lung cancer (Calu-6), prostate cancer (PC-3), breast cancer (MDA-MB-231), colon cancer (LoVo), ovarian cancer (SKOV-3), and vulval malignancy (A431). In phase I studies, objective responses have been seen in 4 of 9 NSCLC patients tested, with duration of response ranging from 126 to 562 days. [Minamih et al, Proc of ASCO 2003]. Randomized phase II studies are comparing this agent to gefitinib, and are assessing this agent in combination with docetaxel versus docetaxel alone. A separate phase II trial is evaluating standard paclitaxel and carboplatin either alone or in combination with ZD-6474. Phase II trials are ongoing in breast cancer and myeloma, and are planned in renal carcinoma, GBM, thyroid carcinoma and SCLC. Preliminary data from study six, a randomized phase II effort assessing this agent at a dose of either 100 mg or 300 mg in combination with docetaxel vs single agent docetaxel, have demonstrated conclusive improvement in time to disease progression (18.7 weeks vs 12 weeks, p value of < 0.05). An objective response rate of 26% has been observed for low dose ZD6474 and docetaxel vs 12% for single agent docetaxel; and at six weeks, the disease control rate is 83% vs 56% for the reference arm. Common toxicities include stereotypical rash and diarrhea, with generally asymptomatic prolongations of the QTc interval. A slight increase in grade 1-3 HTN has also been observed. Full results will be reported at the IASLC meeting in July. This agent will likely undergo a registration trial in advanced NSCLC. Site Specific Committee Reports Drs. Goodyear and Safran reviewed ongoing GI cancer committee trials. Dr. Ettinger performed a similar task for the Thoracic Group. Two separate PCI trials are ongoing: 1) one in limited SCLC, tests different doses and schedules; 2) a much larger trial for patients with locally advanced NSCLC, in patients with no evidence of disease progression, compares PCI to standard observation. Accrual to the latter effort has been sluggish. A phase I trial integrating a fixed dose of cisplatin with BID RT (45 Gy) or single daily RT (70 Gy) in combination with escalating doses of irinotecan is nearing completion. Finally, a phase III trial evaluating the role of induction therapy prior to surgical resection in stage IIIA NSCLC has just been opened. This trial will test indication therapy pre-resection with combination docetaxel and cisplatin alone or combination docetaxel, cisplatin and RT followed by consolidative therapy post resection and docetaxel, with pegfilgrastim support. ASCO Reviews - GI Dr. Safran reviewed pertinent studies from the recent ASCO meeting. The MAGIC trial in esophageal and gastric cancer featured randomization to either surgery alone or surgery combined with 3 cycles of adjuvant and neoadjuvant epirubicin, cisplatin and 5FU (ECF). This trial demonstrated a statistically significant improvement in long-term survival: 36% versus 23%. A similar trial in esophageal cancer (V325) randomized patients to either 5FU and cisplatin at full dose, or to somewhat attenuated doses in combination with docetaxel. Early analysis showed a statistically significant improvement in survival (p=0.0064) with a hazard ratio of 1.50 favoring the triple drug regimen. These trials have cemented adjuvant therapy as part of the standard paradigm in resected esophageal and gastric cancer and strongly suggest a potential benefit for docetaxel or epirubicin in combination with standard 5FU and cisplatin. ECOG 3200 allocated patients with previously treated colorectal carcinoma to FOLFOX x 4 alone or to FOLFOX in combination with bevacizumab. Similar to a trial in NSCLC (ECOG 4599), the addition of bevacizumab yielded a statistically significant improvement in median survival (12.5 versus 10.7 months, p=0.0024). Grade 3 HTN in over 5% of patients and bowel perforation in 1% were the major toxicities observed in the bevacizumab arm. A similar trial evaluating PTK787 in combination with chemotherapy versus chemotherapy alone failed to yield a significant improvement in either PFS or OS. A phase III trial in pancreatic carcinoma compared gemcitabine to combination gemcitabine and capecitabine. The response rates were slightly higher for the doublet: 10.1% versus 7.9%, with median survival of 8.4 versus 7.3 months. In those with baseline KPS of 90 or 100, a significant improvement in median survival was observed: 10.1 versus 7.5 months, (p=0.033). The CONKO-001 trial in resected pancreatic carcinoma compared adjuvant gemcitabine to observation. Over 350 patients were accrued to this effort. This trial yielded a statistically significant improvement in disease free survival: 14.2 versus 7.5 months (p=<0.001). DFS benefit was observed regardless of N status or resection status (R0 versus R1). Finally, a large effort in pancreatic carcinoma comparing gemcitabine plus placebo to gemcitabine plus erlotnib demonstrated a statistically significant, but clinically questionable improvement in median survival (6.37 versus 5.9 months) with one year survival rates of 24% and 17% respectively (p=0.025, HR 0.81). This trial may have actually been somewhat “over-powered.” Ongoing efforts are evaluating gemcitabine in combination with GW 572016 (lapatinib), a dual Erb B1 – Erb B2 inhibitor; a separate trial is assessing this combination with oxaliplatin. To date, it is evident that full dose lapatinib can be given with gemcitabine; with the exception of diarrhea and nausea, there have been no other significant toxicities. Fairly striking responses have been observed in hepatic metastases from pancreatic carcinoma. Thoracic Studies Finally, Dr. Langer reviewed major papers from the thoracic plenary sessions at ASCO. The ANITA trial (Adjuvant Navelbine International Trialist Association) compared standard observation to combination vinorelbine and cisplatin in resected stage I-III NSCLC (Douillard et al, ASCO 2005 A-7013). This was the third largest adjuvant trial ever mounted in resected NSCLC and the second largest to show a survival benefit. 840 patients were accrued over a 6 year period ending in 2000. Patients over the age of 75 were excluded. Nearly 60% has squamous histology, and over 85% were male. The patients were equally distributed by stage (I-35%; II-30%; III-35%). The vinorelbine/cisplatin group had a 22 month improvement in median survival. At 5 years, the adjuvant group enjoyed an 8% absolute improvement in survival (51% versus 43%) and at 7 years an 11% improvement in survival (48% versus 37%). The hazard ratio was 0.76. This benefit was confined largely to patients with stage II and III disease, with minimal, if any benefit in stage I. However, substantial toxicity was observed: 1 in 8 patients sustained febrile neutropenia, and over 25% had grade 3 and 4 nausea and vomiting. This trial now joins the IALT, CALGB, and NCIC trials, each of which has shown a therapeutic benefit for adjuvant treatment post resection. Compliance to treatment mirrored that observed in the NCIC trial, with 76% of intended platinum delivered, but only 56% of intended vinorelbine administered. Pisters et al, reported a preliminary analysis of SWOG 9900, a randomized phase III trial evaluating surgery alone versus surgery preceded by induction chemotherapy with paclitaxel and carboplatin. This trial originally targeted 600 patients for accrual, but was discontinued early, when it was felt that the surgery only control arm was no longer “ethical.” Final accrual was 356 patients. At a median follow-up of just over two years, the pCR rate in the neoadjuvant group was 10%; progression free survival trended favorably for the neoadjuvant group: 31 months versus 20 months, but the two year survival differences (69% versus 63) were not statistically significant (p=0.32), largely because of aborted accrual resulting in decreased statistical power. Ongoing efforts will determine whether a role exists for EGFr inhibitors or angiogenesis inhibitors in combination with chemotherapy in resected NSCLC patients. An alternative strategy pits induction therapy versus adjuvant treatment. Although two year survival results in the SWOG trial are very similar to those observed in the adjuvant trials (70% for IALT, 68% for ANITA), it should be noted patients eligible for neoadjuvant therapy are not identical to those who typically enroll on adjuvant trials. The latter weeds out patients with significant perioperative co-morbidities, as well as those whose disease may have progressed immediately after surgery. Finally, in many parts of Europe, the role of adjuvant treatment, readily accepted now in the US, has not completely caught on. For instance the NATCH trial, comparing surgery alone to surgery combined with either induction or adjuvant chemotherapy, continues to accrue. Unresectable Locally Advanced NSCLC In locally advanced NSCLC, concurrent chemoradiation has become the standard approach. Three separate clinical trials have shown a survival advantage for concurrent chemoradiation compared to sequential therapy, with a 6-8% absolute improvement in 5-year survival rates (16% versus 9 or 10%) in the two largest efforts (p values of 0.04 and 0.038). The chief drawback remains local, normal tissue toxicity, particularly esophagitis. At this year’s meeting, an update of SWOG 9504 was presented by Gandara and colleagues. This trial employed a standard platform regimen of induction RT, etoposide (E) and platinum (P) followed by consolidative docetaxel (D). In the initial report, the 3-year survival rate was 37%, far better than the historic control of 17% observed in SWOG 9019 (EP/RT?EP). At this year’s ASCO meeting, mature 5-year survival figures were presented with an actual survival rate of 29% in long term follow-up. The role of consolidative therapy, however, has never been formally phase III tested. The Hoosier Oncology Group is currently conducting a phase III trial determining whether docetaxel in the consolidative setting is superior to observation after EP/RT. SWOG 0023, presented by Karen Kelly and colleagues evaluated the role of maintenance EGFr inhibition versus placebo after definitive therapy. 