RTOG: Committee Minutes - Gastrointestinal Cancer

Committee Minutes - Gastrointestinal Cancer

GASTROINTESTINAL CANCER COMMITTEE (February, 2007)

Howard Safran M.D. for
Christopher Willett, M.D., Chair

The RTOG Gastrointestinal Cancer Committee first reviewed our active trials: Dr. Lisa Kachnic reviewed RTOG 0529, the phase II trial of IMRT for anal cancer. This trial has just been initiated so accrual to this trial was emphasized. RTOG 0438, the phase I trial of highly conformal radiation therapy for patients with liver metastases was then discussed. Accrual to this trial has been very slow. Dr. Laura Dawson the PI was not able to attend the meeting and Dr. Paul Okunieff substituted to discuss the trial. Unfortunately virtually all accrual has come from Princess Margaret Hospital. Other institutions have not been credentialed. This appears to be a major hurdle. Technical obstacles to credentialing were reviewed. A post RTOG conference call will address these challenges. Dr. Meropol briefly reviewed RTOG 0247. This phase II study has successfully completed accrual.

Protocols in development were then discussed. RTOG 0436 a phase III trial of cetuximab for nonoperable treatment of esophageal cancer has received CTEP approval. Dr. Suntha reviewed this trial. Accrual will be a major focus of the Gastrointestinal Cancer Committee. The follow-up RTOG rectal trial concept, RTOG 0628 was discussed. This trial will use IMRT in the management of preop rectal cancer. Dr. Meropol emphasized that integration of this trial into the framework of the CTSU post operative adjuvant study was critical for the success and activation of this study. The colorectal task force should also be informed of this trial so it does not compete with the phase III neoadjuvant and adjuvant trials.

The majority of the meeting discussed strategy for adjuvant and locally advanced pancreatic cancer. In adjuvant pancreatic cancer, if the cetuximab phase III metastatic trial were positive it would facilitate a phase III adjuvant trial. The gemcitabine arm of RTOG 9704 could be tested with and without cetuximab. This trial could be performed with the collaboration of SWOG. However, if the metastatic cetuximab trial were negative, our emphasis would be to optimize adjuvant radiation with IMRT. Dr. Abrams discussed his review of RTOG 9704. Survival may be inferior if there were radiation deviations. Real time quality control is needed. Toxicity may also be reduced with IMRT. A phase II study of 2 cycles of gemzar, followed by 5-FU/IMRT, followed by 2 cycles of gemzar was agreed upon if the cetuximab trial was negative. The primary goal of the phase II study would be to reduce toxicity in adjuvant pancreatic cancer by using IMRT. A secondary goal would be to optimize radiation quality control

Multiple ideas were discussed for locally advanced pancreatic cancer. Results to RTOG 0411 are pending. With the negative metastatic bevacizumab trial, further large scale evaluation of bevacizumab would be difficult in pancreatic cancer unless RTOG 0411 had spectacular results. There was not much interest in stereotactic radiation. Dr. David Morris of Bristol-Myers Squibb was invited to speak by Dr. Crane on markers of response to cetuximab. However, the data pertained to colon cancer and the applicability to pancreatic cancer was uncertain.

Membership of the GI task forces was also discussed.

In the early part of the general meeting the highlights of the active protocols were again reviewed as described above. However, the majority of the meeting was used to more fully develop the concepts in adjuvant and locally advanced pancreatic cancer.

In adjuvant pancreatic cancer, a simple phase II study incorporating IMRT with fluorouracil was agreed to. Two cycles of gemcitabine will be given pre and post IMRT/5FU. The main goal would be to reduce toxicity from chemoradiation in comparison to RTOG 9704. Other options such as the use of erlotinib were discussed but thought to be overly complicated. The best option was to focus on the radiation.

In locally advanced pancreatic cancer. Dr. Crane brought forth the idea of adding cetuximab to IMRT and fluorouracil. Again the focus would be on optimizing radiation. At MD Anderson Cancer Center there is a pilot study of cetuximab with radiation.

GASTROINTESTINAL CANCER COMMITTEE (June, 2004)

Christopher Willett, M.D., Chair

1. RTOG 0411: Bevacizumab and Erlotinib with Capecitabine and EBRT and Gemcitabine for locally advanced pancreatic cancer. Details regarding Gemcitabine in maintenance regimen to be reviewed with Genentech.

