Committee Minutes - Head and Neck Cancer HEAD AND NECK CANCER COMMITTEE (JANUARY 2008) Kian Ang, M.D., Chair Active Protocols RTOG 0522: Accelerated RT/Platinum +/- Cetuximab More than 400 patients have been enrolled; complete accrual is expected in approximately 1 year. Dr. Ang provided additional examples of deviation of target volume delineations and dose distributions from the IMRT Quality Assurance Reviews collected by Dr. Rosenthal and himself. He also summarized the data of a recent published paper by Dr. Bernier and colleagues in the Annals of Oncology providing management guidelines for cetuximab-related skin reactions. The PET portion of the study was discussed. Approximately 25% of the patients enrolled in RTOG 0522 have had a pre-treatment PET study and only half of these are getting the second scan after treatment. Suggestions were made for how to improve enrollment in the PET portion of RTOG 0522. Sometimes approval of the second scan has been denied by insurance companies. If the ordering physician indicates the scan is needed for "neck dissection planning" it is more likely to be approved. All scans will need to be from credentialed CT/PET scanners, including both the baseline and the post-treatment scan. Test for screening patients for hypersensitivity to cetuximab may soon be available (see last item of the minutes) RTOG 0514: Tissue Banking A revision will be made regarding case credits for tissue acquisition on RTOG 0514. A proposal will be forwarded to headquarters where 1 case credit will be given for fresh tissue or for paraffin blocks and one-half credit for fixed tissue. It is hoped increased rates of tissue acquisition will be seen so we can incorporate future biomarkers such as HPV, EGFR status, and other biomarkers. RTOG 0435: KGF The accrual to this trial, approximately 1½ years ago, has been very slow. So far, only 21 patients out of a targeted 300 have been registered. The assessment module has been revised and reimbursement has been increased in the last few months. Reasons for possible slow accrual are conflicting eligibility with RTOG 0522, rigorous follow-up schedule, high dose platinum required, altered fractionation preferred by some centers, and exclusion of oral cavity sites. A proposal to include post operative patients is under consideration and was presented for discussion by the full committee. This would include oral cavity patients and any other site that is treated with surgery and requires post operative chemoradiation. Another option is to also permit weekly platinum as an alternative to high dose every 3 week regimen. A show of hands from the full committee indicated approximately 60% of those in the audience would be in favor of revising the trial to include post-operative patients and oral cavity patients. This revision will be further discussed in the near future. We are also awaiting results of 2 recently closed Amgen trials where data is expected shortly. RTOG 0514: Head and Neck Tissue Bank Dr. Weber presented recent information including an accrual rate of approximately 8 per month. This study also suffers from slow accrual, in part because there are no current post-operative trials open. There is also competition within each institution for tissue. Of the first 99 patients registered as potentially eligible, only 60% have been enrolled in RTOG clinical trials. Increased case credits for fresh or paraffin embedded tissue (one case credit) and one-half credit for fixed tissue will be proposed to the RTOG Steering Committee to potentially further enhance enrollment. RTOG 0615: Nasopharynx Cancer This protocol has accrued 14 out of 47 patients. Princess Margaret Hospital is soon joining the study. There have been no grade 5 reactions seen. The protocol will be put on hold as planned after enrolling 16 patients for the required assessment of acute toxicity and safety review. Update on NCI H&N Steering Committee Dr. Trotti presented an update on the status of the NCI Head and Neck Steering Committee and Task Forces. The NCI Head and Neck Steering Committee was created in December 2006 as part of the restructuring of the NCI. The purpose is to review and prioritize larger Phase II Trials (> than 100 patients) and Phase III Trials funded by NCI. Other goals are to promote efficiency and accelerate overall progress in head and neck cancer research. The Steering Committee has recently completed the appointment and creation of four task forces including: Previously Untreated/Locally Advanced Disease, Metastatic/Recurrent Disease, Tumor Biology and Imaging, Rare Tumors. Dr. Trotti shared a list of the members of the overall Steering Committee and of each of the Task Forces. There are more than 60 unique members involved in the Steering Committee and Task Forces (overall, approximately 75 total members with some overlap between committees). There is broad stakeholder involvement including patient advocates, representatives of the NCI, NCIC, cooperative groups, cancer centers and Spores. The first trial for review by the NCI Steering Committee will be RTOG 0811 (Phase III trial for adjuvant therapy for patients with intermediate-risk surgical-pathologic features). The previous review process of such trials involved CTEP administrators plus selected invited reviewers. The new process now involves assignment by the Steering Committee of specific reviewers which may involve the Task Forces or other individuals selected for their expertise. One goal of the review process is to minimize the turn-around time so trials are reviewed in an expedited fashion. There are also Conflict of Interest policies to avoid undue influence by any particular parties. Lastly, the NCI Head and Neck Steering Committee is developing a proposal to hold a State of the Science Meeting (SOTS) in the fall of 2008. This meeting will focus on biomarkers, particularly HPV and EGFR. The proposal will be submitted for funding and the outcome is not known at this time. Developing Studies RTOG 0619: Post Op Adjuvant Radiation Platinum vs Platinum/ZD6474 This study has been reviewed several times by CTEP and many questions have been raised and answered by the Principal Investigators and RTOG. Dr. Ang reviewed the rationale for the choice of the agent based on clinical and pre-clinical data. The current plan is to resubmit this study either directly to CTEP or through the new review process now under the NCI Head and Neck Cancer Steering Committee. RTOG 0811: IMRT + Cetuximab for Intermediate Risk Resected Head and Neck Cancer Dr. Machtay presented the history of development of this trial in various forms. It was initially proposed as a Phase II randomized trial and using erlotinib. However, the commitment for further development of erlotinib in head and neck cancer might change because of the positive result of the EXTREME trial. This phase III study showed the superiority of the combination of cetuximab with cisplatin/carboplatin plus fluorouracil versus cisplatin/carboplatin plus fluorouracil in patients with metastatic or locally recurrent head and neck cancer (also see below). The current proposal is for a Phase III randomized trial with or without cetuximab in intermediate risk post-operative patients. The required sample size is 528 patients; the primary end point is overall survival (improvement in 3-year rate from 60% to 73%). The possible issues with this trial were discussed including the possibility of giving post-radiation cetuximab for additional 3-6 cycles based on favorable preclinical data. The details of eligibility are also somewhat controversial. We also plan to introduce IGRT accreditation process. Other groups may be recruited include NCIC or a European group. A poll showed high interest from the committee members. This study will be reviewed by the NCI Head and Neck Steering Committee. Reirradiation Proposal: Cetuximab-Based Biochemotherapy Followed By Reirradiation Plus Cetuximab Stuart Wong reviewed recent results from the EORTC "EXTREME" study. This showed the addition of cetuximab to cisplatin/carboplatin plus fluorouracil improved survival in patients with metastatic or locally recurrent disease. This is the first improvement in systemic therapy for head and neck cancer since almost three decade of studies. It is felt this may lead to FDA approval of this triplet. Dr. Wong described several patient sub-groups that may benefit from induction bio-chemotherapy followed by concurrent radiation and cetuximab. He outlined the patterns of failure and rationale for such a trial. Possible pit falls were discussed. This study will be further reviewed for scientific design and feasibility. Concept: Phase III Trial in Advanced Larynx Cancer Dr. Ang described recent results of the GORTED Larynx/Hypopharynx Trial led by Calais (oral presentation ASCO 2006, unpublished at present). This trial randomized patients to receive either TPF or PF induction chemotherapy followed by radiation therapy alone showing a benefit in favor of TPF. A Phase III Trial with the following three potential arms was proposed: Arm 1) Concurrent radiation - cisplatin per RTOG 9111 Arm 2) TPF Induction x 3 followed by radiation (or surgery in poor responders), Arm 3) TPF Induction x 3 followed by radiation with concurrent cetuximab (or surgery in poor responders). The third arm involving cetuximab will be added to the trial if RTOG joins the study and provides sufficient patient numbers. There is currently a pilot trial of Arm 3 ongoing in the GORTEC Group. The primary end point of such a trial would be larynx preservation, utilizing a composite endpoint of survival without tracheostomy or prolonged G-tube. Also under consideration is a simpler tracheostomy rate comparison. The secondary endpoint would be evaluating whether TPF impacts the rate of metastases. If endorsed by the Head & Neck Cancer Committee, this study will be further developed and submitted to the NCI Head and Neck Cancer Steering Committee for further consideration. Questions will arise regarding data sharing policies between the GORTEC Group and the RTOG. This may also be useful to promote collaboration regarding the two organizations regarding other trials such as RTOG 0811 Intermediate Risk Post-Op Trial. H&N Surgical Subcommittee Dr. Randy Weber reported the data of Salivary Gland Transfer Trial will be analyzed. He updated the committee on plans for a T1 Glottic Trial utilizing PDT. This concept is expected to be reviewed at the June meeting. He also described the ongoing development of the Advanced Skin Cancer Trial using induction EGFR inhibitors, gefitinib. A different type of agent is currently under consideration. He also discussed the implications of HPV in H&N trials in terms of patterns of failure and a possible surgical trial addressing these questions. Translational Research Program (TRP) Report Dr. Christine Chung has become the liaison between Head & Neck Cancer Committee and the Translational Research Program. She reported on five TRP Projects. Standardization of Immunohistochemistry (project leader, Quynh Le). This is in a collaboration with Dr. Tony Magliocco in Calgary, Canada regarding use of AQUA to standardize IHC reading quantitatively. HPV analysis of RTOG studies. (Maura Gillison, project leader). Dr. Gillison will soon be publishing provocative data from a previous ECOG Trial indicating that the overall survival and progression free survival rates are better in patients with HPV+ vs those with HPV- tumors. Her proposal under discussion is to test for the impact of HPV status on outcome in RTOG