620 patients were accrued to this effort. All received the RTOG 9504 platform regimen: concurrent RT, etoposide and platinum followed by docetaxel, and were then randomized to either gefitinib or to placebo. Although 80% or more of patients were projected to go onto maintenance treatment, fewer than half of those initially enrolled successfully completed randomization and initiated treatment. The overall median survival in this trial was only 19 months, far lower than that observed in SWOG 9504. Moreover, while progression- free survival was “equivalent” in the gefitinib and placebo arms (11 vs 10 months, p=0.54), overall survival in the gefitinib arm trended worse compared to the placebo group: 19 months versus 29 months, (p= 0.09). Because of these observations, the trial was closed by the DSMC; it was realized that the chance that gefitinib would ever show a survival benefit was <.01%. The reason for this paradoxical result remains unclear. Of the 100 patients enrolled in the gefitinib arm, therapy-related deaths occurred in only 2%, although there was an increase in grade 3 pneumonitis. The majority of deaths in the gefitinib arm were due to underlying disease, which appeared to occur more commonly in the gefitinib group compared to the placebo. The reason for this remains unclear. There may have been unintended clinical or molecular imbalances. Ongoing investigations will focus on molecular analysis for EGFr mutation, FISH, IHC, and K-ras. Role of Surgery in Stage IIIA NSCLC An update of RTOG 0139 was presented by Kathy Albain and colleagues. This trial tested the role of surgery after chemoradiation in locally advanced, stage III NSCLC. Patients underwent induction therapy with thoracic RT (45 Gy) plus cisplatin and etoposide and were randomized, at that point, to either surgical resection or to continuation of RT to 61Gy without interruption. Patients on both arms received consolidative therapy with etoposide and cisplatin. Albain first presented preliminary data 2 years ago, at which time the 3 year survival rate was 38% for the trimodality arm versus 33% for the chemoradiation arm (p=0.51); at this year’s meeting, 5 year survival rates were 27% and 20% respectively (p=0.24). Although progression free survival was significantly better in the trimodality arm, it also had a higher incidence of treatment-related deaths (7.9% versus 2.1%). On this basis, although long term survival may be trending better for the trimodality arm, the difference will likely never prove statistically significant. Independent favorable prognostic factors included female gender and absence of weight loss. Lobectomy patients had significantly better outcome compared to matched controls on the non-surgical arm with 5 year survival rates of 36% and 18% respectively, (p=0.002), whereas pneumonectomy patients faired poorly compared to matched controls in the non-surgical arm. The median survival and 5 year survival rates were 19 months and 22% for the pneumonectomy patients on trimodality arm versus 29 months and 24% for the bi-modality arm (p=NS). Those with N0 disease in the trimodality arm had a 5 year survival rate of 41% compared to 24% for those with residual nodal involvement and only 8% for those in that arm who did not undergo surgical resection despite being randomized to the surgical arm. The incidence of local and or nodal failure was 23% in the bimodality group compared to 10% in the trimodality group. The implications of this effort are myriad. In the absence of survival benefit, and in recognition of a high rate of peri-operative morbidity and mortality, many would argue that these results reinforce concurrent chemoradiation alone as the standard of comparison. On the other hand, given a trend toward improved survival, and significantly better progression-free survival, others would justify trimodality therapy as the favored approach, especially in lobectomy candidates. Given relatively poor compliance, one must also ask whether consolidative chemotherapy after chemoradiation alone or after chemoradiation and surgery is necessary. A follow-up trial (RTOG 0333), which just recently opened, randomizes patients before surgical resection to either chemotherapy alone (docetaxel and cisplatin) or to combination chemotherapy (docetaxel and cisplatin) and RT. Patients in each arm go on to receive single agent docetaxel and pegfilgrastim support in the consolidative setting. This trial will definitively test whether radiation has a role in the induction setting. Targeted Therapy Although the ISEL trial was not formally reported at ASCO, the results failed to show a statistically significant survival benefit for gefitinib in the second and third line setting compared to placebo control. Nearly 1700 patients were randomized in a 2 to 1 fashion to gefitinib or to placebo. Median and 1-year survival rate was 5.6 months and 27% for gefitinib plus best supportive care (BSC) versus 5.1 month and 22% for placebo plus BSC. In the adenocarcinoma subgroup, the relative median survivals were 6.3 and 5.4 months (p=0.07). Therapeutic benefit was limited to Asians and patients with limited or no smoking history. It is unclear why ISEL proved (-), when BR21, a similar study with erlotinib proved (+). It should be noted that there were fewer prior responders to cytotoxics on the ISEL effort. There may have also been other demographic differences. Finally, gefitnib was dosed substantially below the MTD, whereas erlotinib was not. The SPIRIT trials tested chemotherapy alone versus chemotherapy combined with Bexarotene, a selective activator of RXR receptor. The largely North American trial used paclitaxel and carboplatin as the platform regimen, while the European trial employed cisplatin and vinorelbine. Neither trial showed a survival benefit, and both trials demonstrated substantial toxicity, including elevations in cholesterol and triglyceride level, and, in the North American trial, increased asthenia, dehydration and leukopenia. A retrospective analysis of those patients who sustained elevations in triglyceride despite prophylactic therapy (e.g. Lipitor) showed an improved outcome with median survival exceeding 12 months, compared to subgroup with no elevation of triglycerides levels (median survival 6.9 months). To date, however, there is no a priori predictor of subsequent treatment-induced elevations; hence, the therapeutic implications of this observation remain unclear. Finally, ECOG 4599, a randomized intergroup effort comparing standard paclitaxel and carboplatin to the same combination with bevacizumab demonstrated a statistically significant survival advantage for the bevacizumab containing arm. This is the first positive trial of a targeted agent in the setting of treatment-naïve, advanced NSCLC, and the first positive trial for angiogenesis inhibition in the treatment of NSCLC. This trial design was based on a randomized phase II study that evaluated chemotherapy either alone, or combined with low or high dose bevacizumab every three weeks. 6 out of 99 patients enrolled on this effort sustained life threatening hemorrhages; 4 proved fatal. Risk was increased in patients with squamous histology. But in the non-squamous carcinoma cohort, median survival in the group receiving high dose bevacizumab (15 mg/kg) every three weeks in combination with paclitaxel and carboplatin was 77 weeks, which proved quite promising compared to historic controls of 34-36 weeks in SWOG and ECOG trials evaluating chemotherapy alone. On this basis, ECOG 4599 was launched. 855 patients with non-squamous histology, no ongoing need for therapeutic anti-coagulation or history of CNS metastases were randomized either to standard chemotherapy alone (paclitaxel 200 mg/m2, carboplatin AUC6 every three weeks) or to the same combination with bevacizumab (15mg/kg q 3 weeks). Unlike the phase II trial, crossover to bevacizumab in the control arm was not permitted. Both arms were well balanced demographically: 54% of patients were male; 44% were 65 years or older, and 86% had stage IV or recurrent disease. The bevacizumab arm yielded superior median survival: 12.5 months versus 10.3 months for the control group, with 1 and 2 year survival rates of 52% and 22% for PCB versus 44% and 17% for PC respectively (p=0.007). A similar improvement in progression-free survival was observed: 6.4 months for PCB versus 4.5 months for PC (p<0.0001). In addition, the PCB arm had a response rate of 27% compared to only 10% for the control group. Hemorrhages occurred more often in the PCB arm: 3.8% versus 0.8%; 5 deaths due to pulmonary hemorrhage occurred in the PCB arm compared to none in the control group. There was also an increased incidence of grade 4 neutropenia (24% versus 16%), and febrile neutropenia (3% versus 1.9%), and hypertension (6% versus 0.7%), but no increase in the incidence of venous or arterial thrombosis. Treatment differences were validated across all major subgroups, including stage, prior weight loss, prior radiation, race, performance status and age, but inexplicably, despite a statistically significant improvement in progression-free survival and response rate, women receiving bevacizumab did not appear to have much survival benefit (p=0.8), whereas men had a striking survival benefit (p=0.003). The reason for this difference in survival benefit by gender remains unclear. There may have been an unintentional imbalances in demographic or prognostic factors; there may have also been as yet undiscovered molecular imbalances. Finally, there may have been differences in the use of second and third line treatment, in particular EGFr TKIs, which are known to work better in women. Unlike multiple previous efforts evaluating targeted therapy in combination with chemo du jour versus chemotherapy alone, this is the first to show a survival benefit. In addition, virtually all the other trials were conducted by pharmaceutical companies, whereas this trial was one of the first amongst the cooperative group efforts to evaluate a targeted agent in this setting. At this point, separate phase II and phase III studies will need to be conducted in patients who do not meet the eligibility criteria for ECOG 4599 (e.g. squamous histology, treated brain metastases, etc.) Baseline brain scans at this point are de rigeur in patients that are about to receive bevacizumab for NSCLC. In addition, tremendous interest has emerged in evaluating this agent in the adjuvant and locally advanced setting. MEDICAL ONCOLOGY COMMITTEE (January, 2005) Corey J. Langer, M.D., Chair