2. RTOG 0414: Adjuvant Pancreas trial. LOI has been submitted to NCI. Bevacizumab has been added as follows: Bev+ Gem --> Bev + Gem + EBRT --> Bev + Gem.

3. RTOG 0245: Stereotactic Liver Trial: Statistical section to be finished shortly. Digital transmission required and RTOG physics to review with University of Rochester group.

4. Concept: Non-operative Treatment of Esophageal cancer by Dr. Mohan Suntha. University of Maryland, Brown, and Vanderbilt conducting a phase I/II study looking at C225 + Paclitaxel + Cisplatin and EBRT for esophageal cancer. Protocol will be written to look at first a phase II study using this regimen to be followed by a phase III study comparing EBRT + Paclitaxel + CDDP with and without C225.

5. Discussion with CTEP will be pursued to review potential adjuvant gastric trial looking at the Cisplatin and Paclitaxel and EBRT arm of RTOG 0114 given the likely closure of current adjuvant gastric trial.

6. Concept for treatment of previously irradiated patients with recurrent rectal cancer by Dr. Peter Johnstone approved: Phase I/II study of preop Oxyplatin + 5-FU with hyperfractionated EBRT.

7. Dr. Kachnic to develop a concept employing biologic for anal canal cancer.

8. Retreat to be held in Philadelphia this fall.

GASTROINTESTINAL CANCER COMMITTEE (June, 2004)

GASTROINTESTINAL CANCER COMMITTEE (January, 2004)

Christopher Willett, M.D., Chair

1. RTOG 9811 continues to accrue satisfactorily and projected closure is in one year. Dr. Kachnic and Dr. Sause presented a potential replacement study in which sentinel lymph node biopsy will be used to aid radiation field design. Dr. Kachnic will write this phase II protocol.

2. RTOG 9904 and 0114 will meet accrual goals shortly and close. There will be a conference call in one month to discuss potential replacement gastric studies.

3. RTOG 0113 will meet accrual goals shortly. Dr. Suntharalingam presented a potential replacement study that will compare preoperative radiation therapy (45 Gy) and chemotherapy vs. preoperative radiation therapy (45 Gy with concurrent field within field for an additional 15 Gy). The boost fields will employ PET based treatment planning. There will be a conference call to further discuss this and other concepts.

4. RTOG 0247 will be activated within one month and open to accrual.

5. RTOG 0223 has been submitted to CTEP.

6. RTOG 0245 has been revised and investigators have agreed to submit digital data.
This study will be submitted to CTEP by June of 2004.

GASTROINTESTINAL CANCER COMMITTEE (June, 2003)

Christopher Willett, M.D., Chair

RTOG 0012 - A phase II study, randomizing patients with clinical T3 or T4 rectal cancer to preoperative pelvic radiation therapy with infusion 5-FU and weekly irinotecan or hyperfractionated radiation therapy with infusion 5-FU. This trial successfully met its accrual goals of > 100 patients.

A replacement study to RTOG 0012 has been written and will be submitted to CTEP. This phase II study will randomize patients with a clinical T3 or T4 rectal cancer to preoperative pelvic radiation therapy with Capecitabine and Oxaliplatin or preoperative pelvic radiation therapy with Capecitabine and Irinotecan. This trial will identify a treatment arm that could be served as a template for future phase III studies evaluating targeted therapies.

RTOG 0246 – For operable patients with esophageal cancer, an innovative phase II trial (RTOG 0246) examining a non-operative approach with induction 5-FU, Paclitaxel, Cisplatin followed by radiation therapy with concurrent 5-FU and Cisplatin and selective surgical salvage will be activated shortly.

RTOG 9704 - Building on the experience of RTOG 9704, a single arm phase II (1091) protocol has been submitted to CTEP evaluating the use of Gemcitabine not only as maintenance therapy but also its feasibility administered concurrently with external beam radiation therapy for patients with resected pancreatic cancer. The goal of this study is to establish experience with this approach in preparation for trials incorporating targeted antiangiogenic agents and/or tyrosine kinase receptor inhibitors.