trials. Genome based prognostic and predictive markers (project leaders Torres-Roca and Chung). Dr. Chung described previous work in developing prognostic signatures. She also described work recently done by the Dutch group showing a 42 Gene Signature which appears to be a positive predictive marker for response to radiation-platinum-based regimen. The proposal is to study a Genetic Signature in RTOG trials 9914, 0129, and 0522. Serum proteomics to predict overall survival after cetuximab-based radiation therapy (project leader Christine Chung). Dr. Chung described work done in patients with lung cancer showing a specific protein pattern is predictive for response to erlotinib or gefitinib. Dr. Ezra Cohen has also done a protein analysis on head and neck patients at his institution with similar results. A proposal is under development a similar study in head and neck cancer patients. To be clinically useful, such analyses require a small amount of serum or plasma, has a quick turn around (24 hours), and gives a dichotomized answer. Serum Assay to predict anaphylactic reaction to cetuximab (project leader Christine Chung). Dr. Chung described the higher rates of anaphylactic reactions to cetuximab in the Tennessee and North Carolina region which approach 20-30%. Her study, soon to be published in the New England Journal of Medicine, showed elevated IGE levels in patients with severe reactions. A comparison of IGE levels in normal human volunteers in the Nashville area, the Stanford area, and the Boston area were made and showed a higher rate of elevated levels of IGE in certain regions of the country corresponding to higher risk of anaphylactic reactions. The plan is to develop a 48-hour turn around serum test useful for screening of patients having higher risk for anaphylactic reaction with cetuximab. The plan is to make this test available for screening patients who are eligible for RTOG 0522 and, when activated, RTOG 0811. HEAD AND NECK CANCER COMMITTEE (JUNE 2007) K. Kian Ang, M.D., Chair Dr. Kian Ang opened the committee meeting by presenting an overview of the progress of head and neck cancer research as discussed at the Friday conference. He noted five year survival has increased in several subsites. There have been improvements in overall survival, local control, and organ preservation. He also pointed out ongoing challenges including increased mucositis, late morbidity (especially swallowing) and he questioned whether we are "over treating" some populations. He noted the ongoing efforts for discovery and applications of biomarkers. He believes the future of trials involves an individual patient centered approach as well as a treatment centered approach, in combination. He pointed to the ongoing process of refining endpoints and developing surrogate endpoints. He also noted progress in recording and reporting morbidity and the contribution of Dr. Trotti in this filed. He noted how it is important for all research organizations and investigators to use the same standards and speak "the same language". ACTIVE PROTOCOLS: RTOG 0244: Dr. Jha reported 45 out of 48 patients had been enrolled. He also noted a Canadian phase III trial has been completed and was stopped early due to positive outcome. An intern analysis has been performed and a manuscript has been submitted. RTOG 0522: More than 200 patients have been enrolled at a rate of approximately 20 patients per month. The PET scan component of the study is not accruing as well as planned. Only 26 % of patients who were eligible for this study have been enrolled. A question was asked whether patients who have a pre-treatment test at another institution can be enrolled. Dr. Schwartz indicated they could be and institutions submitting the post-treatment PET scan would receive credit retroactively. Investigators are encouraged to contact Dr. Schwartz for details. Dr. David Rosenthal presented some examples of the IMRT QA review ongoing for this protocol. Drs. Ang, Rosenthal, Nguyen, and Thorstad are conducting this review. He indicated this has been a learning process for all involved and guidelines and feedback is developing as experience increases. He noted some examples where there were insufficient margins around the GTV. He showed some examples where avoidance structures should be considered to limit dose to anterior and posterior tissues. Bilateral parotid sparring is permitted and encouraged when feasible. Circumferential margins should be made around the entire target including above and below the gross tumor volume target ("end-capping"). It is important to truncate the targets at bone or vertebral body interfaces in some cases. It is also helpful to delineate the cochlea and middle ear to minimize dose to these structures. RTOG 0514: Dr. Weber reviewed the eligibility for this trial which includes any patient who is eligible for a therapeutic trial. It is preferable to obtain normal tissue sample from the buccal mucosa. If a patient does not eventually go on to an RTOG study, the tissue will be used for standardization of laboratory procedures. One half case credits will be awarded for fresh frozen tissue (as well as funding). Paraffin blocks will receive funding but no case credit. So far, 53 patients have been enrolled. The local principal investigators are encouraged to share reimbursement among the contributors. RTOG 0435: Dr. Rosenthal described the recent revision submitted to CTEP. This includes standardization for radiation dose to 70 Gray in 35 fractions using IMRT. CTC-based mucositis grading was by simpler scoring system consisting of scores for pain, oral intake, and degree of ulceration. The WHO score will be derived from this data at RTOG headquarters. A new training module, which on average takes 15 minutes to complete, will be used. The first module was found to be confusing to some investigators and an overhaul was deemed necessary. Case reimbursement for this study has increased to $4,000 for CCOP institutions and $5000 for non-CCOP Institutions. RTOG 0615: This protocol for nasopharyngeal carcinoma is now open for accrual. DEVELOPING PROTOCOLS RTOG 0619: Dr. Raben described the protocol concept for testing a new agent, ZD6474 inhibits both the EGFR and VEGFR pathways (a dual target inhibitor). He described the argument for using this agent versus using alternative agents. A show of hands was taken regarding how patients with high risk pathologic features are currently managed. About 80 % of members indicated they prescribed postoperative radiotherapy with concurrent cisplatin. Cetuximab is often used in patients who are not deemed eligible for receiving cisplatin. RTOG 0629: Dr. Machtay briefly presented this trial. He is wondering whether there are sufficient patients available for enrollment. About 20 investigators raised their hands to indicate they have more than 5 patients per year eligible for this trial. There seemed to be a much stronger interest in using erbitux as the sensitizer compared to erlotinib. Development will continue. UPDATE ON THE FORMATION OF THE NCI H&N STEERING COMMITTEE Dr. Trotti presented an overview of the ongoing NCI Clinical Trials Working Group reorganization. The new structure involves development of disease-specific steering committees to evaluate and approve all NCI funded trials. These will replace the previous NCI Concept Evaluation Panel approval process. These new steering committees are composed of membership by the cooperative groups, SPORES, cancer centers, and other grant holders. Thus all stakeholders are encouraged to participate and decide on the best use of NCI resources and ensure the application of the best available scientific evidence. The first steering committee launched was the Gastrointestinal Cancer Steering Committee. This committee has endorsed its first trial, which is the RTOG esophagus trial. The Gynecology Cancer Steering Committee is in development and has not yet generated a trial. The Head and Neck Cancer Committee is the next in line. Three equal co-chairs have been named (Arlene Forastiere, David Schuller and Andy Trotti). This Steering Committee will be charged with approving any future phase III H&N trials generated by any stakeholders within the NCI funded organizations. The next step for the NCI Head and Neck Cancer Steering Committee is development to assemble and to populate members of task forces. Four task forces have been identified to address locally advanced disease, biomarkers and Imaging, rare diseases (including salivary glands and thyroid cancers), and recurrent/metastatic disease, respectively. Individuals interested in participating in these task forces are encouraged to contact Dr. Trotti. SURGICAL SUBCOMMITTEE REPORT Dr. Weber reported the larynx photodynamic trial is still under development. His group is exploring the feasibility of a limited institution participation trial involving carcinoma in situ or T1 carcinomas. He also reported on the squamous cell carcinoma skin trial in development. TRANSLATIONAL RESARCH PROGRAM Dr. Stuart Wong did a brief update on activities of the translational research program. He encouraged participation in the tissue acquisition of RTOG 0514 Protocol. The TRP is struggling with identifying a standard method for IHC analysis. Automated image analysis method, AQUA, is being explored. HEAD AND NECK CANCER COMMITTEE (FEBRUARY 2007) Andy Trotti, M.D., for K. Kian Ang, M.D., Chair Dr. Trotti opened the meeting by welcoming everyone. He announced Dr. Stuart Wong will be the new Head & Neck Medical Oncologist and thanked Dr. Everett Vokes for his years of service to the committee. Business: 1. RTOG 0129: Jonathan Harris reported on the recent DMC data analysis. After 184 deaths, the DMC sees no reason for early reporting. The next planned analysis will occur after 369 deaths. Comment: The next planned analysis will not occur for several more years. By that time, most of the accrual to RTOG 0522 (using the experimental arm from RTOG 0129 as the control arm) may be very far along or completed. At the steering committee, this prompted discussion of using DFS as a surrogate endpoint (for OS) to get an answer sooner. The work by Bourhis/Meta-analysis group suggests DFS is a valid surrogate in chemotherapy RT studies. This would require a new statistical plan to be submitted to NCI. Dr. Tom Pajak indicated he could develop a new statistical plan on RTOG 0129 after the 2007 ASCO Meeting. RTOG Head & Neck Steering Committee also suggested we look into the potential impact of HPV to potentially explain the rising baseline of improved outcomes in recent years where control arms have done better than historically similar groups. This may be why it takes longer to follow-up in RTOG 0129 since fewer events are seen. On a related topic, the proposal to TRP by Gillison to investigate HPV in RTOG 9003 may not be feasible since blocks have been used up by other studies (see list of blocks and materials provided by Liz Hammond). Dr. Tom Pajak indicated we could possibly look at outcomes in control arm of RTOG 0129 where there are 111 blocks available (HPV pos versus negative; and compare overall outcomes to RTOG 9914). The RTOG Head & Neck Steering Committee suggested a conference call on the topic of HPV to discuss ways to address HPV issues including: What is the best method to assay for HPV? Which RTOG studies can be looked at retrospectively? Can we quickly assay and stratify by HPV status in future studies? Adel, Arlene/Maura Gillison and others volunteered to participate. 