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Julia White, MD, Chair
ACTIVE TRIALS:
RTOG 0413/ NSABP B-39: This is a Phase III trial evaluating accelerated partial breast irradiation (PBI) versus whole breast irradiation (WBI) after lumpectomy for stages 0-II breast cancer. As of 5/31//07, 2714 accrued of 4300 targeted and RTOG institutions have accrued 50% of the cases. Accrual has less been less than targeted following the close of two groups of patients as of 1-1-2007: Women who are > 50 years of age with DCIS regardless of hormone-receptor status and women with invasive breast cancer who meet ALL of the following criteria: > 50 years of age and node-negative and hormone-receptor positive. Rationale to support accrual of higher risk patients and potential obstacles for recruitment was reviewed. Q/A requirements for PBI and WBI cases and potential pitfalls were reviewed.
DEVELOPING TRIALS:
A Phase III Trial to Evaluate the Technical Feasibility, Reproducibility and Acute Toxicity of IMRT to Deliver Whole Breast Irradiation (WBI) for Patients versus a four week course of Hypofractionated IMRT for accelerated WBI with a Concomitant Boost. Frank Vicini and Gary Freedman are working on this developing study. The IMRT Subcommittee has been formed to support its development.
A Phase II Trial of Second Breast Conserving Surgery and PBI for Ipsilateral Breast Recurrence
following Breast Conservation Therapy. Doug Arthur is working on this developing study and PBI
on this trial will be 3DCRT.
CONCEPTS PRESENTED:
A developing concept using SBRT for Oligo metastases from Breast Cancer. Steve Chmura and Ralph Weichselbaum and working on the concept. It needs to limit sites, have a translational endpoint and use established RTOG dose/fractionations for SBRT.
OTHER:
There was an update of project goals and progress on Breast Cancer Atlas.
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Julia White, MD, Chair
Active Trials:
RTOG 0413/NSABP B-39: This is a Phase III trial evaluating accelerated partial breast irradiation (PBI) versus whole breast irradiation (WBI) after lumpectomy for stages 0-II breast cancer. As of 1/15/07, 2547 accrued of 3000 targeted and RTOG institutions have accrued 50% of the cases. In response to the excess low risk patients accrued so far, accrual closed to two groups of patients as of 1-2007: Women who are > 50 years of age with DCIS regardless of hormone-receptor status and women with invasive breast cancer who meet ALL of the following criteria:
- > 50 years of age and
- Node-negative and
- Hormone-receptor positive.
Update Closed Trials:
RTOG 9517: Phase II Trial Evaluating Multicatheter PBI in Stage I-II Breast Cancer Patients. Doug Arthur reviewed 5-year outcome data that was presented at ASTRO 2006.
CALGB 9343/RTOG: Phase III Trial of Lumpectomy + Tamoxifen with or without Breast Irradiation for Clinical Stage I Breast Cancer Patients > 70 Years of Age: Beryl McCormick reviewed the 8-year outcome that was presented at SABC 2006.
Endorsed Trials:
NCIC MA.20: A phase III study of regional radiation therapy in early stage breast cancer closed for accrual February 2007.
Concepts Presented:
- Drs. Frank Vicini and Gary Freeman presented a Phase II Trial to Evaluate the Technical Feasibility, Reproducibility and Acute Toxicity of IMRT to Deliver Whole Breast Irradiation (WBI) for Patients Versus a Week Course of Hypofractionated IMRT for Accelerated WBI with a Concomitant Boost.
- Dr. Doug Arthur presented a concept for a second breast conserving Surgery and PBI for Ipsilateral Breast Recurrence following Breast Conservation Therapy.
- Dr. Steve Chmura presented a concept for SBRT for Oligo metastases from Breast Cancer.
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Julia White, MD, Chair
Active Trials:
RTOG 0413/NSABP B-39: This Phase III trial evaluating accelerated partial breast irradiation (PBI) versus whole breast irradiation (WBI) after lumpectomy for stages 0-II breast cancer has continued to accrue briskly. As of 6/21/06 it had met its 50% accrual mark of the 3000 targeted and RTOG institutions have accrued 50% of the cases. A greater percentage of DCIS, node negative, receptor positive breast cancer cases than estimated have been enrolled so far. This is a larger proportion of low risk breast cancer patients than had been anticipated. Use of the full eligibly criteria for enrollment in the trial is encouraged.
RTOG 9804: A Phase III trial of tamoxifen alone versus tamoxifen + breast radiation for good risk DCIS has accrued 611 of targeted 1790 cases. The study will unfortunately closed in July 2006 because of poor accrual. Much thanks to the investigators and institutions that supported and accrued to this important trial.
Endorsed Trials:
NCIC MA.20: A phase III study of regional radiation therapy in early stage breast cancer. Continued accrual through CTSU is encouraged.
Concepts Presented:
- Second Breast Conserving Surgery and PBI for Ipsilateral Breast Recurrence following Breast Conservation Therapy
- A Phase I/II Trial to Evaluate the Technical Feasibility, Reproducibility and Acute Toxicity of IMRT to Deliver Whole Breast Irradiation for Patients with Stage I/ II Breast Carcinoma.
- A Phase II clinical trial of a 4 week course of RT for breast cancer using hypofractionated IMRT with a concomitant boost.
- Phase I/II: IMRT or 3D-CRT for Regional Nodal Irradiation in Stage II - III Breast Cancer.