The meeting convened at 11:00 A.M; nearly 100 attendees were present. Dr. Langer reviewed the subcommittee mission: Cross fertilization of concepts and ideas between various disease-specific subcommittees. Introduction of new systemic agents and radiosensitizers into the RTOG. Investigation of new therapeutic territories, for instance the role of chemotherapy and bisphosphonates in preventing bone metastases or combination chemotherapy and re-irradiation in locally recurrent SCCHN. Vetting protocols: reviewing systemic options, concomitant medications; dose modification criteria; eligibility stipulations; compliance obstacles. Recruitment of new blood, including committee volunteers and replenishing the pool of principal investigators. Quality Control Committee Report Dr. Michael Goodyear of Dalhousie University in Nova Scotia, the Chair of the Medical Oncology Quality Control Committee, presented a review of quality control issues for the period 1/1/04 through 12/31/04. One thousand six hundred and fifteen reviews were completed, similar to previous years, with an overall compliance rate of 97%. The backlog of cases remains an ongoing challenge. This situation is magnified by recent, well-publicized media revelations documenting previously obscured adverse advents in pharmaceutical-sponsored trials. Various corrective actions to enforce compliance were discussed. Site-Specific Committee Reports Disease site-specific committee reports were given by Drs. Ettinger and Safran. The Lung Cancer Committee is well on its way to completing a phase II trial evaluating erbitux (C225) in combination with conventional RT, weekly paclitaxel and carboplatin in locally advanced NSCLC. Two separate, randomized phase III PCI trials continue to accrue, albeit slowly: (1) one focuses on patients with stable disease or remission post definitive therapy for locally advanced NSCLC -- this effort is spearheaded by Dr. Beth Gore; (2) the other trial evaluates different PCI regimens post definitive therapy for limited SCLC. A number of studies in pancreatic, stomach and rectal carcinoma have recently closed, clearing the field for new studies integrating targeted agents as well as recently approved additions to the cytotoxic armamentarium, e.g. Irinotecan, Oxaliplatin. Drs. Crane and Regine are evaluating the role of bevacizumab, concurrent capecitabine and radiation followed by maintenance gemcitabine and bevacizumab for locally advanced pancreatic carcinoma. This study recently opened. A phase II effort in rectal carcinoma assesses the role of combined modality and neoadjuvant treatment, looking specifically at capecitabine, in combination with either irinotecan or oxaliplatin during RT, with post surgical chemotherapy consisting of either FOLFIRI (irinotecan arm) or FOLFOX (oxaliplatin arm). Cox-II Controversies Dr. Goodyear reviewed current Cox-II controversies, putting many outstanding issues into perspective. In particular, he focused on the difficulties encountered by Merck Pharmaceutical, the manufacturer of Vioxx. He reviewed the prostaglandins pathway, the critical role Cox-2 inhibitors have in both inhibiting inflammation and potentially carcinogenesis. He noted ischemia and hemodynamic stress can induce Cox-2 production in the endothelium. Coxibs, since they are selective, can result in unopposed thromboxane production, which in turn can lead to persistent HTN, as well as accelerated atherosclerosis, and increased thrombotic response, hence increased cardiovascular risk, which has been documented in clinical trials and has led to the recall of Vioxx (Rofecoxib). Consequently, this agent, which received fast track approval in 5/99, was withdrawn 10/30/04. In particular, Dr. Goodyear focused on the VIGOR trial in rheumatoid arthritis, in which the relative risk of myocardial infarction was lower in the Naproxen group compared to the Rofecoxib group, with an incidence considerably higher than placebo controls. He also discussed a recent meta-analysis of various primary prevention trials. Similar phenomena were observed in a trial aimed at preventing adenomatous polyps, in which the event rate for rofecoxib was 3.5% compared to 1.9% in the placebo group (Topal NEJM 10/21/04). The implications for celecoxib and the implications for ongoing research with this class of compounds are unclear, but give investigators pause. In the PRESAP trial geared to preventing spontaneous adenomatous polyps, the event rate of cardiovascular events for celecoxib and placebo were virtually identical, whereas in the APC trial (Adenoma Prevention with Celecoxib effort) the event rate was nearly threefold higher: 2.5% versus 0.9%. Similarly, valdecoxib has been shown to increase the risk of serious cardiovascular outcome by factor of 3:1 in placebo-controlled trials in patients post CABG. These observations raise the specter of a class effect, and have essentially helped squelch the anticipated opening of RTOG studies employing Cox-2 inhibitors. Dr. Goodyear concluded by reviewing the obligations of healthcare practitioners to inform study subjects of potential risk, and the need for RTOG to carefully re-evaluate the “risk: benefit ratio” with respect to celecoxib trials. One trial, RTOG 0128, a phase I/II effort evaluating celecoxib in combination with radiation and cisplatin in locally advanced cervical carcinoma, had accrued 84 patients, and, because it was nearing completion, was closed. RTOG 0213, a phase I/II effort combining celecoxib with RT in high risk, locally advanced NSCLC has accrued 16 patients to date out of 122 targeted. No untoward toxicities have been observed; hence this study remains open. Other planned studies remain on hold. Dr. Gelder, the Director of Oncologic Research at Pfizer, similarly reviewed the safety data from the APC trial, which showed increased cardiovascular risk compared to placebo, and the PRESAP trial, in which there was no increased cardiovascular risk. He also reviewed safety data from the ADAPT trial, in which there was no increased cardiovascular risk for celecoxib versus placebo, but increased risk for naproxen versus placebo. At a minimum, any patient on a celecoxib trial needs to be re-consented. Dr. Gelder issued a blanket recommendation all existing protocols establish appropriate DSMBs meet on a regular basis to review safety data. As for other prevention trials, e.g. in Head and Neck Cancer, these efforts remain on hold. Any decision to proceed requires careful risk/benefit analysis with rationale clearly stated in a formal letter to Pfizer. Finally, he suggested wording to amend consent forms could be inserted into virtually any study employing celecoxib. Dr. Langer finished up by reviewing the role of Cox-2 inhibition in NSCLC, the link between increased expression and impaired prognosis (Achiwa H, et al CCR 1999; 5:1001-1005) and the research role of Cox-2 inhibitors in inhibiting PGE2 and IL6 production in tumor cells. He also reviewed preclinical data demonstrating tumor growth inhibition of Lewis Lung Carcinoma by Cox-2 inhibitors as well as existing phase II data pairing this agent with docetaxel. Finally he showed data from an ongoing neoadjuvant trial pairing celecoxib with paclitaxel and carboplatin prior to surgical resection in stage IB/IIA NSCLC, in which no untoward cardiovascular or other unexpected toxicities have manifest. A quick review of RTOG 0213, the phase II trial integrating celecoxib with RT in high risk, locally advanced NSCLC has failed to demonstrate untoward toxicity. Meanwhile, a number of planned trials at RTOG remain on hold: RTOG 0520, Phase III trial in prostate cancer evaluating RT +/- Celecoxib for 2 years. A Chemo-prevention Trial in Head and Neck Carcinoma evaluating the role of Cox-2 inhibition with correlative buccal biopsies. A phase III trial in low grade glioma in patients under 40 evaluating surgery followed by either observation or celecoxib. Trials in meningioma in both low and high risk evaluating celecoxib either alone or in combination with RT. Dr. Langer concluded finally the cardiovascular concerns raised to date may have been overblown, at least insofar as trials using celecoxib are concerned. Only 1 of 40 trials, and only 1 of 3 in the chemo-prevention arena, has shown a significant increase in cardiovascular risk of celecoxib. A p value of < 0.05 means chance alone might be responsible in 1 out of 20 instances. The therapeutic stakes in the treatment of active cancer and in those at grave risk for the development of recurrences are far higher compared to patients with arthritis or in the chemo-prevention realm. The risk: benefit threshold clearly shifts in this group. Oncologists will typically tolerate far higher risks when long-term prognosis is routinely compromised. He agreed with recommendations by Dr. Goodyear and Dr. Gelder of Pfizer our vigilance needs to be heightened, toxicity monitoring be increased, and markers of cardiac risk, if available, be incorporated into upcoming efforts. Implications of ISEL Trial The ISEL trial evaluating the role of gefitinib versus placebo in patients with NSCLC after 1-2 prior treatments was recently reported to have failed to meet its primary endpoint: an improvement in survival. This effort enrolled 1692 patients randomized in a 2:1 fashion to either gefitinib or to placebo. The hazard ratio was 0.89 in favor of the gefitinib arm for the overall analysis, and in the subset of patients with adenocarcinoma, it was 0.83, with p value 0.07. Formal subset analyses of this trial are pending. A careful evaluation of this trial reveals no overt flaws. Thatcher and colleagues, who ran this effort, stated unambiguously that “ISEL is a large and well designed study; the data are robust, there is no methodologic explanation for these findings….” But a number of potential explanations have been raised. Gefitinib may be inferior to erlotinib, which in a similar trial (BR 21) demonstrated therapeutic superiority. Erlotinib is dosed at or near its MTD, whereas gefitinib at 250 mg daily is dosed far below its MTD, which may be critical for patients who lack the activation mutation. A higher percentage of previous responders were enrolled in the BR21 protocol versus ISEL. There may have been a differential percentage of patients who had previously smoked. Serendipity alone may have resulted in