2. RTOG 0421: Dr. Wong conducted a "post-mortem" analysis of why this study failed to accrue. The answer from the survey was reirradiation is offered off-protocol or on an in-house study at many centers. GORTEC ran into the same problem and had to shut down their study after 46 patients enrolled (a combined RTOG/GORTEC analysis may be proposed). A new proposal by Dr. Wong was presented with a fractionation question. Continuous course HFX to 60 Gy in 5 weeks (1.2 BID) versus alternate week HFX (1.5 BID; wks 1, 3, 5, 7to 60 Gy in 7 weeks). Both arms to get weekly cisplatin and cetuximab. There seemed to be strong interest in doing another reirradiation study with both arms containing radiation. Comment: Dr. Stuart Wong got a good response on this proposal from a show of hands at the full committee meeting. Both the full and steering committees were very interested in seeing something new in reirradiation. Physicians may prefer to offer reirradiation on a protocol, rather than an ad hoc/off study, due to high risks of late toxicity and death. The bottom line is that reirradiation studies may not be dead, but we must include RT in both arms. I suggest the development of a new reirradiation proposal be taken up in a conference call for further development. Alternate designs including a comparison of different targeted agents should be considered. 3. Salivary Gland Transfer Study: Dr. Jha updated the current accrual on this study which is 41 patients. The target accrual is 48. Dr. Jha hopes by the next meeting, the study will have achieved its study accrual goal. There is also a phase III comparison of pilocarpine versus salivary gland transfer in Canada and indicated this is accruing well. 4. RTOG 0514: Dr. El-Naggar in Dr. Weber's absence stated the total of number cases is 35 with a total number of institutions contributing cases equaling 11. The rate of accrual is 5 per month. He emphasized that credit depends upon submission of paraffin or fresh tissue only. Breakdown of compensation for tissue was reviewed. A discussion ensued regarding the importance of tissue bank. Adel encouraged groups to participate. 5. RTOG 0522: Drs. Trotti & Rosenthal updated status of the trial. There have been rumors of additional supplementary funding for this study which needs to be confirmed. The current accrual is 123 with a target of 720 patients. The previous rate of accrual was 12 a month and has gone up to 18 per month in December. The accrual rate is expected to continue to rise after correction of restrictive laboratory values on an amendment will be coming out shortly. IMRT Quality Assurance. Dr. Rosenthal discussed QA and showed an example of target and dosimetry deviations. A separate panel of 4 MDs are doing RT QA review. A reminder was given that the first case must be reviewed before the 2nd case is treated in an effort to improve compliance and deviations from target delineation and coverage. Questions were taken from audience regarding study issues (brachial plexus coverage; repeat planning during treatment-issues that are up to investigator discretion) PET sub-study. Dr. Schwartz reviewed the purpose, procedures, and status of the RTOG 0522 PET sub-study and the compliance reviewed is as follows: For 1st PET: Goal is 75%, actual 27% For 2nd PET: Goal is 50%, actual 30% Dr. Schwartz urged the committee to participate in the sub-study. He gave a reminder that this study awards extra dollars and 0.5 case credit if BOTH pre and post- treatment PET scans are submitted. Also he announced Health Care Canada has approved reimbursement for PET imaging of this study. Increased awareness of this study via RA groups with round table discussion was suggested for the next meeting. 6. RTOG 0435: Dr. Rosenthal summarized the study. This study was activated on July 6, however to date only two patients have accrued. A reminder was made this study is now listed on RTOG Head & Neck webpage under both Supportive Care and Head & Neck Trials. Increased funding will be provided by AMGEN and RTOG (to somewhere in the $5000 range). An investigator breakfast meeting was held on this trial to discuss the need for a change to a web-based mucositis grading training module. There is a new training module in the works. The full committee was surveyed as to the reasons why study is not accruing at a higher rate. Comments were made that an AMGEN sponsored study competes. Dr. Rosenthal pointed out this should not impact significantly on the RTOG study; he urged committee to increase awareness of study candidates. 7. RTOG 0629: Dr. Machtay reviewed a study design for an intermediate risk study for a randomized phase II study of IGRT + erlotinib. There was a general committee survey about current use of IGRT utilization: a) A large proportion of audience indicated current or near future use of IGRT (daily imaging) b) A smaller proportion indicated interest in combining a targeted agent to IGRT. Comment: Dr. Mitchell Machtay pitched this to both committees: IGRT +/- tarceva. He thinks the locoregional control in this population is not as good as assumed from single institution studies, but others seem to disagree. Tom offered to investigate the outcome of patients in RTOG 9501 with 2 positive nodes but no other adverse features. There seemed to be strong interest in adding a drug to this population from the full committee if we can develop a rationale for the agent and the endpoints. We still don't have any idea how many intermediate risk patients are available in the RTOG membership for study. Tarceva needs a rationale to impact risk of second cancers, so "failure" can include second primaries. Dr. Mitch Machtay is working on this. We are still struggling with the endpoints: function-free survival may be doable as quality adjusted survival if we think feeding tube dependent patient have a worse overall outcome due to poor nutrition and declining performance status. Dr. Tom Pajak can test this in database and see how patients do with feeding tubes at 1 year to see if they have worse survival at 3 year follow-up than those without feeding tubes at 1 year? 8. Gefitinib Skin Cancer Study: A discussion was tabled until the next meeting when Dr. Weber can provide an update. 9. Eric Sherman: He discussed a concept for adjuvant chemotherapy for high risk patients with LN positive following definitive RT and a phase II cisplatin or carboplatin and docetaxel and ZD 6474 x 3 cycles. This study would need to capture patients not on RTOG 0522 or 0435 so as not to conflict with therapeutic questions in those trials. An investigator interest was polled toward the end of the meeting and the crowd was starting to shrink but a few centers said they see at least 5 patients per year with positive neck dissections. A tentative sample size equaling 47 patients and Drs. Sherman and Pajak estimate 35% of patients post definitive RT will have positive LN on RTOG 9501 & 0234 but rate of neck dissection is declining nationally. Comment: Do we have the patients? Tolerance/compliance of chemotherapy post RT or chemotherapy/RT may be very low. 10. Dian Wang: He discussed a revised concept and its impact of FDG PET on GTV definition. He proposed a companion study to RTOG 0522 and 0435. With a proposed N=42, but not yet confirmed by a RTOG statistician. Critical and supporting comments made by general committee. Survey: a) How many use PET for planning? ~ < 50% b) How many have dedicated PET for tx planning? More than previous question (still <50%) Comment: There seemed to be significant interest doing something in the area of "functional imaging" in treatment planning, but the best study at this time is not clear. Paul Harari indicated this study could be done more quickly by an ad hoc interest group which is a good point. Dr. Wang has resubmitted a revised protocol after the meeting that needs to be carefully considered. Also, we should look at the recently opened RTOG 0515 lung study that appears to be a similar study design. I suggest a conference call on this topic and perhaps invite Dr. Jeff Michalski to join so he can discuss where this fits into IGRT Committee plans. 11. RTOG 0530: Dr. Sidhu presented concept for Curcumen + aspirin for high risk patients (Stage I, II, III [T3, T1-3N0]). N=165, endpoint reduction of second primary tumor. Design open label single arm phase II, using historical control RTOG 9115. Survey of interest: >>50% (High). This trial will soon go to DCP for review. Comment: Informal surveys of the steering and full committees by "show of hands" can be very tricky and depends how you ask the question and how enthusiastic the speaker is. Dr. Stuart Wong noted big decisions are often made based on this unscientific polling which has wide error bars. He suggested we consider more formal feedback from an audience via hand held response devices at the next meeting, I am in favor of trying this as well. HEAD AND NECK CANCER COMMITTEE (June, 2006) K. Kian Ang, M.D., Chair The meeting was chaired by Dr. Ang along with Drs. Trotti and Weber and the following protocols and proposals were discussed. Active Trials RTOG 0234 - High Risk postoperative adjuvant study with radiation + cetuximab. + cisplatin or docetaxel. This randomized phase II study is accruing well and is expected to reach the enrollment goal by November 2006. A follow up trial is being planned (see RTOG 0619 below). RTOG 0244 - Salivary Gland transfer study. This phase III study has now enrolled 38 patients which are slower than anticipated. It will be closed to enrollment if it does not meet the target by November 2006. RTOG 0421 - Reirradiation + chemotherapy vs. chemotherapy alone for local recurrence or second primary in previously irradiated volume. Dr. Wong reviewed the schema of this phase III trial and appealed for accrual. A minor amendment had been submitted to CIRB for approval. RTOG 0514 - Tissue Banking Study. Dr. Weber informed the membership out of the 10 patients enrolled, only 2 had fresh tissue submitted. It was emphasized the main goal of this study is to collect fresh frozen tissues and for reimbursement, centers have to send in fresh tissue or blocks. Patient IDs will be de-linked from tissue samples. RTOG 0522 - Radiation-cisplatin with or without cetuximab for locally advanced HNSCC. Dr. Ang announced the accrual to this phase III protocol is increasing and, so far, more patients have been treated with IMRT. He also clarified if the CT component of the PET/CT scan is not done with contrast, then this imaging modality does not substitute for a diagnostic quality CT or MRI with contrast for staging purpose. PET/CT is investigational in this protocol. The results of PET/CT will be correlated with the pathologic finding of neck dissection, and the local-regional control. Both are needed to evaluate response. PET is to be correlated with local control and pathologic response in the neck. The decision for neck dissection should be made based on clinical and CT or MRI findings. Developing Trials RTOG 0435 - KGF for reduction of mucositis. This trial will be activated soon. David Rosenthal reviewed the design and discussed the need for frequent mucositis assessments. Investigator training session was conducted at a breakfast meeting. RTOG 0615 - Phase II Nasopharyngeal study. Adam Garden presented the background and protocol draft. The rational for this is with the use of IMRT with chemotherapy, distant metastasis has become the primary pattern of failure. Therefore there is a need to address systemic failure with additional agents. Bevacizumab was selected because it had been