-ACOSOG 71053: A Phase III Randomized Trial Comparing Radiation Versus Concurrent Capecitabine/Bevacizumab/Radiation Plus Adjuvant Capecitabine/Bevacizumab for Selected Women Treated with Mastectomy and Chemotherapy.
Publications:
RTOG 9517: Five-year Outcomes - Accepted for presentation at ASTRO November 2006
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Beryl McCormick, M.D., Chair
Dr. McCormick spent the first part of the meeting presenting the concept and time-table of the Group Site Visit for 2007. She summarized the critique for the committee from the last site visit, including strengths, weaknesses, accomplishments and goals. A need to develop a protocol for locally advanced breast cancer was identified again. As well, the committee will continue as a "Working Group", with a limited number of studies asking local-regional questions, rather than attempting to enter the arena of systemic therapy trials. This reflects the make-up and strengths of the group.
A brief report from the CTEP-sponsored meeting with BIG or Breast International Group at San Antonio in December 2005 was also given. The RTOG committee was made aware of the attempts for international collaboration on major breast cancer questions, and for related translational information (TransBIG)
Drs. Julia White and Thomas Julian then updated the group on the RTOG 0413/NSABP B-39 trial. The trial is accruing very well, with 120 patients projected to be entered in January 2006, putting the trial on target for its accrual goal. The total number of women is about 700 to date. Of note, of those women randomized to the PBI arm, about 70% are being treated with 3D XRT. A discussion took place about issues using the MammoSite more often, as it is hoped this most common form of PBI will be used in a representative proportion of women entered onto the trial. Issues identified were the timing of the consult and the CT scan. Issues with the volume of reviews coming through the ITC were also discussed at this meeting and in a smaller meeting that followed.
Dr. McCormick updated the group on the status of the DCIS Trial, RTOG 9804. She announced Dr. Henry Kruer had offered to help raise awareness of the trial within the surgical community, and as a result, the trial will remain open through the end of May, with a goal of 60 additional patients accrued in that time interval. At that time, it will again be evaluated by the DMC. A letter written by Drs. Kruer and McCormick was electronically distributed to 3 medical societies for breast cancer, and a version of the letter is being prepared for ASTRO News. The letter outlines the importance of the study, and provides links to RTOG and CTSU for more information.
Accrual to the NCIC Nodal Study continues; Dr. Whelan was not available for a full report.
The final portion of the meeting was a discussion regarding a possible trial for women with locally-advanced breast cancer. At prior meetings, possible studies with taxol (Dr. Formenti), and with Herceptin (Dr. Sartor), had been discussed. Dr. White presented a concept of a study which will be opened at Medical College of Wisconsin within the year. Dr. McCormick presented a concept from ACOSOG; Dr. Tom Buchholtz had submitted this concept for locally advanced breast cancer to CTEP, and was asked by CTEP to modify it. The study would focus on women with locally-advanced breast cancer who had residual disease after neoadjuvant chemotherapy, at the time of mastectomy. The study proposes to randomize those women to a standard arm of post-mastectomy radiation or the same radiation plus Xeloda and Avastin. The group expressed support of the ACOSOG study and Dr. McCormick will follow-up with Dr. Buchholtz, provided the Research Strategy Committee approves.
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Beryl McCormick, M.D., Chair
The committee meeting was held on Saturday morning, and the first discussion item was the accrual to the DCIS study, RTOG 9804. Accrual has been going down in the past few months, despite a large number of CTSU sites now approved to enter women on the study (53). In contrast, a comment from the audience suggested accrual to the new NSABP DCIS trial, B-39, is increasing, which may be another issue for the RTOG study. Dr. McCormick emphasized accrual increases this year will be critical to keeping the trial open after the next Data and Safety Monitoring meeting in early 2006.
The RTOG 0413 PBI trial is opening rapidly in many hospitals and accrual is beginning to increase. To date, no issues have been identified with this new Phase III trial.
The MA-20 trial of regional nodal radiation vs. none continues to accrue about 5 cases/month from RTOG centers. Total accrual as of June 20, 2005 was 1322 patients. The trial has been amended to allow for the use of Herceptin.
Manuscripts for both the Brachytherapy PBI Trial RTOG 9517 (Toxicity) and the external beam PBI Trial RTOG 0319 (Feasibility) have been submitted to the Red Journal. The RTOG 9517 local control manuscript is awaiting LOH data on the few cases that failed locally.
Dr. Vijay Khatri presented a new concept to the group. He has done work using radiofrequency ablation as primary surgery for women with early stage breast cancer. He reviewed the other novel techniques for the group, including cryosurgery, hyperthermia, laser and U/S high frequency ablation. He then reviewed his own experience with radiofrequency surgery. A lively discussion took place, with strong opinions voiced against opening a trial with this technique in RTOG. Issues identified included possible pathology problems, especially with margin information, and the advantage to the patient vs. conventional surgery. No concept was endorsed.
Dr. McCormick polled the group regarding a possible collaboration with ACRIN; they are hoping to develop a study investigating the use of MRI in staging women with breast cancer. Incorporating a trial into the existing RTOG 0413 PBI trial was discussed. Dr. Larry Marks also proposed studying women with a diagnosis of breast cancer, who required a re-excision, using the MRI before the second surgery was scheduled. Dr. McCormick will bring these ideas back to Dr. Etta Pisano at ACRIN.