these findings. As a consequence, Astra Zeneca has suspended the marketing of gefitinib as well as all investigator-initiated trials. Protocol consents have been altered to state the results of this effort. Ongoing trials in locally advanced NSCLC and in the adjuvant setting continue. However, RTOG 0320 in patients with oligo-metastases to the brain, which featured randomization to WBRT and stereotactic radiation either alone or in combined with gefitinib or temozolomide, has been amended to drop the gefitinib arm. RTOG is actively soliciting Genentech to have erlotinib substituted for this agent. If this comes to pass, the study will be initiated as soon as possible; the targeted accrual is 381 patients. Similar dilemmas have been raised for RTOG 0417, phase II effort in locally advanced cervical cancer evaluating gefitinib in combination with definitive RT and cisplatin. As with the RTOG 0320 effort, the principal investigators will solicit Genentech’s input and involvement. Study Proposal Review: Leptomeningeal Metastases Drs. Chang and Robbins of University of Wisconsin – Madison reviewed a proposal evaluating the role of temozolomide and concurrent RT in the treatment of leptomeningeal carcinomatosis (LMC) due to NSCLC. Approximately 10,000 cases of carcinomatous meningitis are diagnosed each year in the US. Current therapy remains inadequate, with no intrathecal regimen yielding consistent benefit. Outcome in this group is complicated by the generally poor performance status of patients. On average, survival is no better than 8 weeks. Intrathecal therapy is limited by the requirements for subcutaneous reservoir and ventricular catheter, frequent impairments in CSF flow, difficulties penetrating bulky disease, and the use of agents (e.g. methotrexate, ara-c, etc) with little or no activity in non-small cell lung cancer and other epithelial malignancies. Temozolomide in combination with WBRT has yielded improved response rates compared to WBRT alone in patients with newly diagnosed brain metastases. And there is recently published evidence in GBM that temozolomide (TMZ) in combination with RT can improve survival compared to RT alone. Preclinical data also suggest that temozolomide may be a radiation potentiator. In addition, single agent temozolomide has resulted in a smattering of responses both in the brain and in extracranial sites in patients with refractory disease, including patients with NSCLC. Dr. Chang presented a study design for LMC in NSCLC, a protocol randomizing patients with stable systemic disease, KPS > 60, and no prior WBRT to either RT alone (30 Gy/10 fx) +/- IFRT or to combined RT and TMZ 75 mg/m2 daily during RT. If disease remains stable or improved, then TMZ would be continued on a daily basis for 6 weeks every two months until disease progression or excessive toxicity emerge. The primary endpoint of this study would be overall survival, with secondary endpoints to include toxicity, as well as alterations in neurologic status and performance status. In addition, this trial would include an exploratory analysis evaluating MGMT expression and its linkage to TMZ. This trial was discussed at length by multiple members of the audience: issues related to feasibility and accrual was raised, though the study concept, in general, was well received. Pipeline Discussions Finally, speakers from pharmaceutical industry presented pipeline talks. Roy Baynes of Amgen discussed Neulasta, a long-acting granulocyte-colony stimulating factor as well as potential role of panutumomab. David Ramies from Genentech discussed erlotinib. He focused on the results of the NCI CTG BR.21 trial, which compared erlotinib to a placebo control in the second and third line therapy of advanced NSCLC; this effort demonstrated a survival advantage as well as a quality of life benefit. This represents the first (+) phase III trial of a targeted agent in the treatment of NSCLC. A subgroup analysis revealed benefit across the board, regardless of performance status, gender, age, histology, prior weight loss, the number of prior regimens or prior taxane exposure. Of note, in a hypothesis-generating subset analysis, those whose tumors were tested for EGFr by IHC and proved (-) did not appear to benefit, whereas those who proved EGFr (+) seemed to have a profound benefit. Five percent (5%) or fewer patients discontinued erlotinib because of adverse events. Ramies also discussed the mutational analysis from the Tribute Trial, a placebo-controlled effort which evaluated paclitaxel and carboplatin +/- oral erlotinib. This trial failed to demonstrate a survival advantage overall, but in the never smoking subset (~10% of enrollees), median survival was 22.5 months for those receiving erlotinib compared to 10.1 months for those receiving the placebo. The mutation frequency in 228 accessible patients was 12.7%; those with mutation who received combination erlotinib and chemotherapy were far more likely to respond (53%) versus 18% with wild type; the respective response rates were 21% and 27% for those with the mutation and those with the wild type receiving chemotherapy alone. He also discussed the results of a prospective, randomized placebo-controlled phase III trial in advanced pancreatic cancer evaluating gemcitabine either alone or in combination with erlotinib. This effort, which accrued 569 patients, also demonstrated a statistically significant survival improvement: median survival of 6.4 versus 5.9 months, and one-year survival rates of 26% and 20% respectively (p=0.025). In addition, he showed data underscoring the potential synergy of EGFr inhibition and radiation, and discussed ongoing and upcoming trials evaluating erlotinib in the setting of definitive RT. He reviewed the results of a trial in advanced colorectal carcinoma, which demonstrated a 5 month median survival improvement for bevacizumab in combination with IFL versus IFL plus placebo (20.3 versus 15.6 months, p=0.00003). He also discussed recently completed efforts evaluating paclitaxel and carboplatin +/- bevacizumab as well as gemcitabine/cisplatin +/- bevacizumab in advanced NSCLC. He finished up by describing phase II studies orchestrated by Roy Herbst and Alan Sandler integrating erlotinib with bevacizumab. Both drugs can be combined at full dose: erlotinib 150 mg daily; bevacizumab 15 mg/kg every 3 weeks. In a phase II effort in the second line setting in NSCLC, this combination yielded a median survival of 12.6 months and a response rate of 20%. As a consequence, this regimen will be developed further in NSCLC and in other epithelial neoplasms. MEDICAL ONCOLOGY COMMITTEE (June, 2004) Corey Langer, M.D., Chair The Medical Oncology Meeting was held from 11:00 AM until 1:00 PM. More than 100 individuals, including medical oncologists, radiation oncologists, RTOG staff members, and individuals from the pharmaceutical industry, attended. Subcommittee Mission Dr. Langer reviewed the subcommittee mission, including cross fertilization between various disease specific subcommittees; introduction of new systemic agents and radiosensitizers into the RTOG, relatively early in the development process; the crucial protocol setting process, including the review of systemic therapies, concomitant medications, dose modifications, obstacles to compliance; streamlining eligibility criteria, an ongoing challenge; investigation into new therapeutic territories, including the role of cytotoxics in patients with brain metastases, and combined re-irradiation and chemotherapy in relapsed SCCHN, and finally membership recruitment. He invited members and non-members to contribute their expertise to each of these goals. Medical Oncology Quality Control Dr. Goodyear of Medical Oncology Quality Control reviewed data for the period 1/1/03 through 5/26/03; 1872 reviews were completed with overall compliance rate of 93%. A backlog of cases remains a continuing problem with no obvious evidence this backlog can be significantly reduced without major changes in policy. Ongoing recommendations included discontinuation of final reviews when interim toxicity analysis has already been performed (e.g. phase I and II trials); periodic gated suspension of accrual to assess safety; the continuing widespread distribution of CDs to principal investigators, which remains popular at headquarters, despite resistance on the part of some investigators; and finally enhanced discipline of principal investigators by modality chairs, making certain reviews are accomplished on a timely basis. Goals at this point include decentralization of the review process, and assurance of timeliness, with corrective measures implemented to make certain reviews do not fall by the wayside. Eligibility Task Force Dr. Langer also reviewed the goals of the Eligibility Criteria Task Force, an initiative to streamline entry criteria onto RTOG protocols, revise the outmoded chemotherapy boilerplate and eliminate unnecessary impediments to accrual. The revised eligibility criteria have been worked on jointly by medical oncology and by the executive officer Dr. Mitchell Machtay, along with varius members of RTOG headquarters. The ultimate goal is the production of a standard template can be revised, expanded, and adapted as necessary, without “reinventing the wheel” for every protocol. Conditions for patient ineligibility were also defined, including definitions for “severe, active co-morbidity,” and the elimination of the unnecessary five-year rule for prior invasive malignancy. Specific Protocol Discussions Dr. Wong updated attendees on a developing phase III trial comparing conventional chemotherapy alone to re-irradiation and concurrent chemotherapy in previously irradiated head and neck cancer patients with local recurrence or new primaries within the RT field. Suggestions were made. Dr. Berk of Cancer Control/CCOP also presented a concept evaluating the role of anabolic steroids (Oxandrone) in hypoactive males receiving chemotherapy and radiation. This trial, if activated, would randomize patients between Oxandrone and placebo. ASCO Reviews - Gastroenterologic Malignancies Dr. Safran of the gastrointestinal cancer committee reviewed recent papers from ASCO. In particular, he reviewed the results of CALGB 89803, a phase III randomized trial which failed to show a therapeutic benefit for the addition