shown to enhance the effects of chemotherapy in colorectal, lung, and breast cancer. A phase II, single arm study involving radiation plus platinum and bevacizumab, adjuvant cisplatin-fluorouracil with bevacizumab, followed by 6 months bevacizumab maintenance was approved conceptually at the previous meeting. With the subsequently endorsement of CTEP a protocol was written and submitted for review. RTOG 0619 - This is a replacement of postoperative adjuvant trial for patients with high-risk features (RTOG 0234: post-op RT + cetuximab + cisplatin or docetaxel). David Raben presented a proposal using ZD6474, an oral dual inhibitor of both EGFR and VEGF. This would be a randomized phase II trial comparing ZD (at 100mg or 300mg QD) + weekly plat (30mg/m2) versus a high-dose plat/RT control arm. The preclinical data on ZD6474 are compelling. The protocol will be developed. Skin cancer concept. Dr. Weber presented ongoing dose escalation study at MDACC of 2 cycles of ZD1839 as induction therapy in advanced SCC of the skin. Patients with resectable disease underwent surgery (+/- post op RT) after induction. This study was developed in response to an NCI RFA, and presented for informational purposes at this time and consideration of future RTOG multicenter study development. A proposal for IGRT/IMRT as adjuvant therapy for patients with intermediate risk features was presented by Dr. Machtay. The concept was well received. The dose constraints to normal tissues and QA procedures need to be developed for further consideration. Photodynamic therapy (PDT) for dysplasia or T1 carcinoma of the glottic larynx was proposed by Dr Biel. There was concern about accrual because many states do not reimburse the procedure and RTOG has no patient enrollment track record of this treatment modality. Dr. Biel was encourage to work out the detail and survey commitment of head and neck surgeons through the Head and Neck Surgical Subcommittee. Adjuvant systemic therapy after patients with positive neck dissection (ND) after receiving chemoradiation was proposed by Dr. Sherman. The adjuvant therapy consists of cisplatin, docetaxel, and ZD6474 x 4 cycles. He was encouraged to assess the trend and number of patients who still underwent ND in recent studies from RTOG database (e.g., protocols RTOG 9703, 9914, 0129). HEAD AND NECK CANCER COMMITTEE (January, 2006) K. Kian Ang, M.D., Chair Active Trials RTOG 0234: High Risk postoperative adjuvant study with radiation + cisplatin/docetaxel + cetuximab. Paul Harari noted incorporation of IMRT appeared to have increased enrollment; 8 out of the last 16 patients enrolled were treated with IMRT. At first analysis, toxicity was about equal in both arms. Paul reviewed the history of post-operative RTOG and EORTC trials using platinum and radiation and suggested any future phase III trials conducted by the RTOG trial will need to use platinum-radiation as the standard control arm. RTOG 0244: Salivary Gland transfer study. This study has now enrolled 20 patients, up from 12 at the last meeting. However, 3 patients were found to be ineligible. Enrollment will continue. RTOG 0421: Reirradiation + chemotherapy versus chemotherapy alone for local recurrence or second primary in previously irradiated volume. Stuart Wong reviewed the trial schema. He indicated a baseline PET-CT scan is not acceptable unless contrast is used for the CT component. The interval between registration and start of radiation therapy has been extended due to the need to obtain PET scan and other work up. He appealed for enrollment to this trial. RTOG 0514: Tissue banking Study. Dr. Randy Weber reviewed the intent and eligibility for this trial. There was a suggestion from the audience a letter be sent directly to pathologists and surgeons from the principal investigators to enlist their support and explain the nature of this study. RTOG 0522: Radiation-cisplatin with or without cetuximab for locally advanced HNSCC. Kian Ang noted Centers for Medicare Services (CMS) had selected this trial for reimbursement. There are some logistical issues which still to be worked out, whether the medication is provided free or will be reimbursed by CMS at a later time. He discussed the role of the PET component of the study, which is to correlate PET parameters with local control and pathologic response in the neck. Neck dissections are determined by CT findings primarily. There were questions regarding the timing of the PET scan. Some investigators feel PET scan at 8 to 9 weeks is not as reliable as done at a later time. This timing was a compromise because of the concern of delaying neck dissection for more than 10 weeks after completion of therapy. Dr. Weber confirmed there was concern about fibrosis and he agreed on getting PET scans at 8 to 9 weeks to address the role of this test in determining the need of neck dissection. Kian noted IMRT is an option on RTOG 0522 and 36 RTOG centers had been fully credentialed and 86 additional centers had done some components. We expect most of these to convert to full credentialed status allowing many institutions to use IMRT. He also encouraged electronic data submission of treatment planning data. Jeff Michalski discussed the credentialing process for electronic data submission for PET/CT scans. Developing Studies RTOG 0435: KGF for reduction of mucositis. David Rosenthal reviewed the design of the KGF trial and discussed the need for frequent mucositis assessments. There will be an investigator training session at the next RTOG meeting in June as well an online web-based video training program. All investigators will need to complete training/credentialing for mucositis assessment prior to enrolling patients. Prevention in of second maglancy and vascular injury. Dr. Sidhu had previously made a proposal using statins (fulvastatin) and aspirin. This was study RTOG 0530. However recent clinical evidence in colorectal cancer suggests statins have no benefits in preventing second malignancy. An alternative proposal was made by Dr. Sidhu involving omega-3 fatty acids. This could be in the form of lipocapsules made by Meade-Johnson, a division of Bristol-Meyer Squibb. There are also omega-3 fatty acids in Prosure nutritional supplements. Pros and cons of this concept were discussed and this will be further developed for consideration. Nasopharyngeal replacement study. Nancy Lee discussed the history of nasopharynx studies and the use of IMRT. Emerging data revealed with the use of IMRT, distant metastasis has become the primary pattern of failure and there is a need to address systemic failure with additional agents. Bevacizumab was selected because it had been shown to enhance the effects of chemotherapy in colorectal, lung, and breast cancer. She proposed a phase II, single arm study involving radiation platinum and bevacizumab, adjuvant cisplatin-fluorouracil with bevacizumab, followed by 6 months bevacizumab maintenance. There was high level of interest from the committee and this study will be further developed. Proposal for PET/CT guided IMRT and orpharynx cancer. Dian Wang once again presented a concept for using PET scans to determine target volumes in IMRT. He took a number questions from the audience. The proposed primary end point was toxicity. Suggestions included further defining the toxicity endpoints. There was some doubt whether significant improvements in disease control can be detected in the favorable populations proposed. It was thought that the group should wait for the results of RTOG 0022 before planning a study. New concepts for high-risk postoperative adjuvant therapy (replacement for RTOG 0234). RTOG 0234 (see above) was projected to complete accrual by the end of 2006. Data will not be available to design a phase III trial until early 2008. Therefore, there will be room for testing newer agents in the intervening time. David Raben presented a concept for integrating a dual kinase inhibitor (anti-VEGFR2 and anti-EGFR), ZD6474. This group of patients was thought to be a suitable candidate for testing the study as they have an approximately equal probability of experiencing local-regional or distal relapse. There was enthusiasm for pursuing this study. HEAD AND NECK CANCER COMMITTEE (June, 2005) K. Kian Ang, M.D., Chair ACTIVE STUDIES: RTOG 0129 - Locally advanced H&N cancer. Kian Ang announced this study is now closed. A total of 737 patients have been enrolled. Data will be updated and analysis will be undertaken when the number of event are met in order to potentially contribute to the design of the next phase III trial in advance Head & Neck cancer (0522). RTOG 0225 - Nasopharyngeal cancer. This trial is accruing nicely and only needs about 10 more patients. Discussion ensued regarding possible translation of the consent form into Chinese. A possible ECOG study is in development but a satisfactory design has not been identified. RTOG 0234 - Post-Op cetuximab trial. Paul Harari discussed some tips for enhancing enrollment by encouraging multidisciplinary communication at the time of diagnosis and evaluation. He encourages investigators not to give the patient a break from radiotherapy unless there is grade 4 mucositis. Radiotherapy should be resumed after three to five days once the mucositis returns to grade 3. There are stopping rules regarding the use of cetuximab and this section of the protocol will revised soon. A poll was taken to see if the need for IMRT significantly limits patient accrual. About 1/3 of the members in the room indicated it does significantly limit accrual, about 2/3 indicated it did not. RTOG 0244 - Salivatory Gland transfer study. This study was on probation but accruals have increased. Four new centers have been added and hopefully this study will complete accrual in a more rapid fashion. RTOG 0421 - Chemotherapy vs chemo-reirradiation for recurrent disease. This study was activated in April 2005 it also opened through ECOG. IMRT is permitted, institutions are encouraged to become credentialed in IMRT. RTOG 0435 - KGF trial. The design of this study in head and neck patients was presented. KGF is now an approved drug by the FDA in the peripheral stem cell transplant population. A reduction in duration of WHO mucositis is the primary endpoint. A discussion regarding CTC versus WHO scales was presented. It was emphasized the study will require mucositis assessments twice a week for approximately fifteen weeks. Web-base training of mucositis assessment will be provided and required. Follow-up will be ten years. Questions were taken regarding the risk of tumor stimulation. Interim analysis of recurrence rates and tolerability of KGF will be performed as part of the evaluation plan. Additional work needs to be evaluating patients with prophylactic feeding tubes. RTOG 0522 - Dr. Ang discussed the completion of the design of this trial he reviewed the data from the pilot study by Dr. Pfister showing 76% 3-year survival in advance disease. Dr. Pfister supports the use 100mg/m2 of concurrent radiation q 3 weeks. The regimen for accelerated IMRT will deliver six fractions per week (twice a day, one day or on Saturday). PET Scans will be obtained at baseline in institutions and patients agreeing to be part of PET/CT component of the study. The PET/CT will be repeated at 8 to 9 weeks post treatment in patients with N2-N3 disease. Approximately 250-300 patients are expected to participate in the PET/CT portion of the study. The initial PET/CT will be correlated with primary tumor control and the second PET/CT will be correlated with