Other ideas for investigation included possible studies of Locally-advanced Breast Cancer, with a radiation sensitizer, a trial of concomitant “boost” during whole breast radiation using IMRT, and possible participation in a trial proposed to the NSABP looking at the role of “adjuvant” chemotherapy in women with isolated local failures after breast conservation therapy. Dr. Julia White also suggested creating an atlas for breast anatomy, similar t those existing for other disease sites.
Finally, it was announced that Dr. Eric Strom will be stepping down at Vice Chair of the Committee, and Dr. Julia White has agreed to serve as his replacement.
Translational research opportunities will be the focus of the winter 2006 meeting.
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Beryl McCormick, M.D., Chair
The Breast Cancer Committee suspended its regular business to conduct a two and one half hour “Workshop” in anticipation of the opening of NSABP B-39/RTOG 0413, the Phase III trial comparing standard whole breast radiation to Partial Breast Treatment, for women with early staged breast cancer.
Drs. Julia White and Douglas Arthur organized this workshop. The speakers included Drs. White and Arthur, as well as Drs. Frank Vicini, Rachel Rabinowitz, Robert Kuske, Geoffrey Ibbott, and from the NSABP, Dr. Thomas Julian and David Parda. All practical aspects of the trial were presented and discussed by this panel of speakers, including rationale, randomization, credentialing, QA, and surgical and radiation techniques. An open discussion with questions from the audience concluded the informative morning.
The workshop had three sections. The first section covered protocol overview which included rationale, schema, scientific endpoints, eligibility and ineligibility criteria, a QOL component and NSABP – RTOG collaboration on this study.
The second section covers protocol treatment and quality assurance. Specifically, it covered surgical perspective, partial breast irradiation using 3DCRT, MammoSite and catheters with volume definitions for contouring and dose parameters. They reviewed the quality assurance process using rapid versus timely random reviews with feedback to institutions and submitting information. A discussion about protocol methods and the quality assurance process in relationship to whole breast irradiation ended this section.
The third section was dedicated to suggestions and approaches for processes, patient flow issues and credentialing.
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Beryl McCormick, M.D., Chair
The meeting began at 8 am. Dr. McCormick reminded the group she would present the data from the RTOG/CALGB Elderly trial at the scientific/publications session this afternoon. She also updated the group on the Status of RTOG 0319, which met accrual in record time; patient characteristics and reported toxicity of the first 40 cases on study were reviewed. This information has been sent as an abstract for consideration of presentation at the 2004 San Antonio Breast Cancer Meeting, by the PI, Dr. Frank Vicini. The information will also be forwarded to the NSABP to facilitate including “external beam 3D conformal PBI” as an arm in the planned Phase III trial.
Dr. Doug Arthur and Dr. Julia White then updated the group on the status of NSABP B39/RTOG 0413. This large Phase III trial has gone through the revision/review process by both cooperative groups and is returning to the NCI for what is hoped will be a fairly rapid review; autumn 2004 is the target date to open the study. Dr. White reviewed some of the details of patient eligibility, randomization, and the credentialing process. A recent change is centers submit test cases for RTOG 0319 will have to submit a second case for the new study.
Dr. Arthur then reviewed details of each of the three “experimental” arms, including definition of the target volume, evaluation volumes, allowable proportion of the normal breast to reach a given percent of the prescribed dose, and QA measures in each technique. He also led a discussion of the definition of IMRT for the whole breast arm, which is evolving as the details of the study are worked out.
The DCIS trial RTOG 9804 was reviewed. Accrual to this study is still behind what we anticipated; Dr. McCormick reminded the group the entry criteria had been expanded to include those patients with incidentally found DCIS, which meets all other entry criteria. She also presented data on patient characteristics, Tamoxifen use, and pathology characteristics, including margins. Although this is an “Intergroup” study, the RTOG has accrued the largest number of cases, and CTSU contribution to date has been the smallest of all sources.
Dr. White reviewed the status of the MA-20 NCIC trial, for Dr. Tim Whelan. This trial has reached 50% of planned accrual, but the number of cases RTOG has placed on this endorsed trial is low. Early statistics on side effects such as arm edema were review, and trial details again presented to the group.
The planned review of preliminary cosmesis and local control data from the RTOG Breast Brachytherapy Trial were postponed until the January meeting, because Dr. Taylor and Dr. Kuske were unable to attend.
The last part of the meeting was a discussion for new ideas and a Phase I/II trial using the growing data from translational research. Dr. McCormick reviewed the ideas presented to the group during the last few meetings, which have included Taxol and radiation for locally advanced disease (Dr. Strom and Dr. Formenti), Herceptin and radiation for the same group (Dr. Sartor) and Gemcitabine with radiation (Dr. Berk). The January meeting will continue with this theme.
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Beryl McCormick, M.D., Chair
The committee met on Saturday, January 17, 2004. Dr. McCormick updated the group on the status of RTOG 9004. Accrual fell slightly short of the goal set by the Data Monitoring Committee; members were encouraged to think of this study for their patients.
Dr. Tim Whelan updated the group on the status if the NCIC study randomizing women with 1-3 positive axillary lymph nodes and getting breast radiation, to regional nodal radiation or none. This study is asking the same question, in a different way, as the SWOG study which closed because of poor accrual; members were encouraged to think of this study, which has been endorse by the RTOG. Information on this study is available to members on the CTSU web site, and under “Endorsed studies” in the RTOG web site. Because of procedural rules, listing it under “Breast Studies” is not an option.