of irinotecan to standard 5FU/leukovorin compared to 5FU/ leucovorin alone in the adjuvant therapy of resected, stage III colorectal carcinoma. In this trial, Irinotecan exacerbated toxicity, most notably grade 3 and 4 neutropenia, and treatment-related deaths. On the other hand, the MOSAIC trial demonstrated a borderline significant reduction in recurrence rates for patients receiving FOLFOX 4 (Oxaliplatin, 5 Fluorouracil, Leucovorin) versus standard 5FU and Leucovorin, with a 3% improvement in DFS in stage II patients, and a 6.3% improvement in DFS for stage III patients. He also updated attendees on the status of Bevacizumab in advanced, metastatic colorectal carcinoma, which in combination with ILF proved superior to ILF alone; this trial demonstrated a statistically significant, clinically meaningful 5-month improvement in median survival. However, there was no overt benefit for Bevacizumab in combination with 5FU and Leucovorin in the third line setting, or in patients who progressed after Irinotecan and Oxaliplatin-based chemotherapy (Chen HX et al ASCO 2004, A-3515). Dr. Safran also reviewed the results of the XACT study, a phase III trial comparing single agent Capecitabine to conventional 5FU and leucovorin days 1-5 every 28 days. This effort accrued nearly 2000 patients with resected colorectal carcinoma, and showed a borderline advantage for Capecitabine with a 3.6% improvement in relapse free survival (p=0.0407), and a 3.7% improvement in overall survival (81.3% versus 77.6%, p=0.0706). In addition, Capecitabine was associated with less toxicity, particularly less stomatitis, nausea and vomiting, and diarrhea, compared to 5FU and Leucovorin, although there was more hand foot syndrome (Cassidy et al ASCO 2004, A-3509; McKendrick et al ASCO 2004, A-3578). Dr. Safran finished his presentation with pancreatic cancer and reviewed a long list of agents (5 Fluorouracil, Cisplatin, Irinotecan, R-115777, Marimastat, Pemetrexed), which in combination with Gemcitabine have failed to produce survival advantages compared to standard Gemcitabine alone. In this context he reviewed the results of a recent study comparing Gemcitabine to combination Gemcitabine and Oxaliplatin. This trial, which may have been compromised by underpowered accrual, showed a nearly two-month improvement in median survival (9 months versus 7.1), although this difference proved non-significant (p=0.13). He also reviewed the results of a recent phase II effort in advanced pancreatic cancer combining Bevacizumab with Gemcitabine, which yielded a partial response rate of 19%, a median survival of 8.7 months, and a one-year estimated survival of 29%. Lung Cancer Highlights Dr. Langer reviewed critical studies from the thoracic plenary sessions presented at this year’s ASCO. In particular, major headway was observed in the adjuvant treatment of resected NSCLC, with two strikingly positive efforts, each following the promising phase III IALT results presented last year. Recent protocols investigating locally advanced NSCLC, however, proved a major disappointment, with no obvious breakthroughs. Finally, in a placebo-controlled, randomized phase III trial, the role of EGFR TKIs was firmly established, showing a survival benefit for Erolotinib vs best supportive care (BSC) in the salvage therapy of NSCLC. Last year at ASCO, the IALT effort presented by Thierry LeChevalier (ASCO 2003, A-6; NEJM 2004) demonstrated a statistically significant improvement in survival for patients receiving Platinum based therapy compared to those under observation alone after resection of stage I-IIIA NSCLC. This benefit, however, was modest with only a 4.1% absolute advantage, and a relative 10% improvement. Multiple criticisms were leveled at the IALT, including (1) the heterogenous means of staging, use of chemotherapy, and non-uniform application of TRT inherent in this effort; (2) the absence of elderly individuals (>75); and (3) the fact that the study closed earlier than planned, which might conceivably have biased results. Moreover, hazard ratios clearly favored stage III patients, not those with stage I or stage II NSCLC. At year’s end, a number of provocative questions remained regarding IALT, including: Were the results sufficiently positive to justify adjuvant therapy post resection outside the protocol setting? If so, were we obligated to use one of the second-generation regimens employed in IALT, or could these results be safely extrapolated to Carboplatin or to the Taxanes/Gemcitabine? What was the role of radiation? Should it be considered concurrently, sequentially or not at all? At this year’s ASCO, two separate papers, either one of which would have been accepted for the main plenary session in a leaner year, were presented; each cemented the role of adjuvant treatment in resected NSCLC. NCIC BR10 was an intergroup trial evaluating the role of cisplatin and vinorelbine for four cycles versus observation in resected stage IB-II NSCLC. 482 patients were randomized from 1994 through 2001. The adjuvant group enjoyed a 15% absolute improvement in 5-year survival (69% versus 54%, p=0.012), despite relatively poor therapeutic compliance (59% of patients receiving 3 or 4 cycles). While Cisplatin dose delivery was fairly good (84% of targeted dose), delivery of vinorelbine was compromised (52% of targeted delivery), and only 50% of enrollees in the experimental arm were able to complete chemotherapy. 13% stopped treatment because of toxicity, and an additional 29% refused to complete treatment, presumably because of side effects that did not otherwise mandate protocol cessation. Patients with pneumonectomy were far more likely to discontinue adjuvant therapy early due to toxicity (27% versus 8%, p<0.001), and those from Canada, intriguingly, were more likely to “refuse” adjuvant treatment after it had been initiated (41% versus 18%, p<0.001). A companion trial, CALGB 9633, compared adjuvant Paclitaxel and Carboplatin for 4 cycles to observation in patients with resected stage IB NSCLC. This paper was presented by Gary Strauss (ASCO 2004, A-7019); 344 patients were accrued over a 7-year period. Stratifications included histology (squamous versus other); differentiation (poorly versus other), and the use of mediastinoscopy (Y versus N). The median age of enrollees was 61; 64% were males. Nearly 90% underwent lobectomy. Just fewer than 40% had squamous histology. Adjuvant therapy with Paclitaxel/Carboplatin resulted in a 12% absolute improvement in 4-year survival (71% versus 59%, p=0.28) with a 48% reduction in lung cancer mortality. Compliance with chemotherapy was excellent with 85% receiving all 4 cycles, at least 65% of full dose. Toxicities were acceptable. Based on the IALT effort, and the NCI-C and CALGB intergroup studies, it is clear now that adjuvant therapy is indicated for fit patients with resected stage IB, II and IIIA NSCLC. Platinum-based chemotherapy for 3-4 cycles is standard. The literature supports the combination of Platinum (Cisplatin or Carboplatin) with either vinorelbine or Paclitaxel. There are no data as yet for Gemcitabine. Finally, the role of radiation for stage IIIa (N2) and hilar N1 remains controversial. Future and current research directions include the investigation of targeted agents, including EGFR TKI, as well as angiogenesis inhibitors. Planned trials will also evaluate the role of induction therapy versus adjuvant; and there is emerging interest in comparing an oral fluorinated pyrimidine to Paclitaxel/Carboplatin in stage IB NSCLC, based on phase III studies from Japan (Kato et al ASCO 2003, A-2498) showing a clearcut survival advantage for UFT versus observation in pathologic stage I adenocarcinoma, with the bulk of this benefit confined to T2N0 patients (84.9% versus 73.5% 5 year survival rate, p=0.005). A subsequent meta-analysis presented by Hamada at ASCO (A-7002) has shown that therapeutic advantages for UFT extended across all stages, histologies and both genders. A recent trial by the RTOG (RT 9705) evaluating concurrent Paclitaxel and Carboplatin and adjuvant RT in stage IIIA (N2) and stage II (hilar N1) NSCLC yielded a median survival of 56.3 months and a 3 year survival rate of 61%, which compared favorably to the historic control of 50% for individuals on E 3505 for those receiving concurrent TRT, Cisplatin, and Etoposide in the adjuvant setting (Keller et al, NEJM 343:1217-1222, 2000). Interest has emerged in comparing chemotherapy alone to combination chemotherapy and RT in this setting. Alternatively, the role of Bevacizumab in this setting will also be considered. No major headway was observed in locally advanced NSCLC. At this point, concurrent chemoradiation remains the standard approach; with three out of four phase III trials (Furuse, RTOG, Zatloukal) showing a survival advantage compared to sequential therapy, albeit with heightened esophagitis. At this year’s ASCO meeting, Vokes et al presented the results of CALGB 39801 a phase III trial comparing concurrent chemoradiation with weekly paclitaxel and carboplatin to identical chemoradiation preceded by two cycles of induction chemotherapy. This trial was flawed in part by the inclusion of patients with more than 5% weight loss (21% of the induction arm, 32% on the concurrent arm). Results were very disappointing, with a non-significant 2.3 month difference in survival (13.7% versus 11.4 months for induction plus concurrent versus concurrent alone). Amongst those with less than 5% weight loss, the median survival times were 15.9 months and 14.3 months respectively. There is interest, at this point, in comparing systemic versus low dose radiosensitizing chemotherapy during the concurrent phase of treatment. In addition, separate groups are testing the role of consolidative treatment. HOG is assessing Docetaxel post chemoradiation versus observation. SWOG 0023 is accruing rapidly; it evaluates Gefitinib maintenance therapy versus placebo in patients who have received definitive chemoradiation with Etoposide and platinum followed by consolidation with Docetaxel. RTOG 0234, a phase II trial recently initiated within this group, is assessing the role of Cetuximab in combination with chemoradiation (definitive RT; weekly Paclitaxel and Carboplatin) followed by two additional cycles of concurrent chemotherapy and Cetuximab. Neal