pathologic outcome of neck dissection and overall neck control. A poll was taken regarding participation in the PET/CT portion of the study and a large majority of the members in the room indicated they would participate in that part of the study. CMS has agreed to pay for the second PET scan in Medicare patients. There will also be additional funding from the NIH Imaging Program to support electronic data submission of the PET scan to ACRIN. The study has recently gone through initial CTEP review and will be forwarded soon to the central IRB. Additional funding for specimen collection and a biomarker study is being pursued. RTOG 0530 - Developing study of prevention of second malignancies using fulvastatin and aspirin. Dr. Sidhu presented a proposal using these agents to reduce the risk of relapse of primary Head & Neck cancer and development of second malignancies. Low doses of these drugs will be used to prevent cancer and potentially reduce the risk of stroke. Patients will be eligible at a minimum of four months after primary head & neck treatment. Stage I-III cancers will be eligible. A baseline biopsy of mucosa will be required. Evaluations of the carotid using ultrasound were discussed. Approximately 160 patients may be required; the first draft of this trial is now at Norvartis for consideration. There was a fair amount of enthusiasm for enrolling patients in this trial by the committee membership. Proposal for PET/CT guided IMRT for oropharynx cancer. Dr. Wang from Medical College of Wisconsin proposed using PET/CT technology to enhance target definition. He presented the result of a pilot of 28 patients. Guidelines for GTV were developed and results suggest better targeting was achieved. An RTOG proposal involving 64 patients was presented. Objectives include feasibility in the multi-institutional setting, disease control, and SUV as a predictor of outcome. Discussion ensued regarding the standardization and normalization of SUV density. The RTOG membership was split about 50/50 in terms of being able to support this trial with enrollment. Risk stratification by gene expression profile. Christine Chung presented data of analysis with chips of 25,000 genes. Pilot work was done at Chapel Hill in a heterogeneous 60 patient cohort. The concept is to develop a genetic "bar code" to look for patterns and groupings of genes, which may predict for radiosensitivity, local regional control and survival. This was done on fresh tissue. A subsequent study was done using paraffin blocks and similar results were seen. This shows it is feasible to use formalin fixed tissue. This permits risk stratification of patients groups by genetic profile. Assays of circulating hematological cells as well SNP analysis will be performed to try to predict tumor control as well as normal tissue toxicity. Questions were taken regarding the use of supervised versus unsupervised analysis. Dr.Chung indicated uniformly treated patient populations such as those enrolled into RTOG 9501 would be ideal to perform supervised analysis since the treatment approach and eligibility was more uniform. A proposal will made through the translational research program committee to access RTOG archival blocks. CpG Oligonucleotides. Dr. Luka Milas presented results of preclinical studies testing this class of agents. He presented some< background on Toll-like receptors on immune cells (plasma and dendritic cells). Stimulation of these cells results in amplification of T&B cells population for participation in immune anti tumor responses. Chemotherapy and radiotherapy are known to release antigens but this often leads to T-cell tolerance. The use of CpG would be prior to treatment to cause activation of immune cells and enhancement of immunogenicity and tumor control. Questions regarding the use of radiotherapy which may affect immune functioning cells was discussed. It was felt B cells are activated are rather resistant to radiotherapy. The CpG molecules could also be used in a neoadjent setting with chemotherapy. CpG is given subcutaneously into regional lymph nodes or directly injected into the tumor. Dr. Ridge gave an update on the activity of Head & Neck Surgical Subcommittee. The fresh tissue tumor bank protocol is moving along nicely and should be open before the end year. He also presented the RAD-PLAT concept. Concern was expressed regarding the availability of interventional radiologists and the learning curve related to the procedure. There seem to be some portion of membership interested in this trial. Dr. Ridge also presented the ECOG biochemotherapy adjuvant study. Accrual has not been sufficient to keep this study alive and he is seeking RTOG participation to enhance accrual. Interest appears to be rather poor. It is unlikely RTOG can commit more than 1 patient per month, which might not be sufficient to support this trial. HEAD AND NECK CANCER COMMITTEE (January, 2005) K. Kian Ang, M.D., Chair Active Protocols: RTOG 0022 - Oropharynx IMRT protocol completed enrollment several weeks ago. A total of 66 patients were accrued. RTOG 0129 - This protocol has accrued 600 out of 720 patients and is expected to complete accrual this summer. RTOG 0225 - Nasopharynx protocol will complete accrual at the end of 2005. New concepts are under discussion. RTOG 0244 - Salivary gland protocol is under probation. It will be closed if enrollment does not pick up. RTOG 0234 - This protocol was activated in April 2004; enrollment is picking up. The principal investigator reminded the members to think of patients pre-operatively for this trial. Pre-operative imaging is required--this question was recently addressed and confirmed. In addition, a revision to the protocol will permit patients to begin radiotherapy within 8 weeks of surgery and C225 within 7 weeks of surgery. RTOG 0421 - Reirradiation vs Chemotherapy alone. This protocol has been approved by the Central IRB and should open within the next two months. It is stressed 3D planning radiotherapy is mandatory; IMRT certification is required if IMRT is to be used. ECOG has agreed to participate in this trial. Doppler studies; CT angiograms or MR angiography is recommended to rule out invasion of the carotid or significant vascular disease. Patients with circumferential tumor around the carotid will be excluded. Patients may receive reirradiation off protocol if they progress on the chemotherapy arm. Developing Protocols: Locally Advanced HNSCC: RTOG 0522 - The design of this trial was discussed with the membership at large. This protocol will test whether the addition of cetuximab to RT-cisplatin regimen will improve outcome. So, eligible patients will be randomized to receive RT-cisplatin or RT-cisplatin plus cetuximab. Cetuximab will be given weekly as used in the international phase III trial. Approximately 45 minutes was spent in discussing the dose of cisplatin. The options are: 1) high dose cisplatin in both arms, 2) weekly cisplatin in both arms; 3) high dose cisplatin in RT arm and weekly plat in RT-cetuximab am. The pros and cons of each option were thoroughly addressed. At the end discussion a show of hands was taken regarding, which options the members favored: The vote was option 1 (13), option 2(25), option 3 (6). A second vote was taken to indicate if the membership would enroll patients in options 1 or 2, if that is the final decision regarding the protocol design. Very high and equal numbers of members indicated they would enroll patients to both option 1 and option 2. A specific count was not taken. A third vote was taken asking the members if they would specifically NOT support option 1 or option 2. Only two people indicated they would specifically NOT support option 1 and six people indicated they would NOT support option 2. In summary, option 1 or 2 would be supported by the membership, although there is a preference for option 1. The PI of study, Dr. Ang, will take these votes into consideration when making a final decision with RTOG leadership, the FDA, the pharmaceutical sponsors. A permission will also be sought to review the phase II data of Memorial Sloan Kettering Cancer Center. NPC - As RTOG 0225 will complete accrual within a year, a new concept is sought. A proposal from SWOG and ECOG was considered. This study proposes to randomize between 3 cycles of carbo-Taxol induction followed by high dose platinum every 3 weeks with conventional radiotherapy (arm 1) versus carbo-Taxol-cetuximab followed by high dose platinum every 3 weeks with conventional radiotherapy and cetuximab (arm 2). Cisplatin dose will be reduced to 75 mg/m2 in arm 2. This is a phase II randomized trial and the best arm would be selected for comparison to the classical standard of current platinum/radiation followed by adjuvant plat/5 FU. It was noted the RTOG would plan to do an analysis of the current nasopharynx IMRT protocol sometime in 2006. This will influence the design of any study that is selected. In the mean time there was support to work with the ECOG group in developing a new nasopharynx trial. Kara Bucci gave a brief report of the current results of the UCSF IMRT/Platinum study. The 4-year local control rate is very high (93%) and overall survival rate is 74%. This information will be informative in designing a new study. RTOG KGF Study - Dr. Rosenthal reviewed the development of this trial. This study will now go into a protocol-writing phase to hopefully open within the next six months. Presentation – Dr. Rachel Rabinovitch presented result of a secondary analysis of RTOG 9003 looking at the effects of nutritional support on outcomes. There was less mucotisis and less weight loss in patients who receive baseline nutritional support, but there was also lower local regional control and lower overall survival in patients who had baseline nutritional support. The paper submitted to JCO was rejected. Another analysis was done using recursive partioning and similar and again statistically significant result was found. This revised paper was also rejected by the red journal. There was a significant interest in this surprising finding from the membership. A second revision was made and submitted to Head and Neck. It was suggested prospective studies are needed which include tumor related factors and circulating cytokines and detailed nutritional support. However a specific design has not been developed at this point. HEAD AND NECK CANCER COMMITTEE (June, 2004) K. Kian Ang, M.D., Chair New members of the committee, James Parsons, Mohammed Akra, and Kara Bucci, representing the new investigators committee were welcomed. ACTIVE PROTOCOLS 1. RTOG 0022: IMRT Oropharyngeal Cancer. 48 out of 64 patients have been enrolled. Enrollment will complete by December 2004. This trial establishes the quality assurance procedures and will help to define the role of IMRT. In the future most RTOG trials will allow IMRT. Therefore, credentialing for IMRT was encouraged. 2. RTOG 0129: This phase III trial has enrolled 480 out of 720 patients. Complete enrollment of the trial is expected in June 2005. Dr. Ang reminded the membership to provide a diagram of adenopathy if diagnostic CTs are not available. This will facilitate review process. 3. RTOG 0225: IMRT with or without chemotherapy for nasopharyngeal cancer. 18 out of 64 patients have been enrolled. Completion is expected by May 2007. 