The remainder of the time was devoted to updating the group on the progress of the NSABP and RTOG efforts to open a Phase III trial to compare standard whole breast radiation in early stage breast cancer, to partial breast radiation. Dr. Julia White, the Principal Investigator for this proposed study for RTOG, moderated the remainder of the meeting.
Dr. Frank Vicini first discussed the accrual to the RTOG 0319 study, which will become one of the experimental arms in the new trial. This study is accruing quickly, and test cases from many RTOG centers have been received as well. Dr. Vicini also reviewed the status of the MammoSite database, kept for the first year by the Proxima Company, and now being managed by the American Society of Breast Surgeons. He explained the rationale for inclusion of various sub-sets of women in the proposed study, the status of the quality assurance efforts, and the requirement of a baseline CT prior to randomization.
Dr. Thomas Julien from the NSABP then discussed the history of the NSABP trials for early stage breast cancer, and the reasons for developing such a trial jointly with the RTOG. Rationale for aspects of the trial, based on NSABP data from prior large studies, was explained as well.
Dr. White then asked Drs. Vicini, Julien, Kuske, Arthur and Rabinovitch to the podium, for an open panel discussion of the proposed trial. Questions asked were generally to clarify details of the trial, and overall support by committee members was voiced.
Dr. McCormick then closed the meeting as scheduled at 9:30 am.
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Beryl McCormick, M.D., Chair
The first agenda item was the closing announcement for the SWOG Post-Mastectomy study, due to poor accrual in every cooperative group.
Drs. McCormick and Strom then discussed accrual to the DCIS study, RTOG 9804. Dr. Strom analyzed all possible patients in his center for this trial, and concluded that about 10% of women with low grade DCIS were not eligible because they did not have a corresponding mammographic finding. To increase accrual, the committee agreed to amend the study to allow for inclusion of these “incidentally found” DCIS cases on study, and to use the pathology size since no mammogram finding was available to measure. Ms. Winter also informed the group of the need to increase accrual further. Ultimately the accrual needs to increase from the present 12 patients per month, to 20 patients per month. As a short-term accrual goal, the Data Monitoring Committee, at their recent meeting, set a target accrual of 400 patients by the end of 2003.
Dr. McCormick also noted that the first round of pathology review for RTOG 9804, was done by Dr. Sneige, produced excellent results, with only 2 of the 28 cases reviewed showing Grade III lesions. This is the first confirmation that the web-based pathology-teaching tool is a success.
Dr. McCormick presented an update of the CALGB elderly trial (RTOG 9702), which is now showing a significant increase in local failures in the Tamoxifen only arm, compared to the standard RT plus Tamoxifen arm. This data has not yet been published. For the Brachytherapy trial, RTOG 9517, Dr. Marie Taylor now has the needed photographs for cosmetic analysis, and is hoping to have an abstract ready for ASCO or ASTRO in 2004. Ms. Winter also announced that she would be doing the first round of data analysis for local control on this study, in the same time frame.
New trials opening include Dr. Vicini’s Partial Accelerated Conformal XRT Trial (RTOG 0319), and Dr. Rabinowitz’s MammoSite Trial, which is awaiting statistics (RTOG 0329).
Dr. Whelan reminded the group that RTOG has endorsed the NCIC study of regional lymph node treatment vs. none, for women having breast RT after conservation surgery, who have 1-3 nodes positive. As of this meeting, only one patient had been entered on this trial thru RTOG. He reviewed the process of using the CTSU mechanism to enter patients. This trial is identified as MA-20 in the CTSU menu. He also presented a new concept for a study for elderly women with breast cancer. Due to time constraints, this will be fully discussed in January.
Dr. Carolyn Sartor presented a concept for combining radiation and Herceptin in women with locally advanced breast cancer. Again, because of time, this as well as prior related concepts for this locally-advanced group of patients, will be fully discussed in the January, 2004 meeting.
Dr. Douglas Arthur presented the NSABP concept for a Phase III trial comparing whole breast radiation to partial breast radiation using catheters, the MammoSite balloon, or 3D conformal accelerated radiation. As written, this concept included about 6000 patients, with early invasive lobular or ductal carcinoma, or DCIS. It was returned from CTEP with a request that NSAPB work with RTOG, as the experimental arms were or are RTOG Phase II studies. There was considerable discussion about this trial. Points raised included the selection criteria, which are considerably broader as written in the NSABP trial, than the criteria used in the RTOG Phase II studies. The group was concerned about the inclusion of women with DCIS, and the existence of competing DCIS trials already in both RTOG and NSABP. There was also concern about including women with invasive lobular cancers, and those with an EIC, especially given the continued use in this proposal of the NASBP definition of a “clear margin” as one with no cancer at the inked edge of the specimen.
There was also concern about using the MammoSite device without any Phase II information. Although Proxima Therapeutics has a registry for users, reportedly only about 20% of users are sending information back to the company. Similarly, outside of the William Beaumont Hospital experience, using 3D conformal XRT for partial breast radiation is just being explored thru RTOG 0319. Finally, a discussion took place about how appealing such a trial would be to women, given that many practices are already offering the MammoSite treatment off study. Dr. Arthur stated that the NSABP was holding a focus group at their semi-annual meeting to gather information on that issue.
Despite these concerns, the group in general was highly supportive about proceeding with a Phase III trial to address this question, and expressed a willingness to work with the NSABP group.