Ready et al have reported preliminary toxicity data for Gefitinib, in combination with radiation in both a poor risk group (PS 2 +/- comorbidity), and risk groups (PS 0-1, < 5% weight loss). To date, in the poor risk group receiving concurrent Gefitinib and RT with no chemotherapy given during the RT phase, we have yet to observe untoward toxicity. In the second cohort receiving Gefitinib plus concurrent chemoradiation, one of six patients has experienced DLT. Finally Langer presented preliminary data from the Tribute and Talent trials, both of which failed to demonstrate a survival advantage for erlotinib grafted onto either standard paclitaxel/carboplatin (Tribute) or Gemcitabine/Cisplatin (Talent). These efforts, in aggregate, accrued over 1200 patients, and showed absolutely no survival advantage compared to standard chemotherapy alone. However, a retrospective subset analysis of the Tribute trial evaluating survival in non-smokers showed a striking survival benefit: 22.5 months for patients receiving combination Paclitaxel/Carboplatin/Erlotinib versus 10.1 months for the control group; this must be investigated further. The most important news from ASCO were the results of BR21, a phase III randomized placebo-controlled trial assessing Erlotinib in patients whose disease had progressed after one or two prior regimens. Stratification factors included the number of prior treatments, stage (IIIB versus IV), PS (0-1 versus 2), treatment center, and the use or omission of prior Platinum therapy. Roughly one-third of enrollees came from Canada, two-thirds from the rest of the world (ROW) with only 3 patients out of more than 700 accrued coming from the United States. The study was designed to detect a 33% improvement in median survival (4 - 5.33 months). Patients were randomized 2:1 between the investigational arm and the placebo control. Eligibility permitted PS 2 and 3, as well as asymptomatic CNS involvement, as long as patients were stable and not requiring corticosteroids. Frances Shepherd of the NCIC presented the final results. Median potential follow-up at the time of presentation was nearly two years. Nearly 20% of enrollees were PS 2, with fewer than 2% PS 3. Both arms were well balanced with respect to gender, histology, and prior Platinum exposure. 40% of enrollees had previously responded to therapy. As anticipated, erlotinib resulted in a significantly higher incidence of grade 3 and 4 rash (76% versus 17%) and diarrhea (55% versus 19%). It also resulted in a substantially higher incidence of dose reductions (19% versus 2%). Of note, treatment duration was substantially longer in the erlotinib group (16% versus 5% still on study at 36 weeks; 10% versus 2% at one year). Most importantly, a clear-cut survival advantage was observed, with improvement in median survival from 4.7 months in the control group to 6.7 months in the erlotinib cohort (p=0.001), and commensurate improvement in one-year survival rate (22% versus 31%; p=0.0045), Those with good PS 0-1 (p=0.0001) and those who had responded to prior treatment (p=0.013) enjoyed a significant improvement in survival compared to PS 2 patients and those whose disease had not responded to prior treatment. This landmark effort is the first trial to show a survival advantage for an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in the therapy of advanced NSCLC. At this point, EGFR TKIs have established their role as the standard of comparison in the third-line setting. Moreover, these results strongly suggest that the activation mutation reported by Lynch and others and associated with tumor response to EGFR TKIs could not completely explain the survival benefit since it was apparent that stable patients also enjoyed a significant survival improvement. Head and Neck Report Dr. Stuart Wong completed the round of disease-specific presentations from the recent ASCO meeting. The highlight of this past meeting was a landmark phase III study comparing radiation therapy alone to combination radiation and Cetuximab, a monoclonal antibody inhibiting EGFR. Well over 400 patients with oropharyngeal, hypopharyngeal, and laryngeal carcinoma were randomized to this effort. The majority (56%) received concomittant boost RT; roughly 80% had positive IHC stains for EGFR. The addition of Cetuximab resulted in no overt exacerbation of mucositis, although skin reactions were nearly twice as common in the Cetuximab group: 34% versus 18% (p=0.05). Local regional control proved significantly better for the Cetuximab cohort: median time to treatment failure was 36 months versus 19 months in the control group (p=0.02). The addition of Cetuximab yielded a near doubling in median survival (54 versus 28 months p=0.02) and a 13% absolute improvement in 3-year survival rate (57% versus 44%). This trial, however, did not address the potential benefit of Cetuximab in combination with standard chemoradiation in locally advanced head and neck cancer. Nevertheless, this is the first prospective randomized phase III trial to show a survival benefit for targeted therapy in combination with radiation versus standard RT alone, and, in this context, represents a trailblazing study. Dr. Wong also reviewed RTOG 9911 a pilot effort evaluating concurrent split course hyperfractionated radiation with low dose daily Cisplatin/Paclitaxel in recurrent, previously irradiated patients with head and neck carcinoma. Despite a fairly high incidence of grade 4 and 5 toxicity rate, the median survival in this effort exceeded one year, and two year survival rate approached 25%, considerably higher than the historic RTOG control (9610) which yielded a median survival just over 8 months, and a 2 year survival rate of 17%, and better than most cytotoxic combinations in this setting. Emerging data regarding targeted agents in the advanced disease setting were also reviewed. Rhoades (Abstract 5541) assessed erolitinib in combination with Docetaxel in relapse patients and observed a 33% response rate. Humblet (Abstract 5513) evaluated combination Cetuximab and Cisplatin versus Carboplatin 5FU and observed a relatively high rate of response. Maurer reported on preliminary data combining Bevacizumab and Erlotinib and reported 4 responses out of 12 patients enrolled. Similarly, a phase II study by Worth et al (Abstract 5540) combining Gefitinib and Celebrex at full dose of (500mg daily and 400mg bid respectively) yielded 3 responses in 9 patients assessed. Finally, a meta-analysis of chemotherapy in head and neck cancer highlighted the role of concomitant chemoradiation in the treatment of locally advanced SCCHN (Bourhis et al, ASCO 2004 A-5505). With nearly 18,000 patients accrued to 87 separate randomized phase III trials, concurrent chemoradiation generated an 8% survival improvement compared to only 2% for neoadjuvant chemotherapy. There was no significant difference with respect to anatomic site or stage, though age clearly had an impact: those over 50 enjoyed a 24% relative improvement in survival compared to only 3% in those over 70. Guest Speaker: Isabella Tabah-Fisch, M.D., of Sanofi-Synthelabo Dr. Fisch, the Corporate Medical Director of Sanofi-Synthelabo, France, reported on the role of Oxaliplatin in combination with radiation. She highlighted in vitro colonic cancer lines treated with either radiation alone or radiation in combination with Oxaliplatin; these studies showed therapeutic additivity, if not synergy, and suggested a clear dependance on Oxaliplatin concentration and duration of exposure (Hess and Blackstock, AACR; 2000; Blackstock et al IJMM 2002). Oxaliplatin has been investigated in combination with a number of systemic agents including 5 Fluorouracil (5 FU), Capecitabine, and Gemcitabine. She reviewed a number of studies in rectal cancer assessing the role of preoperative radiochemotherapy with 5 FU, Leucovorin, and Oxaliplatin, each of which demonstrated feasibility as well as pathologic complete response (pCR) rates ranging from 14% to nearly 50+%. She also reviewed studies combining Oxaliplatin with Capecitabine with similar pCR rates, and acceptable incidences of diarrhea and rash. A number of studies have explored a variety of weekly and monthly schedules. The ongoing CORE study, orchestrated by the EU evaluates combination radiotherapy, Oxaliplatin, and Capecitabine prior to rectal cancer esection. The STAR (Studio Terapio Adiuvante Retto) trial evaluates preoperative radiation and fluorouracil infusion, either alone or in combination with Oxaliplatin. 230 patients will be accrued to this effort. RTOG 0247, a neoadjuvant trial in rectal carcinoma, will directly assess radiation (50.4 Gy) in combination with either Capecitabine and Oxaliplatin or Capecitabine and Irinotecan followed by FOLFOX or FOLFIRI respectively. In a 2 by 2 design, NSABP R-04 will stratify by gender, tumor stage (II versus III) and intended surgery (sphincter saving versus other) and randomly assign patients to RT (45 Gy) in combination with continuous infusion 5 FU or capecitabine +/- oxaliplatin followed by surgical resection. E3201, an ambitious postoperative rectal cancer trial, will ultimately enroll 3150 patients and compare FOLFIRI versus FOLFOX versus standard 5 FU and leucovorin in the postoperative or preoperative setting. In esophageal carcinoma, Khushalani (JCO 2002) reported on a pilot trial in 38 patients receiving XRT (1.8 Gy in 28 Fractions), combined with continuous infusion 5 Fluorouracil and Oxaliplatin 85mg/m2 every two weeks times three for two cycles. Of 13 patients who underwent surgery with curative intent, 5 had pCR. Giovanni (ASCO 2004) reported preliminary data combining 5FU/Leucovorin, Oxaliplatin, and XRT in operable locally advanced/metastatic esophageal carcinoma. At the conclusion of RT, patients received an additional 3 cycles of FOLFOX 4. Phase I and phase II studies are also assessing Oxaliplatin in combination with Gemcitabine and radiation in locally advanced pancreatic carcinoma. To date, there are no studies or data in NSCLC evaluating combination Oxaliplatin and RT and only fledgling data in head and neck cancer. In aggregate, multiple studies have demonstrated the feasibility of combining Oxaliplatin with Fluoro-Pyrimidines and XRT. Dr. Tabah-Fisch finally touched upon the potential role of Tirapazamine, a hypoxic cell Cytotoxin and sensitizer of platinating agents. An ongoing phase III trial in locally advanced head and neck cancer (EFC4690) is assessing this agent in combination with definitive RT and Cisplatin versus standard Platinum and RT alone. 