4. RTOG 0244: Salivary gland transfer. Six patients have been enrolled in selected centers. Chemoradiotherapy is now allowed on the trial 5. RTOG 0234: Cetuximab and chemotherapy in high-risk postoperative patients. Dr. Harari reviewed the result of RTOG 9501 as well as the EORTC study using concurrent platinum showing improved local regional control and overall survival. The improved results with Cetuximab and radiotherapy in patients with locally advanced head and neck carcinoma recently reported at ASCO also provide the rational for combining chemotherapy with Cetuximab in current postoperative trial. This recently activated phase II trial will compare weekly Docetaxel to weekly Cisplatin both in combination with radiation and Cetuximab. The most promising arm of this phase II trial will be selected for future testing against radiation and Cisplatin from RTOG 9501. Supplemental funding from the company is currently being negotiated. This protocol has recently been activated. DEVELOPING STUDIES 6. RTOG 0421: Reirradiation versus chemotherapy in previously irradiated patients. Dr. Wong presented a summary of the results of RTOG 9911 and 9610 showed two-year survival in the 20-25% range compared to 10% range for chemotherapy alone from ECOG studies. The planned trial will compare chemotherapy alone versus reirradiation using hyperfractionated radiotherapy and weekly Cisplatin/Paclitaxel, as used in RTOG 9911. Patients with circumferential involvement of the carotid artery will not be eligible. Patients will be allowed to crossover to the other arm upon progression. The survival endpoint and crossover issues were discussed with the membership. The committee was reminded the mission of RTOG is to improve survival using radiotherapy in diseases where local control of tumor is a major determinate of outcome. There will be a plan to build in futility analyses at interim points in the trial. It expected that ECOG and SWOG would join the study. 7. RTOG 226: Phase II chemoprevention using celecoxib. Sponsorship issues have been resolved. This trial will require 136 patients. Revisions have made and the protocol will be submitted to CTEP in the near future. 8. KGF for prevention of mucositis. Dr. Rosenthal presented the rational for a phase III trial designed to test the efficacy of KGF given “upfront” and/or “outback.” Grade 3-4 mucositis will be the primary endpoint of the proposed study. Supplemental funding from AMGEN is expected. 9. RTOG 0129 replacement. Dr. Ang presented several potential designs. At this point, the preference is a randomized phase II comparing Radiation plus Cisplatin-C225 vs Cisplatin-Bevacizumab vs C225-Bevacizumab. 10. Radiation plus Intra-arterial high dose Cisplatin (Rad-Plat). Dr. Robbins proposed a phase II trial in resectable stage T2-T4 carcinoma of the oral tongue requiring at least hemiglossectomy. The use of C225 for a one-month run in and concurrently with Rad-Plat is being considered. Patients with circumferential involvement of the carotid artery will not be eligible. Biopsies will be performed pre, during, and post treatment for molecular markers. Functional measures will also be included. 11. ECOG trial of induction chemotherapy followed by concurrent chemoradiotherapy. Dr. Argiris presented ECOG’s plan to compare three cycle of Cisplatin and Docetaxel followed by three cycles of concurrent Cisplatin and conventionally fractionated radiation with concurrent Cisplatin and conventionally fractionated radiation in a phase III trial for patient with very advanced disease, particularly T4b and N3. A total of 460 patients will be required. Projected survival differences are 49% versus 37% at 3 years. This could require five years of accrual at 80 patients per year. The concern was expressed regarding the tolerability of six cycle of Cisplatin chemotherapy. ECOG is currently conducting a pilot trial to test the feasibility and tolerance of this program. A show of hands indicated limited enthusiasm for this aggressive sequential and concurrent therapy approach. 12. Socio-demographic variables in Head & Neck cancers. Dr. Konski presented the data of secondary analyses of RTOG 9003, 9111, and 9703. The data of 1800 patients were studied in multivariate analyses. It was found in addition to stage and gender, unmarried males without a support system or spouse have a worse prognosis. Various strategies for interventions and further studies were discussed. LENT WORKSHOP UPDATE 13. Dr Trotti updated the Committee on the presentations and committee work at the recent LENT V workshop. Initiatives relevant to H&N are the development of adverse event reporting standards by the newly formed AERO-H&N working group. A website for committee work on standards development will be created, with a goal of a full draft for consideration by the H&N Intergroup committee by fall. The same group has recommended development of an H&N protocol template, also to be endorsed by the H&N Intergroup Committee. This is to improve consistent capture, reporting and comparison of endpoints across trials, including adverse events. Representatives of the EORTC H&N Committee have agreed to collaborate on this effort. Further updates will be presented. K. Kian Ang, M.D., Chair ACTIVE STUDIES: RTOG 9512 - Dr. Trotti reported that accrual to this trial was completed in June 2003 and a first analysis will be planned for summer 2004. In the meantime, replacement designs have been considered. A proposal to compare IRESA plus RT vs RT alone has been under development for approximately 1 year. Dr. Pajak has run the numbers on the required accrual for this proposal. It was noted that RTOG 9512 required 7 years of accrual to obtain 250 patients in a specific sub-site (T2 glottis). The goal of a new trial would be to extend this concept of defining “an intermediate stage” risk group in other disease sites such as oropharynx and hypopharynx. Dr. Pajak has estimated the number of these site cases available from the RTOG registry and other RTOG studies. In addition he made projections on the number of patients required to reduce the failure rate by 50% in this multi-site population (about 300 patients). A lesser impact on the failure rate of 33% would require more than 700 patients. It was felt that it may not be reasonable to expect the currently available biologics to reduce failure rates by 50% and that we cannot accrue 700 patients within 3 years. Furthermore, we do not know the outcome of hyperfractionation on local control at this time. The answer may come, however, within the next 6-12 months. It was decided to wait for the results of RTOG 9512 and the international trial with C225. In the meantime, Dr. Trotti proposes to continue developing the rationale for identifying an “intermediate stage group” by exploring individual patient data (IPD), meta analysis databases from Pignon and Bourhis to see if either altered fractionation or concurrent chemo radiotherapy have any significant impact on local control in this intermediate stage group. If there is little to no impact then we may have identified a group that is not at sufficient risk to warrant the toxicity of (or benefit from) traditional chemotherapy, but still in need of improvement. Future promising biologic or other agents would then be tested when available. The concept of developing the intermediate stage cohort of patients will remain on the agenda for future development. RTOG 9903 - Dr. Machtay presented the recent results of the German trial of Beta-erythropoietin noting a number of deaths due to thromboembolic and vascular events potentially associated with the investigational agent. RTOG has since examined the number of fatal adverse events in the RTOG 9903 trial: there were approximately 7 cases of possible thrombolic events in the RTOG experience. This trial was, therefore, recently closed due to safety concerns. RTOG 9911 - The results are promising with a 2-year survival of 28%. Overall, 77% of patients received all 4 cycles of chemotherapy. The first 60 patients out of 105 enrolled have been analyzed. An abstract has been submitted to ASCO. RTOG 0022 - Dr. Eisberg indicated that 15 institutions have been credentialed and 30 out of the planned 60 patients have been enrolled and accrual is steadily increasing. RTOG 0129 - Accrual for this trial has increased steadily over its life cycle. The accrual has increased from 13 to 25 cases per month over the last six months. The trial is projected to complete accrual in July 2004 unless there is an amendment to extend the trial. A proposal was presented to NCI/CTEP to extend/amend this trial in order to detect a reduction in death rate from 25% to 20%. If the current proposal is accepted it means we would accrue additional 240 patients for a total of 720 total patients, extending the accrual period for approximately 1 more year. In addition, an interim analysis is planned to look for significant differences that may prompt early closure. DEVELOPING STUDIES: Dr. Machtay proposed comparing palliative chemotherapy alone to the treatment regimen used in RTOG 9111. This would be in previously unresected disease and would answer the question whether there is an improvement in survival with concurrent chemoradiation as tested in RTOG 9111 over the current standard of care (palliative chemotherapy). Survival figures were presented and a sample size of 154 or 232 patients were projected depending on the projected reduction in death rate (40% or 33%). The proposed trial will stratify by IMRT vs Non-IMRT and the interval since prior radiation (less than 30 vs greate than 30 months). A show of hands among the full committee showed the majority was in favor of pursuing this trial of palliative chemotherapy vs chemotherapy and reirradiation. It was concluded that we should keep twice a day radiotherapy as part of the program. RTOG 0225 - A Nasotherangial trial reported by Dr. Nancy Lee. The first 11 patients enrolled and enrollment is continuing and picking up. RTOG 0234 - Paul Harari updated the committee on the status of this post-operative high-risk protocol. This phase II randomized trial will have only 2 arms and compare RT plus C225 plus weekly platinum vs RT plus C225 plus weekly docetaxel. This will require a total of 214 patients for the 2 arm randomized phase II trial. The idea would be to take the best arm of this phase II trial and compare it to concurrent platinum radiation in the future. RTOG 0244 - A salivary gland transfer trial which three institutions have been credentialed, 3 additional institutions are in progress and 1 patient has been enrolled. RTOG dev – A developmental study for prevention of second primaries. A brief report was given that the investigator is trying to identify a source of Celebrex for development of this trial. RTOG dev – A larynx preservation functional outcome study. David Rosenthal discussed a possible future 3-arm trial using radiation plus a biologic in each of the arms. The specific biologic agents have not yet been selected. The discussion then focused on the proper toxicity questionnaires and functional outcomes including barium swallow, fiberoptic endoscopic evaluation of swallowing and speech (“fees”) and various quality of life or symptom questionnaires including a list of performance status scale, the voice handicap index, the symptom distress scale and a MD Anderson swallowing scale. There seemed to be good interest from the membership for studying function. RTOG dev – A replacement study for RTOG 0129. A new concept is under development comparing 2 different biologics, yet to be selected. ANALYSIS AN D MANUSCRIPT UPDATES: Dr. Ang updated the committee on a number of manuscripts that have been published or are in analysis: 1. RTOG 9111 – Has been published in New England Journal of Medicine. 