Dr. McCormick briefly reviewed the ongoing IORT trial at Memorial Sloan Kettering Cancer Center, for women aged 60 years and over. Dr. Sartor noted that her center had a similar trial open, using a portable electron beam. This concept will also be addressed in depth at the January meeting. Finally, Dr. McCormick introduced Dr. Peggy Wilmoth, who will be the Quality of Life liaison and has much experience in assessing sexuality issues in trials.
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Beryl McCormick, M.D., Chair
Overall accrual to open breast trials is up about 40%, from 90 to 128 cases.
OPEN TRIALS:
RTOG 9915 - (SWOG) Accrual to this trial is poor, in all seven cooperative groups participating. Forty-seven (47) patients were enrolled as of June 2002. The RTOG has 29 women enrolled, through November 2002. NSABP was the most recent cooperative group to endorse the trial; an amendment under development now would allow women receiving only hormonal systemic treatment to enter the trial
RTOG 9804 - Average monthly accrual to this trial in the last six months has been 8 patients, close to our target. Two Hundred and seventeen (217) women have been entered, including 186 from RTOG, 28 from CALGB and 3 through the CTSU menu. SWOG and NCIC now also endorse the trial.
Information on patients entered includes the following: 90% on tamoxifen, 70% with a primary size of 1 cm or less on mammogram, and margin width of 3-9 mm 33%, 10 mm or greater 13%, and negative by re-excision 54%.
Dr. Sneige is beginning the first review of sample slides to assess the web-based teaching pathology tool. All centers requested to send in slides are also requested to have their participating pathologist fill out the one-page web usage questionnaire.
NCIC CTG MA.20 (RTOG endorsed) Julia White, PI for RTOG, reported that accrual to the study has reached 507 patients of a targeted 1822. She reviewed the steps to take to enroll on this trial through the CTSU menu and received RTOG credit.
CLOSED TRIALS:
A manuscript is in final preparation for the CALGB/RTOG elderly trial RTOG 9702 and an update on the data is expected for the Montreal meeting
Marie Taylor updated the group on the progress of the cosmesis analysis of RTOG 9517. A spread sheet is awaiting linkage with available photographs taken for the study. The goal will be an abstract for ASTRO or the San Antonio breast meeting.
DEVELOPING TRIALS:
The committee strongly endorsed a Phase II trial using the MammoSite balloon catheter. Rachel Rabinovitch has written this up, using the same dose schedule, entry criteria and endpoints as RTOG 9517 and Frank Vicini’s 3-D Conformal partial breast Phase II trial. From a show of hands, the device has already been used by several committee members. Comparison of all three methods would be facilitated by this design.
The group discussed naming a co-PI and endorsing the new NSABP trial for DCIS, B-35. In this trial, all women receive 50 Gy to the breast, and are then randomized to receive 5 years of tamoxifen or of anastrozle. Because our open trial does not include patients with high-grade DCIS, this would not be a conflicting trial for this patient sub-set. Support was voiced for joining, both to continue to increase numbers on breast trials for the RTOG, and to support the NSAPB. But since details of the trial regarding margin status, and post-operative mammogram requirement had not yet been posted at the NSABP web-site, this discussion was tabled until the June meeting.
Eric Strom updated the group on the highlights of the NCI sponsored meeting on the status of partial breast radiation that took place in December 2002. This was followed by a lively discussion on the idea of a Phase III trial comparing whole breast radiation to partial breast treatment given over a short time course. There was a strong sentiment expressed that the RTOG should be involved with such a trial
NEW BUSINESS:
A focus of the group in Montreal will be on developing a trial for locally-advanced breast cancer. Any center with pilot data was encouraged to contact the chair.
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Beryl McCormick, M.D., Chair
The meeting was opened at 3:30 pm. First agenda items for discussion were the accrual numbers to RTOG 98-04 and 99-15. Although the accrual to the post-mastectomy study has doubled, numbers are very low, with 9 cases this year compared with 4 cases in 2001. Dr. McCormick noted that this study is not meeting accrual nationwide, and no one had enlightening comments regarding this.
Accrual to the DCIS study has increased since the Tamoxifen was made optional, to almost 10 cases per month. Dr. McCormick noted that the developing studies in both the NSABP and EORTC groups will include radiation for all arms, with variations in adjuvant hormone therapies being proposed as the randomization options. Thus, this study remains the only study to address the question of leaving out radiation in selected low-risk DCIS patients. She encouraged members to remind their surgeons again of entry criteria; this study is on the CTSU menu, and with the support of both NCIC and ACOSOG, hopefully accrual goals will soon be met.
Dr. Tim Whelan updated the group on the status of his study comparing regional nodal RT to none, in women who undergo breast conservation surgery and radiation. This concept has been approved for RTOG participation; the study will soon be posted on the CTSU menu. Dr. Whelan reviewed the web site, so members could see how to reach the study and how to obtain RTOG credit. Dr. McCormick asked for anyone interested in acting as the RTOG PI to let her know; the study will also be assigned an RTOG number to improve visibility.
Drs. Kuske and Taylor then updated the committee on the progress in the evaluation of the breast Brachytherapy study. Dr. Kuske will present acute toxicity data at ASTRO 2002 and Dr. Taylor is presently working with her committee to begin to gather initial cosmesis data.
Dr. Dar then presented a proposal for studying Celecox in a Phase I, II trial. His proposal included women with DCIS as well as invasive cancer, and he was asked to return to the group with a more focused concept.