850 patients with locally advanced SCCHN will be accrued to this effort. MEDICAL ONCOLOGY COMMITTEE (January, 2004) Corey Langer, M.D., Chair The Medical Oncology Committee Meeting was convened at 11:00 AM on January 17, 2004. Over 120 attendees were present. Corey Langer, Committee Chair, reiterated the goals of the committee: The introduction of new systemic agents and radio sensitizers into RTOG The investigation of new therapeutic territories, including re-irradiation and chemotherapy in head and neck; combination radiation and cytotoxics in CNS metastases, etc. Optimization of study design, including comprehensive reviews of dose modifications, eligibility, concomitant medications and toxicity management. Quality Control Committee: In Dr. Goodyear’s absence, Dr. Langer reviewed quality control issues. Overall compliance remains reasonably good at 95%. Of 899 cases reviewed from 1/01/03 through 12/31/03, major deviations were observed in only 4.56%. One study in which a disproportionate percentage of unacceptable deviations occurred was RTOG 0021 (RT and tamoxifen for GBM). The reason for this is unclear. The goal of the Quality Control Committee is to streamline case report forms on a protocol specific basis, to make certain that individual institutions are adhering to protocol guidelines, and to assure that medical oncology principal investigators are reviewing reports on a timely basis. In an effort to expedite review, the process, to a great extent, has been successfully decentralized from Philadelphia to individual investigators. A system will be put forth to discipline investigators who are delinquent in their reviews. Site Specific Reports: Head and Neck Cancer Committee Dr. Wheeler, on behalf of the Head and Neck Cancer Committee, reviewed pertinent studies. RTOG 0129, a Cisplatin-based phase III chemoradiation trial comparing conventional standard daily fractionation to concomitant boost is accruing rapidly – ahead of schedule. A proposal to increase the targeted accrual from 480 to 720 has been made and will likely go forth, thereby enhancing the power of the study. Based on the current accrual rate, even with a 50% increase in targeted enrollment, the study will still complete on schedule in spring of 2005. Proposals for placement studies include the integration of other cytotoxics and newer biologic agents such at Cetuximab. A post-operative radiotherapy proposal (RTOG 0234), orchestrated by Dr. Harari, will evaluate RT and Cetuximab (C225), either alone, or in combination with weekly Cisplatin or Docetaxel. Both BMS and Aventis have indicated support for this approach. Dr. Langer reviewed the results of RTOG 9911, a phase II study evaluating concurrent, split course hyperfractionated re-irradiation, in combination with low dose daily, radiosensitizing Cisplatin/Paclitaxel. Despite a fairly high incidence of grade 5 toxicity, the one-year survival rate in the first 60 patients exceeds 50% and the 2-year survival rate is 27.5%. Dr. Wong of the Medical College of Wisconsin has proposed a study comparing standard systemic chemotherapy to concurrent chemotherapy and re-irradiation in this setting. (See comments by Dr. Wong at end of report). Dr. Machtay reviewed RTOG 9903, a phase III trial evaluating RT +/- recombinant Erythropoietin (rEPO). This trial was initially suspended at Ortho Biotech’s behest, because of concerns about excess thromboembolic phenomena in other similar studies featuring recombinant erythropoietin, and ultimately closed at the request of the DSMB because of a trend toward inferior survival on the rEPO arm. These results parallel those from Europe evaluating definitive head and neck RT +/- epo beta. Finally, a number of upcoming studies will evaluate interventions for mucositis, including Gelclair and Keratinocyte Growth Factor (KGF). Thoracic Studies. Dr. Langer, on behalf of the Thoracic Surgical Subcommittee, reviewed ongoing and proposed trials. The ping-pong phase I trials are nearing completion. RTOG 0017 evaluates standard RT in combination with Gemcitabine and either Carboplatin or Paclitaxel. The second effort (RTOG 0123), evaluating 3-D conformal RT in escalating doses in combination with standard weekly Paclitaxel/Carboplatin continues to accrue. In the SCLC arena, RTOG 0241, a phase I assessment of fixed dose Cisplatin and escalating doses of Irinotecan in combination with either once daily RT or BID RT is accruing well. RTOG 0324 to be led by Drs. Bluemenschein, Robert, Komaki, and Curran, a unique phase II effort combining Cetuximab (C225) and standard chemoradiation with Paclitaxel/Carboplatin, and is due to be initiated imminently; this is the first effort by the Thoracic Surgical Subcommittee to integrate EGFR inhibition in combination with chemoradiation. Development of the proposed neoadjuvant trial for stage III NSCLC (RTOG 0412) is nearing completion. This phase III effort will evaluate induction chemotherapy (Docetaxel/Cisplatin) either alone or in combination with radiation followed by surgical resection. In addition, Dr. Langer highlighted the results of the extensive debate regarding appropriate adjuvant trials for stage II (N1 hilar only) and stage IIIA (N2) NSCLC. By a large majority vote, members of the thoracic core committee favor a study comparing chemoradiation (along the lines of RTOG 9705) to chemotherapy alone (~ 9633); this approach was favored over other options, including chemoradiation +/- Avastin (rhuMAb anti-VEGF). Finally, two separate PCI trials are ongoing. RTOG 0212 assesses two different doses and fractionation schedules for PCI after successful therapy for limited SCLC. Accrual to this effort has picked up over the past few months. On the other hand, RTOG 0214, an intergroup, randomized phase III effort comparing PCI versus observation after definitive therapy for stage IIIA/B NSCLC, is accruing slowly. Targeted enrollment is 1058; to date, only 40 patients have been accrued. GI Studies Dave Ilson, as representative of the Gastrointestinal Cancer Committee, reviewed ongoing trials and planned interventions. The RTOG 9811 effort, a phase III study of RT, Fluorouracil infusion and either Mitomycin or Cisplatin, is nearing completion, with more than 510 patients accrued as of 11/03. Three other trials are also nearing completion. These include RTOG 9904, a phase II trial evaluating induction chemotherapy employing Fluorouracil, Cisplatin, Leucovorin followed by Chemoradiation with 5FU CVI, Cisplatin, Paclitaxel, and concurrent RT (45 Gy) followed by surgical resection; RTOG 0113, a randomized phase II effort in esophageal cancer assessing induction chemotherapy with Fluorouracil, Cisplatin, Paclitaxel for two cycles followed by concurrent RT, 5FU, and Paclitaxel or induction chemotherapy with Paclitaxel and Cisplatin followed by concurrent RT, 96 hour Paclitaxel infusion, and weekly Cisplatin (56 of 84 projected patients have been accrued as of 12/16/03); and RTOG 0114, a randomized phase II comparison in resected gastric carcinoma, assessing 5 FU, Cisplatin, Paclitaxel for two cycles followed by concurrent 5FU, weekly Paclitaxel, and RT or Cisplatin and Paclitaxel for 2 cycles followed by concurrent 96 hour Paclitaxel infusion, weekly Cisplatin, and concurrent RT. Finally, RTOG 0246 is a phase II study of Paclitaxel, Cisplatin, and 5FU with growth factor support followed by chemoradiation incorporating concurrent RT, continuous Fluorouracil infusion, and bolus Cisplatin. This study just opened in September of 2003, and targets 42 patients for enrollment. RTOG 0315 is a randomized double blind placebo-controlled phase III study evaluating the efficacy of depot Sandostatin in preventing or reducing the severity of chemoradiation-induced diarrhea in patients with anal or rectal carcinoma. Developing trials include RTOG 0223, a phase I – II post-operative pancreatic trial evaluating Gemcitabine followed by concurrent Gemcitabine and radiation, and RTOG 0247, a randomized phase II trial evaluating neoadjuvant Capecitabine in combination with radiation and either Irinotecan or Oxaliplatin followed by surgical resection and either adjuvant FOLFIRI or FOLFOX. Brain Tumor Committee Dr. Yung, the Medical Oncology Chair of the Brain Tumor Committee, reviewed active and developing studies employing cytotoxics and other systemic agents. RTOG 9813, a phase I – III effort in anaplastic astrocytoma (AA) evaluates RT 59.4Gy in combination with Temozolomide or BCNU; the phase I component opened 6/2000 and closed 1/2002; the phase III component opened 10/02. 84 patients to date, of 483 targeted, have been accrued. RTOG 0118, a phase III trial comparing standard whole brain irradiation (WBRT) at a dose of 37.5 Gy versus WBRT in combination with thalidomide in patients with multiple brain metastases; 131 of 332 patients targeted for accrual have been enrolled. RTOG 0131 assesses induction therapy with Temozolomide in AA: complete responders are observed, while those with stable disease and partial response go on to full dose RT and concurrent Temozolomide; 29 of 37 patients targeted for accrual have enrolled. Finally, RTOG 0211 assesses Gefitinib (Iressa) in combination with full dose RT for GBM; the phase I component is now completed, and the ongoing phase II component separately targets patients either on or off enzyme-inducing anticonvulsive drugs (EIACDs). 