2. RTOG 9003 – Has been published in International Journal of Radiation Oncology, Biology and Physics. 3. RTOG 9501 – Has been submitted to New England Journal of Medicine. 4. RTOG 9703 - Has been accepted to Journal of Clinical Oncology. 5. RTOG 9914 - Has been submitted to Journal of Clinical Oncology. 6. RTOG 9505 - Has been submitted to International Journal of Radiation Oncology, Biology and Physics. 7. RTOG 9003 - The first draft has been received. 8. RTOG 9003 - The first draft has been received. 9. RTOG 9610 - The first draft has been received. 10. RTOG 9003 - Statistical 3 analysis has been done. In addition, a number of abstracts have been drafted and will be submitted to various meetings including International Head and Neck cancer meeting in August, ASTRO and ASCO. In addition, it was announced that Dr. Ridge and Dr. Weber are collaborating on a study of the role of neck dissection in the RTOG database in particular RTOG 9111. TOXICITY PROPOSAL Dr. Trotti proposed to develop a new reporting method to summarize the global toxicity associated with various treatment options. Validation of the concept would involve a secondary analysis of toxicity and outcomes data from multiple head & neck cancer studies. Several members of the committee and Dr. Pajak have expressed their support. Preliminary data will be generated for an extramural grant application. TRP COMMITTEE PROPOSAL Dr. Wong updated the committee about Translational Research Program (TRP) activities. A number of projects are under consideration including genomics, p53 dependent repair genes, etc., to predict for normal tissue response. It was suggested in the TRP committee that every disease site should have an appointed TRP representative. The goal would be to assess the feasibility of this proposal for having a representative of each disease site committee and to develop a disease-specific TRP agenda. Good support was expressed. Dr. Stuart Wong will be the head and neck cancer committee liaison to TRP. HEAD AND NECK CANCER COMMITTEE (June, 2003) K. Kian Ang, M.D., Chair ACTIVE STUDIES: RTOG 9512, 9911, and 0024 - Dr. Ang announced that these studies have recently completed accrual. Concepts for replacement studies have been submitted and are being discussed. RTOG 9903 - Although the enrollment has increase from an average of 3.8 to 6 patients per month, it is still below the projected rate of 10 per month. The Data Monitoring Committee was concerned about the slow accrual and put this protocol on probation. There was a recommendation from the NCI to conduct pharmacokinetic studies of Erythropoietin. It was thought that this could only be addressed when accrual rate improves. RTOG 0022 - This study continues to have slow accrual due to the process of institutional credentialing required for IMRT verification. A number of centers are doing dry runs and will likely enroll patients in the near future. RTOG 0129 - This phase III trial for advanced HNSCC is currently accruing more than 20 patients per month, which is better than anticipated. Minor protocol amendments have been made. For example, ionized calcium is no longer required and blood samples can now be sent to Dr. Hammond’s center in Salt Lake City. Dr. Weber is developing fresh tissue collection protocol to bank samples for future translational studies. Dr. Ang announced Dr. Arquette passed away unexpectedly (a moment of silence was requested). Dr. Wheeler has assumed the Medical Oncology Study Chair. Based on its current accrual rate, this trial is projected to complete accrual in the spring of 2005. Therefore, the committee needs to start planning for a replacement study. RTOG 0225 - This study is recently opened for patient enrollment. RTOG 0244 - This study is in the final stage of approval by NCI and will be activated soon. DEVELOPING STUDIES: RTOG 0226 - Prevention of Second Primary Tumor – Sidhu updated the proposal for chemoprevention with Celecoxib. The protocol has been refined to include biomarker studies. A final draft will be sent off for review in a few weeks. RTOG 0234 - Postoperative Radiotherapy Proposal - Paul Harari updated the progress of drafting a 3-arm phase II randomized trial. The treatment arms are post-operative radiotherapy (PoRT) plus C225 (anti-EGFR antibody), PoRT plus C225 and Cisplatin, and PoRT plus C225 and Docetaxel. There was good support for development of this trial. The protocol will be finalized with the input of Bristol-Myers Squibb and Aventis. The aim is to submit it for review within 4-6 weeks. RTOG dev - Re-treatment for recurrent tumor or second primary developing within previous radiation field Dr. Wong presented several options of combining radiation with concurrent chemotherapy followed by OSI-774 for patients with resected or unresected local recurrence or second primary in the previously irradiated region. There was enthusiasm to pursue such study. He received feedback from membership for refinement of the protocol. RTOG dev - Replacement study for larynx cancer - Dr. Rosenthal updated the group that given the high control rate of concurrent radiation-cisplatin, it is not feasible to undertake a phase III trial to demonstrate an improvement in control rate within a reasonable time span. Therefore, the consensus is to develop a phase II trial to address toxicity reduction. A working group has come up with a tentative 3-arm proposal (AFX-C + bevacizumab, AFX-C + C225, and AFX-C + C225 + COX-2 inhibitor) and is still working on a practical method for assessing swallowing and speech functions. RTOG dev - Palliative therapy using quad-shot radiation regimen (bid for two days) with or without Taxane Dr. Carrascosa presented preliminary results of a study conducted at the University of Louisville testing combination of quad-shot with Docetaxel in the palliative management of patients with head and neck and pelvic neoplasms. He than proposed a phase III trial to compare this regimen with quad-shot alone in HNC. A poll of the members revealed that we might not have a sufficient number of patients to conduct a randomized trial. RTOG dev - Reduction of xerostomia-mucositis - Dr. Wynn presented a phase III proposal on behalf of Cancer Control Program. The three proposed arms were Pilocarpine, Amifostine (sc), and Pilocarpine plus Amifostine (sc). A survey showed a rather modest interest from the membership. ADDENDUM Unknown Primary – The plan to collaborate with the EORTC on patients with cervical nodal metastasis from unknown primary was presented by Dr. Spencer and endorsed by the Head and Neck Cancer Committee on several occasions. The Full Member PI/Executive Committee had previously approved the concept. However, upon further investigation we learned that due to regulatory issues the protocol has to be submitted to the NCI for review and approval to permit US centers to enroll patients. This will use up significant resources at RTOG headquarters. This new information along with the lack of track record of EORTC investigators in honoring their commitment to enroll patients into RTOG protocols reduced the enthusiasm of the Executive Committee members. Consequently, the protocol was assigned a very low priority. HEAD AND NECK CANCER COMMITTEE (January, 2003) K. Kian Ang, M.D., Chair ACTIVE STUDIES: RTOG 9512 (A. Trotti) - Dr. Trotti reported the study is 10 patients short of completing the target accrual. Dr. Ang encouraged members to submit proposals for a potential replacement study. RTOG 9614 (W. Koch) - This protocol has completed enrollment. Dr. Koch announced that the planned correlative studies will be undertaken when follow-up data becomes available. Meanwhile, investigators are encouraged to think about additional studies that can be performed with the remaining samples. RTOG 9903 (M. Machtay) – This study continues to enroll very slowly. An amendment was made to allow chemotherapy using Platinum alone at 80 mg/m2 or carboplatin-based regimens. Enrollment was strongly encouraged. RTOG 9911 (C. Langer) - This study should complete accrual within the next 2-3 months and replacement studies will be entertained. Dr. Stuart Wong will present a concept. RTOG 0022 (A. Eisbruch) - This study continues to have slow accrual due to the process of institutional credentialing required for IMRT verification. Centers are encouraged to complete this procedure. A dialog between RTOG QA center and Nomos regarding data transfer problems is continuing. RTOG 0024 (D. Rosenthal) - This study has accrued relatively well during the last year. It is anticipated to complete enrollment within the next 3-4 months. A replacement study is being developed by Dr. Harari (SEE BELOW). RTOG 0129 (K. Ang) – This is a new 2-arm phase III trial for advanced unresected head and neck carcinomas. Dr. Ang reported that the study has recently been activated and encouraged members to apply for institutional IRB approval ASAP. RTOG 0225 (N. Lee) – This study is in the final stage of review by CTEP. It will be open for patient enrollment soon. RTOG 9111 (S. Mukherji) - 20 patients have been accrued in this pilot study of tumor volume measurements. Eight investigators (four radiologists and four radiation oncologists) have outlined the gross tumor volume. Although there have been some variations between observers in term of the shape of the tumors at individual CT cuts, the variations in the total volumes has been less than anticipated. The data is being analyzed and a manuscript is being drafted for possible expansion of this study. DEVELOPING STUDIES: Prevention of Second Primary Tumor – Sidhu updated the proposal for Celebrex. The protocol is being refined to include biomarker studies. A final draft is expected for review within RTOG in 2-3 months. Re-treatment for recurrent tumor or second primary developing within previous radiation field – Dr. Wong presented a concept of combination of conformal radiation with concurrent weekly Paclitaxel and Carboplatin followed by OSI-774 for patients. This concept will be refined for further presentation. Unknown Primary - Dr. Spencer informed the membership that a final discussion took place between the RTOG H & N Steering Committee members with a representative of EORTC (Dr. Gregoire). An agreement has been reached. The concept was approved by the executive committee and the protocol will be finalized. Postoperative Radiotherapy Proposal - Paul Harari presented a 3-arm phase II randomized trial. The treatment arms are post-operative radiotherapy (PoRT) plus C225 (anti-EGFR antibody), PoRT plus C225 and Cisplatin, and PoRT plus C225 and Docetaxel. There was good support for development of this trial. The protocol will be finalized during the next few months. Larynx Studies Using EGFR Inhibitors/Irressa - Dr. Rosenthal updated the group that gave the high control rate of concurrent Radiation-Cisplatin, it is not feasible to undertake a phase III trial to demonstrate an improvement in control rate within a reasonable time span. Therefore, the consensus is to develop a phase II trial to address toxicity reduction. A working group will work on a proposal to be presented at the next meeting. HEAD AND NECK CANCER COMMITTEE (June, 2002) K. Kian Ang, M.D., Chair ACTIVE STUDIES: RTOG 95-12 - Dr. Trotti reported that this study will complete enrollment in the next six months after almost 7 years of total accrual. EORTC has not contributed patients and will not likely do so due to regulatory issues. RTOG 96-14 - This protocol is close to completion and should terminate