The last topic of discussion was the MammoSite device, recently approved for use as an after loading device by the FDA. There was a general consensus that a trial parallel to the RTOG brachy breast trial, using this balloon, would help members feels confident about offering this treatment to selected women. Dr. Rachel Rabinowitz will begin to develop such a concept.
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Beryl McCormick, M.D., Chair
The meeting opened at 3:30 pm, and the first item on the agenda was the discussion of the accrual of the two open phase III breast cancer trials. Accrual to the DCIS study, RTOG 98-04, included 79 patients in 2001, an improvement over the accrual of 54 patients in calendar year 2000. None the less, with a trial goal of 1800 patients, all centers will need to prioritize this trial. Dr. McCormick noted that the study has recently been amended to hopefully have more physicians comfortable with enrolling patients on the trial. The Tamoxifen has now been made optional, and an additional fractionation schedule has been added, to accommodate centers in Canada. The trial is now open in CALGB, NCIC and has been endorsed by the Southwest Oncology Group (SWOG).
Accrual to the post mastectomy trial, RTOG 99-15, has been very slow with only 11 patients put on trial. This has been the trend throughout the country, and the floor was open for suggestions.
The next discussion item was the initiation of a cosmetic analysis of the Brachytherapy trial. Dr. Kuske took the podium to announce that he had organized a committee, which will proceed with this task. They had their organizational meeting at this meeting. Dr. Marie Taylor, who will be the chair of that committee, then took the podium to announce that the committee will include several radiation therapists who did not participate in the Brachytherapy trial, as well as a patient advocate and a surgeon.
Dr. Frank Vicini then presented his developing trial of conformal quadrant radiation therapy as the sole treatment for breast cancer. He presented some initial information on the development of this technique at his institution, William Beaumont Hospital. He presented background information leading up to the launching of this trial, information on how selection criteria were arrived at, continuing development of ideas on how to define the target volume, his work looking at organ motion, and finally he presented one case showing how this is actually done at his institution, in a step by step fashion.
Dr. Vicini also had a series of slides and he updated the group on the progress on the phase III trial in the Milan Cancer Institute, comparing quadrant radiation given by an electron beam-IORT technique, to whole breast radiation. This trial is presently open for women aged 55 years and older, and has accrued over 200 of the planned goal of about 800.
Dr. McCormick then announced that at her institution, Memorial Sloan Kettering Cancer Center, a phase II trial is opening similar to the Milan trial, but using the HAM applicator to deliver a single dose of 20 qy at the time of the primary excision of the tumor.
A discussion then took place about the probability of a needed phase III trial in the United States comparing whole breast radiation with one of several techniques of quadrant radiation, including the RTOG proven brachytherapy technique, and the developing conformal and IORT techniques. This discussion will be an agenda item brought back to Research Strategy tomorrow morning.
Drs. Craighead and Lukka from Canada updated the group on the status of Dr. Tim Whalens study looking at the randomization between whole breast radiation or whole breast plus regional node radiation to the first three interspaces and the SCV nodes for patients opting for breast conservation therapy with no positive disease after ancillary node dissection. This trial was presented and endorsesed at the June meeting, and again there was enthusiasm for doing this trial.
Dr. McCormick then closed the session with a presentation of an emerging EORTC trial. This trial will randomize patients who have positive axillary’s node disease on sentinel lymph node biopsy to either standard of care axillary node dissection or experimental arm axilla radiation, along with whole breast radiation. The group also expressed interest in this trial, and more information will be presented at the next meeting.
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Beryl McCormick, M.D., Chair
The meeting was called to order at 3:30pm in Montreal, Quebec.
Susan Smith, the liaison from the Clinical Trials Support Unit, spoke to the group for about ten minutes, answering questions on the new NCI initiative with the (CTSU) cancer trials support unit. Several questions were answered by her. The new patient advocacy liaison was also introduced, Rita Foust.
The next item up for discussion was the DCIS phase III study RTOG 98-04. Dr. McCormick remarked that the accrual has initially been very slow with only 11 cases entered on study so far. She asked for a show of hands indicating of those present how many had the protocol through their IRBs. More than half of those present indicated that the protocol had gone through their IRB. She then asked for problems in terms of entering patients on the trial. The majority of comments from the audience centered on perceived problems with pathology. The group was reminded that the protocol definitions are for use in this study only, to ensure uniformity and was not meant to represent any particular viewpoint on the classification of DCIS. She also pointed out that the necessary information includes the classification by the pathologist of the DCIS as being low or intermediate nuclear grade, which can include some necrosis providing it is less than 1/3 of all of the ducts. She also reminded the group that although serial sectioning of the lesion represents the ideal, information that the pathologist must provide is the distance to the nearest margin as well as the classification into low or intermediate grade. She encouraged those RTOG members present, who have pathologists having a problem with the teaching information on our web site, to directly contact Nour Sneige at the MD Anderson Hospital.
Dr. McCormick also mentioned that the optional tissue accrual and epidemiological question part of the study is very important to establish a tissue bank for future translational research. All committee members present were reminded to encourage patients to donate one tube of plasma and five to ten unstained slides if blocks of unstained tissue were not possible to obtain. She also noted that Memorial Sloan Kettering Cancer Center has developed video to help with consent process for patients on this study, and she will be inquiring as to whether or not this video might be shared by Memorial.
A final question about this protocol included the frequency of follow up visits as specified in the study. Apparently many HMO groups will not authorize these patients back to radiation oncologists, following the first visit post completion of treatment. Dr. McCormick noted that this had been raised in the strategy meeting, and the research associates in this situation can and should contact the primary physician, to still get the needed information for the protocol, as well needed follow up tests.