98 patients have been accrued to date. Developing studies will integrate farnesyl transferase inhibitors, motexafin gadolinium and Cox-2 inhibitors, in combination with RT. An intriguing meningioma study will assess Vioxx, either alone or in combination with RT. In addition, an imminent trial in lung cancer patients with CNS metastases (RTOG 0320), will assess WBRT followed by SRS, and either alone or in combination with Temozolomide or Gefitinib. Pipeline Discussions Pfizer Dr. Kraker of Pfizer Pharmaceutical reviewed the current state of its development pipeline. Agents under investigation include signal transduction inhibitors, multi-targeted kinase inhibitors, angiogenesis inhibitors, cell cycle inhibitors and conventional cytotoxics. CI-1033 is a pan erb-B kinase inhibitor, with irreversible binding for all erb-B family members. Phase I trials have demonstrated safety for this agent at a dose of 150mg daily continuous, as well as 250 mg daily 7 days on, 7 days off. A separate phase I trial in 32 patients demonstrated an MTD of 450 mg daily 2 weeks on, 1 week off, with diarrhea, rash, anorexia, and edema dose limiting. In biopsy-accessible tumor, suppression of erb-B1 and erb-B2 receptor phosphorylation has been demonstrated, as has clinical activity. Ongoing phase II studies are assessing this agent in stage IV breast carcinoma, and, at 3 different dose levels, in stage IIIB/IV NSCLC. CI-1040 is a signal transduction inhibitor, which, at a variety of doses, suppresses MAP kinase. SU-11248 is another receptor tyrosine kinase inhibitor, targeting PDGFr, VEGFr, Ckit, and FLT3. Ongoing phase I – II studies are evaluating a number of different schedules. Activity has been observed in metastatic renal carcinoma and in rectal neuroendocrine tumors. Correlative work has demonstrated a decrease in plasma VEGFR 2 in each of the ongoing phase I trials. A similar decline in skit plasma levels has been observed, and appears to correlate with objective response. This agent is undergoing development in imitinib (Gleevec) – refractory GIST, metastatic renal carcinoma, neuroendocrine tumors, lung and breast cancer. Other agents in development include poly ADP-ribose polymerase inhibitors and glycinamide ribonucleotide formyl transferase (GARFT) inhibitors. In addition, Pfizer is evaluating the role of edotecarin-Indolocarbazole, an inhibitor of Topo-isomerase, in metastatic CRC; an oral formulation of Irinotecan; and monoclonal antibodies targeting CD-40 and CTLA – 4. Edotecarin induces single strand DNA cleavage more effectively than Camptothecin. The cleavage site is distinct from that of Camptothecin, Irinotecan, and SN-38. Unlike other topo-1 inhibitors, it is less cell cycle dependent. An ongoing phase II trial in 5FU-exposed metastatic colorectal carcinoma employs Edotecarin 13mg/m2 by 2 hour infusion every three weeks (Nahum Abstract 1099 ASCO 2003); 50% of enrollees had metastases to the liver. The incidence of grade 3 diarrhea has been minimal (4%), with only a 38% incidence of grade ³ 3 neutropenia. The response rate to date is 12%, with median survival 9.9 months. Oral Irinotecan has been assessed in phase I trials at escalating doses from 50 to 60 and ultimately to 70mg/m2 daily x 5 every three weeks (Berlin J et al, Abstract 521 ASCO 2003). The recommended phase II dose is 60mg/m2; DLTs include diarrhea, nausea, febrile neutropenia, and transaminase elevation. Partial responses have been observed in esophageal carcinoma and in SCLC. In addition, investigator-initiated trials are evaluating the role of Celecoxib in combination with either radiation or chemoradiation. Celgene Dr. Zeldis reviewed the Celgene pipeline. Thalidomide, which was previously taken off the market because of its Teratogenic effect in developing fetuses, was re-discovered in the 60’s and 70’s to have efficacy in the treatment of leprosy. In 1998, Celgene obtained FDA approval of this agent for use in erythema leprosum. More recently, activity has been discovered against myeloma, as well as other tumors; and using a human umbilical artery explant assay, its antiangiogenic effect, previously surmised, has been verified. A new class of agents includes the immunomodulator/antiangiogenic compounds (IMiDs) including Revimid and Actimid. Unlike thalidomide, these agents are non-teratogenic, non-sedating, non-constipating, with little evidence of neuropathy. Each of these agents is given orally, and each has similar effects on adhesion molecules, inflammatory cytokines (particularly IL6, IL8,IL10), immune cell modulation and angiogenesis. Revimid has undergone multi-center randomized phase II testing, either alone or in combination with dexamethasone in patients with relapsed or refractory multiple myeloma. A > 10% CR rate was observed with few adverse events, and no obvious difference in response rate between BID and once daily regimens, though the once daily regimen was better tolerated. A phase I/II trial of CC-4407 has established 2mg daily as the MTD; DLTs include neutropenia and thrombocytopenia. In this effort, 66% of 24 patients evaluated had more than a 25% decline in M protein; in addition, several CR’s were recorded. Median survival equaled 77 weeks. Thalidomide has also been evaluated in myelodysplasia, producing erythroid responses in severely anemic, previously transfusion-dependent individuals. An evaluation of CC5013, its congener, in MDS in 36 evaluable patients demonstrated an erythroid response of 67%, a major platelet response in 17%, and a major neutrophil response in 20%. 10 of 11 major responses occurred in patients with 5 q (-) syndrome. This agent will also be developed in renal cell carcinoma, NSCLC, myeloma, and inflammatory diseases such as Crohns, each of which has been associated with 5q deletions. In particular, deletion of 5Q13/Q33 confers the greatest degree of sensitivity to this compound. Ongoing studies are assessing thalidomide in combination with WBRT for GBM. A separate, ongoing phase I protocol orchestrated by Dr. Fine of the NCI assesses CC-5013 in combination with WBRT in GBM. Interim analyses in other studies have demonstrated tolerability with an unanticipated fringe benefit of vanishing seborrheic or senile keratoses. Daliani has documented a 72% major PSA response in chemo-refractory androgen independent prostate carcinoma in patients receiving combinations Estramustine, Thalidomide, and Paclitaxel. Cell Therapeutics (CTI) Dr. Robert Earhart of CTI reviewed the latest trials evaluating Xyotax (CT-2103). This is a polyglutamated Taxane, noted for its putative therapeutic advantages over conventional Paclitaxel. The polyglutamated vehicle improves delivery of water- insoluble agents, avoids toxic carriers such as cremophore, proves stable in plasma, and is non-degradable by plasma esterases, with presumably less exposure of active compound to normal organs. In addition, in vitro, it bypasses the MDR pump because of uptake by pinocytosis; theoretically, this leads to enhanced half life and enhanced accumulation in tumors. It exploits highly permeable tumor vasculature, and is retained at the tumor site because of its resistance to lymphatic drainage. Against NCIH 460, a human large cell lung cancer cell line in nude mice, it has proven far more potent compared to Docetaxel. In addition, compared to Paclitaxel, it yields a far lower plasma free Paclitaxel AUC. Whole body autoradiographs of mice after tail vein injection of PG-3H Paclitaxel demonstrate uptake after one week in the reticulo-endothelial system (RES), and in the tumor sites, but virtually nowhere else. The distribution half-life therefore is 7-10 hours while the elimination half-life is more than 160 hours. In addition, the amount of unconjugated Paclitaxel is less than 3% of the total plasma content at the conjugated taxane. There does not appear to be any accumulation on a q3 week schedule. Xyotax has been administered in phase I studies in multiple tumor types as well as in NSCLC in both first and second relapse. It has also been tested in combination with either Cisplatin or Carboplatin. The MTD for Xyotax in combination with Cisplatin (75mg/m2) is 210mg/m2. The MTD for xyotax in combination with Carboplatin (AUC6) is likely in the range of 235mg/m2. Despite its putative advantages, neuropathy has been observed in these trials. Phase I data have demonstrated activity in NSCLC, ovarian cancer, and breast cancer, and tolerability in doses above standard Paclitaxel. Because of polyglutamation, routine premedications are not required, and HSRs are infrequent. Three separate phase III registration trials are ongoing. STELLAR 2 in relapsed NSCLC is a direct comparison of Docetaxel 75mg/m2 to xyotax at 210mg/m2 every three weeks. To date, of 840 patients targeted for accrual, 501 have been enrolled. STELLAR 3 is a phase III trial comparing Paclitaxel 225mg/m2 and Carboplatin (AUC6) to xyotax 210mg/m2, and carbo (AUC 6) in treatment-naïve, PS2 NSCLC. A companion trial (STELLAR 4) with identical eligibility compares single agent Xyotax to either single agent Gemcitabine or Vinorelbine. STELLAR 3 has completed accrual with more than 400 patients enrolled. STELLAR 4 has enrolled 206 of 370 patients targeted. There is also evidence of synergy between Xyotax and radiation. In OCA-1, 80mg/kg 24 hours before XRT yields an enhancement factor (EF) of 4.28 while 60mg/kg 24 hours after XRT yields an EF of 4.44. In addition, XRT appears to enhance tumor uptake of PG-TXL. In summary, PG-TXL is a potent enhancer of tumor radio- response both after and before single fractionated radiation. The effect is far stronger than that predicted by the parent drug. Finally PG-TXL does not modify normal tissue radio-response; therefore it potentially has a higher therapeutic ratio compared to parent drug. Dr. Earhart actively solicited LOI’s for studies evaluating combination PG-TXL and RT. An ongoing phase I study at MD Anderson tests CT-2103 in combination with XRT for locally advanced unresectable NSCLC. Separate trials at MSKCC and Brown University are evaluating Xyotax, Cisplatin, and RT for both esophageal and gastric carcinoma. Finally, Dr. Erhardt reviewed the role of Trisenox, an agent affecting multiple cellular signaling pathways, leading to cellular differentiation, growth inhibition, and apoptosis. Pre-clinical models have demonstrated synergy between Trisenox and RT in the therapy of glioma, and a phase I trial at Stanford is evaluating arsenic trioxide (Trisenox) and stereotactic radiosurgery for recurrent malignant glioma. A separate pediatric trial at Hopkins is evaluating arsenic trioxide in the treatment in diffuse, intrinsic pontine gliomas of childhood. Specific Protocol Reviews Dr. Wong of the Medical College of Wisconsin presented a phase III concept for head and neck cancer comparing systemic chemotherapy alone to re-irradiation in combination with systemic therapy for patients who had failed previous definitive RT. Standard therapy in this group generally consists of cytotoxic agents alone, but a number of “boutique options” are emerging, including re-irradiation +/- chemotherap