soon. RTOG 99-01 - This protocol is also accruing well and will complete enrollment soon. Dr. Scarantino discussed 3 possible alternatives new concepts. Studies are being considered including a comparison of Pilocarpine plus Traumel (a homeopathic preparation). RTOG 99-11 - This study should complete accrual within the next 6 months and replacement studies will be entertained. RTOG 99-13 - The study accrued more than 547 patients over 18 month for almost 31 patients per month. RTOG H-0022 - This study continues to have slow accrual due to the process of institutional credentialing required for IMRT verification. Centers are encourages to complete this procedure. RTOG 91-11 – Twenty (20) patients have been accrued in this pilot study of tumor volumes. That data are being analyzed for possible expansion of the study. RTOG H-0129 – This is a new 2-arm phase III trial for advanced unresected head and neck carcinomas. Dr. Ang reported the final plan approved by CTEP and indicated that we would be opening this trial as soon as possible. RTOG 99-03 – This study continues to enroll very slowly. An amendment is planned to allow chemotherapy using Platinum alone at 80 mg/m2 or carboplatin-based regimens. Enrollment was strongly encouraged. DEVELOPING STUDIES: Conformal Radiotherapy for Advanced Nasopharyngeal Carcinoma - This is in the final phase of development and should be activated within the next 6-8 months. The toxicity measures will use the Common Toxicity Criteria (CTC) and there will not be any Quality of Life or any other associated studies. Postoperative Re-Irradiation - Dr. Machtay asked RTOG membership if there was any interest in participating in a postoperative trial developed for re-irradiation. There was substantial interest and he was encouraged to create a protocol for this population. It was suggested that he consider fusing this with a re-irradiation of unresected disease study in order to maintain consistency between the two re-irradiation approaches. Unknown Primary - Dr. Spencer indicated that the RTOG Head & Neck Cancer Steering Committee will suggest to the EORTC that there be a more clearly defined and standardized chemotherapy before the RTOG can join. Postoperative Radiotherapy Proposal - Paul Harari presented a 3-arm phase II randomized trial. The treatment arms are post-operative radiotherapy (PoRT) plus C225 (anti-EGFR antibody), PoRT plus C225 and cisplatin, and PoRT plus C225 and docetaxel. There was good support for development of this trial. PG Taxol Proposal - Merrill Kies described the rationale for a re-irradiation trial using Xyotax (polyglutaminated Taxol), a radiation sensitizers. Dr. Milas presented exciting pre-clinical data supporting the clinical rationale of uses of Xyotax as a radiation sensitizer. Prevention of Second Primaries - Dr. Sidhu described a possible study under development utilizing Celebrex for 3 years to prevent second malignancies. Further pre-clinical work and funding needs to be acquired before this can move ahead, but there was generally good interest. Larynx Studies Using EGFR Inhibitors/Irressa - Dr. Forastiere presented a concept targeting moderately advanced laryngeal carcinoma exploring the use of EGFR inhibitors. There was consensus that this is a different population with different survival and different endpoints and should be studied separately. There was good support for her proposal and it will be pursued. HEAD AND NECK CANCER COMMITTEE (November, 2001) K. Kian Ang, M.D., Chair I. Active Studies: RTOG 95-05: Microvessel Density in NPC. Dr. Hammond reported the results of this study showing that high microvessel density count was associated with a higher incidence of metastases in patients with nasopharyngeal cancer. RTOG 95-12: Hyperfractionation for T2 vocal cord cancer. Dr. Ang reported on behalf of Dr. Trotti that patient accrual has been rather slow but steady. The EORTC has officially activated this trial but so far no patients have been accrued. Dr. Ang will contact the EORTC Radiation Oncology Chair to query the status. RTOG 96-14: Molecular analysis of Surgical Margins and Nodes. This protocol is accruing well and will meet the patient accrual goal likely in another year. RTOG 99-01: GM-CSF for Reducing Mucositis. Dr. LeVeque was not present. Dr. Ang reported that the accrual has been slow so far and participating centers were encouraged to enroll patients. RTOG 99-03: Erythropoietin + RT for Anemic patients. Dr. Machtay updated the status of protocol revision to expand the eligibility criteria to include patients who will receive radiation plus Cisplatin. RTOG 99-13: Biafine® for radiation-induced skin toxicity. Dr. Elliott updated the status of this protocol. The patient accrual rate is high. RTOG 99-14: Concomitant boost + CDDP for stage III-IV H & N Cancer. Dr. Ang reported that this protocol completed the patient accrual several months ago. He encouraged participating centers to send in the data collection forms so that toxicity analysis can be done in the near future. RTOG H-0022: Conformal RT for H & N Cancer. This study has been activated. However, there is some problem encountered regarding electronic data transfer to the QA center. The lead physicists are working to resolve this problem. RTOG H-0024: Post operative chemo-RT for advance HNSCC. Dr. Rosenthal announced that this protocol has been activated. Members are encouraged to submit this protocol to the respective IRB for approval so that patient enrollment can begin as soon as possible. ACRIN 66-58: Pilot volume study as a companion to RTOG 91-11. Dr. Ang announced that this collaborative pilot study with ACRIN will be activated soon. It’s objective is to assess whether tumor volume affect treatment outcome in patients with larynx carcinoma. II. Developing Studies: Chemoprevention. Dr. Ang presented on behalf of Dr. Khuri that the latest version of the protocol that will be sent to the NCI for review in the next couple of weeks. Conformal RT + chemotherapy for Nasopharyngeal Cancer. Dr. Lee presented the latest protocol design. This study will assess the feasibility of IMRT alone for early stage and IMRT + chemotherapy for advanced stage nasopharyngeal cancer. The protocol will be finalized soon and circulated for comments. Unknown Primary Cancer. Dr. Spencer presented the concept originating from the EORTC proposing to randomize patients with unknown primary tumor metastatic to the neck node(s) to receive either comprehensive radiotherapy or ipsilateral neck irradiation. Other details of the protocol were also discussed. A survey at the end of the presentation revealed enthusiasm in pursuing this study. Therefore, Dr. Spencer was encouraged to further develop this protocol including seeking input from the Head and Neck Surgical Oncology Subcommittee. Salivary gland transfer to prevent xerostomia. Dr. Jha presented one more concept of this study. A survey revealed that quite a number of centers would like to pursue this study. Therefore, Dr. Weber, Co-Chair of Head and Neck Surgical Oncology Subcommittee were assigned to finalize the details of surgery and finalize the protocol. Phase III Trial Comparing Radplat vs RT + Cisplatin. Dr. Kumar informed the committee members on behalf of Dr. Robbins that an RO1 application is pending to support this study. Phase III Trial for Unresected Advanced Head and Neck Cancer. Dr. Ang presented the NCI review of the concept for a 3-arm randomized trial to the committee members. The 3 arms are conventional radiotherapy + cisplatin, conventional radiotherapy + cisplatin and paclitaxel, and concomitant boost + cisplatin. This proposed study addresses whether the addition of paclitaxel will further improve the outcome and evaluate whether altered fractionation would yield therapeutic advantage in a combined modality treatment setting. The NCI review team recommended to the group to either conduct a randomized phase II study or to launch a phase III trial with 2-arms, i.e., eliminating one of the two experimental arms. There was a lengthy discussion. The members were not in favor of a randomized phase II trial since both experimental arms had been tested in phase II trial within the RTOG. The vast majority of the centers recommended going ahead with the 3-arm trial with the addition of toxicity and biomarker endpoints. A survey revealed that many members would not consider enrolling patients if the study was changed to a 2-arm trial. A few members would consider pursuing a 2-arm study if the combination of concomitant boost + cisplatin was chosen as the experimental arm. Therefore, it did not appear converting the trial to a 2-arm study would shorten the accrual time. HEAD AND NECK CANCER COMMITTEE (June, 2000) K. Kian Ang, M.D., Chair The meeting was chair by Kian Ang with the assistance of co-chairs Andy Trotti, Everett Vokes, and Randy Weber. Update of Active Studies: Updated data or other information of trials RTOG 91-11, 91-15, 94-18, 95-01, 95-05, 95-12, 96-14, 96-15, 97-03, 97-09, 99-01, 99-03, 99-11, 99-13, 99-14 were briefly presented to the membership. Developing Studies: Dr. Eisbruch presented the status of H-0022, Conformal RT for H & N Cancer. The draft has been completed and has been submitted to NCI for review. Meanwhile, sample cases are being finalized for trial runs and will be posted on the RTOG website. Dr. Khuri updated the status of the replacement protocol RTOG 1019 on chemoprevention. This proposal was sent to the NCI for review. He also presented the proposal on adjuvant biologic therapy on behalf of Dr. Shin. Dr. Ang informed the membership that the Steering Committee reviewed this proposal the previous evening and found it to be in competition with the postoperative trial to be presented by Dr. Rosenthal, which was already approved for further development. Dr. Rosenthal presented the final proposal for postoperative adjuvant chemoradiation RTOG 1071. This calls for brief adjuvant chemotherapy with weekly taxol followed by taxol and cisplatin given concurrently with radiation. The protocol will be finalized soon and send to the NCI for review. Patient accrual rate for this study is anticipated to be high. Therefore, Dr. Harari presented a concept of combination of C225 with radiation given in a postoperative setting as a follow up study of RTOG 1071. This concept was received enthusiastically and therefore, Dr. Ang asked Dr. Harari to draft the proposal. Dr. Mukherji updated the proposal for a pilot study to assess the feasibility of measuring the tumor volume of patients enrolled into RTOG 91-11 for correlation with therapy outcome as presented at the previous meeting. This study received support from ACRIN and RTOG. Dr. Jha updated the results of submandibular gland transfer to prevent xerostomia. A number of institutions expressed interest in testing the feasibility of implementing this procedure in multi-institutional setting. Therefore, Dr. Jha was encouraged to work with Dr. Weber, Co-Chair for surgery, to develop a protocol. Dr. Jacobs presented his preliminary experience of intraoperative chemotherapy for advanced head and neck cancer. Survey of membership revealed little interest for pursuing this type of study. Dr Spencer presented a proposal for a phase trial randomizing patients with neck node metastasis from unknown primary lesion to receive comprehensive radiotherapy or ipsilateral neck irradiation. Dr. Gregoire from the EORTC submitted this proposal. Many centers expressed interest in participating. Dr. Spencer will work with Dr. Gregoire in finalizing the protocol.