Eric Strom announced to the group that the RTOG 99-15 version of SWOG post mastectomy trial (S9927) is now open through SWOG and will be opened through RTOG shortly. There was a lively discussion amongst most present as to the timing of post mastectomy radiation, should a patient be randomized to this arm if the patient received Taxol as adjuvant chemotherapy. Several studies recently showed an increase in radiation pneumonitis, in patients who received combinant Taxol and radiation. Dr. Strom noted that at the MD Anderson Cancer Center they have been using Taxol for a number of years, and in the situation where at least three weeks is allowed between the last Taxol and the beginning of radiation, pneumanitis has not been seen as an increasing problem. This was confirmed by others in the audience.
Dr. McCormick noted that part of the reason accrual for breast patients has been low in the first six months of calendar year 2000 is that both the Biafine ® study (RTOG 97-13) and the brachytherapy study (RTOG 95-17) have closed. Although the DCIS study was technically opened in December, the process of getting the study through IRB is slow. Hopefully, with both RTOG 99-15 and 98-04 being open for the remainder of the calendar year, accrual of breast patients to RTOG studies will again increase.
The next item of business was to discuss the possibility of doing a phase III trial comparing standard whole breast external beam radiation to quadrant radiation. Although the Breast Cancer Committee enthusiastically supported a phase III trial with the non standard arm being quadrant brachtherapy at the last semi-annual meeting, Dr. McCormick noted that when this enthusiastic support was presented to the Research Strategy Committee, the statistics, of just over 400 patients total in such a study, provided in letter form from CTEP in response to Dr. Kuske’s request for putting more patients on the phase II brachytherapy trial did not appear to met the statistics standards of the RTOG. Drs. Pajak and Lu have provided statistics, that actually require between 1500 and 2000 patients, in such a stage III trial, looking for true equivalence in the range of 10% local recurrence differences with just a few percentage points variance. Dr. Pajak was present to discuss all the aspects of his statistical analysis. Dr. Kuske strongly objected to the NCI estimate that just over 400 cases was likely to provide the same information. Multiple opinions from the audience were voiced. Although all concluded that Dr. Kuske’s pilot study certainly demonstrates that quadrant radiation therapy may be very effective in terms of local control, designing a study that may actually change the paradigm of breast radiation after breast conservation surgery needs to be carefully done. Others in the audience expressed an interest in being able to do this with external beam therapy, since the Brachtherapy techniques are not widely practiced in the community at this time. After a heated discussion, Dr. McCormick asked for a show of hands supporting a carefully designed phase III trial measuring whole breast radiation to quadrant radiation, which could be done by either brachytherapy or external beam conformal or IMRT techniques. More than half of those present raised their hands in support of a trial such as this, although it would require more planning time. The accrual of 1500 to 2000 patients as outlined by Dr. Pajak, and most importantly demonstration by pilot studies that conformal/IMRT radiation is an effective way of delivering quadrant radiation. Dr. Sylvia Formini from NYU Hospital was particularly vocal in this discussion and will soon share some preliminary 3D quadrant data that she compiled when she was in Los Angeles. As well, Dr. Frank Vicini, who was not present, at this meeting, will be encouraged to proceed with an IMRT phase II trial. Clearly, the theme at this committee meeting was that a test case type scenario, such as that in the brachytherapy trial, should be formulated, but to allow institutions to deliver conformal radiation by either IMRT techniques or conventional 3D conformal techniques. Dr. McCormick will bring this back to the Research Strategy Committee, as well as seek input from both Medical Physics and 3D-CRT committee chairs.
In terms of old business, Dr. Ed Sauter’s idea to study nipple aspirations to screen for local recurrence following surgery and radiation did not receive enthusiasm as a possible developing study. The idea of Dr. Schomberg, presented in January, using a 1.6 fraction, BID, to 48 Gy, to accelerate whole breast radiation was discussed. In this setting, it was thought that this may be more important for development as a treatment for patients with advanced inoperable disease or persistent local failure, in conjunction with a radiation senitizer or with combination chemotherapy. Again, Dr. Syliva Formini was particularly vocal in sharing her experience using Taxol and radiation. It was concluded that at the next meeting in Tampa, Dr. Formini, the MGH group, the group from the University of Chicago, the MD Anderson group, and anyone else that has pilot studies looking at unique ways of treating locally advanced or persistent local failure disease, will share these with the committee.
Dr. McCormick also mentioned that Dr. Tim Whelan and the NCIC have gone ahead with a study looking at whole breast radiation in early stage disease, randomizing to +/- local regional radiation as well. Dr. Whelan was not present at the meeting but will be updating the group on this study at our next meeting.
Finally, Dr. McCormick mentioned a possible replacement of the CALGB study (RTOG 97-02) for the special population of older patients, those seventy years of age and older. Unfortunately, the results of the CALGB trial which we participated in are not yet available to us. The Institute Curie technique of 800 centigrade, once a week times 5 to 6 treatments was also mentioned as a possible treatment for elderly patients. These will be discussed and hopefully developed in more detail over the next six months.
Dr. McCormick concluded the meeting noting that there is a new ASTRO educational tape discussing primary treatment options for women with early stage breast disease.
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Beryl McCormick, M.D., Chair
The meeting was called to order at 3:30pm. Dr. McCormick started the meeting by showing the overhead summary of the committees track record to date, which she prepared as a rehearsal presentation for the site visit and was given earlier in the meeting to the research strategy committee.
The first item of business was the opening of the DCIS protocol in December, RTOG 98-04. Several quote “housekeeping” items were discussed, and have been identified by calls to Headquarters to date. The first was the issue of Tamoxifen. It was clarified that one 20mg tablet can be given daily, or the Tamoxifen can be prescribed as two 10mg tablets taken as one 10mg tablet bid. The entire process of accrediting the pathologist involved in reviewing the slides was then discussed. Dr. McCormick made it known about the entire process is on a “honor system”. She also explained that Dr. Sneige has developed an excellent teaching pathologist web site, which is easily available through the RTOG web site. She encouraged all potential participants in the trial to review the web site. She also explained that the web site would have an advantage over a set of glass teaching slides, because all of the images are consistent. She circulated downloaded black and white and color images from the web site, and encouraged all participants to have their pathologists review these images, either on-line or down load it off a good quality printer, before deciding that the glass slide sets need to be reviewed. The American Cancer Society booklet describing surgical techniques is referred to in the protocol as obtainable through the American Cancer Society. Dr. McCormick explained that this actually needs to be obtained from Headquarters is in Philadelphia. Finally, for the optional Epidemiology and tissue and plasma repository, Dr. McCormick noted that in cases were limited material is available because of the small tumor size, one or two unstained slides can be substituted for a block of tissue, in addition to the tube of frozen plasma.
Dr. Eric Strom reported that the Southwest Oncology Group (SWOG) post mastectomy trial is in the process of final approval at the NCI. He reported that he assumed that this trial would be open no later than mid-year this year.
Dr. Frank Vicini presented his growing experience with IMRT optimization. His presentation included several treatment planning slides from his system, looking at the possibility of using IMRT to treat either the whole breast or a volume similar to that know treated in the brachytherapy study RTOG 95-17. Dr. Robert Kuske followed this up with an update to the group on the status of the brachytherapy study. He read the NCI review of the request to increase the number of patients on our phase I/II trial. In that letter of January 14, a randomized trial in a phase III setting was the next step that the NCI thought would be appropriate for our group. Dr. Kuske presented the patient numbers suggested by the NCI, and follows this with a discussion of how much support there would be within the Breast Cancer Committee for such a phase III study. There was unanimous and enthusiastic support for this developing protocol, and Dr. Kuske developing concept will be taken tomorrow to the Research Strategy Committee for approval to develop.
Dr. Rachel Rabinowitz presented a hand-out exploring the possibility of developing an MRI study for the Breast Cancer Committee, looking at the role of MRI Magnetic Resonance Imaging in assessing the volume of cancer in patients who opt for breast conservation and by standard techniques, appear to have negative margins. She emphasized that such a study would need to be a blinded study, since the role of MRI in assessing this unknown at this point in time. A concept was meet with general approval, and she will work with Dr. McCormick, Dr. Steven Harms, and Dr. Elizabeth Morris in developing this, with a significant hurdle seen as the cost of each MRI study.
Dr. Richard Hudes from Thomas Jefferson University Hospital, then gave the group a presentation on a possible phase I trial of radiation and concurrent Paclitaxel, with an Amifostine used as a radiation protector. At the conclusion of his proposal, there was significant discussion about the goal of the trial. It was pointed out that although his proposal would move the time of external beam radiation up, that the timing, in light of ACT chemotherapy, is an issue of which we do not know the consequences yet. Thus, to address it as a problem that needs to be resolved before it is identified as a problem was one topic of discussion. Dr. Eric Strom also had some doubts in terms of using Amifostine, with its potential ability to interfere with the efficacy of the radiation. There was no consensus at all to go ahead with this all treatment scheme at this time, although there was a consensus that the group needs to look further at existing experience with neo-adjuvant or concomitant chemotherapy and radiation, especially in patients with locally advanced breast cancer. Dr. Strom will try to summarize the experience of the MD Anderson in this regard, at the next semi-annual meeting. Dr. McCormick encouraged any other committee members who have a similar experience to review this as well the next time our group meets. Dr. Edward Sauter, a surgeon from Thomas Jefferson University Hospital, reviewed his experience with obtaining nipple aspirates from patients treated with breast conservation surgery and radiation, and evaluating cytology to predict which patients which may experience local recurrent breast cancer. He reviewed the biology behind his proposal. There was considerable interest in the group learning more about his experience, especially in terms of reviewing and any publications he might have. Dr. Sauter promised to forward the five publications he has to the committee chair that will distribute them to steering committee and other committee members who are interested.
Dr. Ivy Peterson presented a concept looking at accelerated hyperfraction, for stage II breast cancer, again as a means of shorting the time of external beam radiation and therefore bringing it closer to the time from surgery, with assumed intermittent chemotherapy. In her pilot study, two daily 1.6 Gy fractions were delivered, to a total of 48 Gy to the breast and regional lymph nodes if three or more lymph nodes were involved. She presented early and excellent cosmetic scoring, and there was considerable interest in the committee in developing this concept further. Dr. Peterson and Dr. Schomberg will be encouraged develop a protocol for our group looking at this as another way of working through the sequencing problem, if approved by the Research Strategy Committee.
Dr. Strom summarized the new proposals at the meeting, at addressing either issues of increased efficacy of radiation by using radiation sensitizer of some category, or in the second category, looking at shortened and accelerated courses of radiation, to address the potential sequencing problems.
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