RTOG 9811 – A phase III Intergroup study randomized 650 patients with anal cancer to one of two treatment arms: radiation therapy with concurrent 5-FU and Mitomycin-C versus radiation therapy plus induction and concurrent 5-FU and Cisplatin. Accrual for this trial continues to be excellent.

RTOG 9904 - A phase II study, evaluates an induction approach of chemotherapy followed by 45 Gy of radiation therapy with concurrent 5-FU and Paclitaxel and surgery for 49 patients with potentially resectable gastric cancer. Accrual for this trial has been satisfactory and the trial should close next year.

RTOG 0020 – A Randomized phase II study, evaluates the combination of concurrent weekly Pacltaxel and Gemcitabine with radiation therapy ± a farnesyl transferase inhibitor, R1157777. Accrual to this trial has been robust and the trial will be closing shortly.

RTOG 0113 - Is a randomized phase II study that randomizes non-operable esophageal cancer patients to induction chemotherapy (5-FU, Cisplatin, and Paclitaxel) followed by moderate dose radiation therapy with 5-FU and Paclitaxel or induction chemotherapy (Paclitaxel, Cisplatin) followed by moderate dose radiation therapy with Paclitaxel and Cisplatin. Although slow initially, accrual has improved in the past year.

RTOG 0114 - Is a randomized phase II study that randomizes resected high risk gastric cancer patients to induction chemotherapy (5-FU, Cisplatin, and Paclitaxel) followed by moderate dose radiation therapy with 5-FU and Paclitaxel or induction chemotherapy (Paclitaxel, Cisplatin) followed by moderate dose radiation therapy with Paclitaxel and Cisplatin. Because of higher-grade 3 GI toxicity observed in the 5-FU, Cisplatin, and Paclitaxel with moderate dose radiation therapy arm, the trial has been amended to a single arm phase II study evaluating Paclitaxel and Cisplatin with moderate dose radiation therapy. The study continues to accrue well.

To examine the use of sophisticated 3-D conformal irradiation techniques in GI malignancies, a phase I/II trial of extracranial stereotactic radiation therapy for patients with unresectable primary hepatobiliary cancer and liver metastastes has been written and is currently being reviewed by the Image-Guided Radiotherapy Committee.

As a replacement study to RTOG 0020, a randomized phase II study employing a common template treatment of Capecitabine and Paclitaxel with radiation therapy as successfully piloted at the University of Maryland and evaluating the addition of Bevacizumab, Tarveva, or a combination of Bevacizumab and Tarceva. The protocol is currently being written.

Initial discussions regarding potential replacement to RTOG 9811 employing sentinel lymph node biopsy as well as Amifostine. Drs. Sause and Kachnic will discuss this further.

GASTROINTESTINAL CANCER COMMITTEE (January, 2003)

Christopher Willett, M.D., Chair

Dr. Hedy Kindler from the University of Chicago spoke of a phase I trial evaluating Avastin (anti-VEGF antibody) and Gemcitabine for patients with metastatic pancreatic cancer. Partial response rate was 38%. Tolerance appeared reasonable.

Ms. Paula Kim updated the GI group on the activities of PALS, a pancreatic carcinoma advocacy group. A number of excellent initiatives are underway.

Esophageal Carcinoma

1. RTOG E-0013: Accrual 23/84 patients. Accrual to trial has been slow. Study will be reassessed in 6 months for accrual.

2. RTOG 0246: Trial is currently being reviewed at the National Cancer Institute.

Gastric Cancer

1. RTOG 00-04: Accrual 28/49 patients. Accrual to study has been slow. Study will be reassessed in 6 months for accrual.

2. RTOG 01-14: Satisfactory accrual 47/94 patients. Increased incidence of G3 and G4 toxicity in treatment arm evaluating Paclitaxel, Cisplatin, and 5-FU with radiation therapy, approaching stopping rules. Toxicity analysis limited to first 23 patients. Additional patients will be evaluated and decision regarding study will be made.

Pancreatic Cancer

1. RTOG 00-20: Trial accruing well – 78/154 patients.

2. RTOG 0223: Protocol at headquarters. Study to be sent to NCI for review.

3. Discussion regarding replacement studies to RTOG 00-20 and 0223. Conference call to be held in approximately 1 month to discuss further.

Rectal Cancer

1. RTOG 00-12: Study closed this week meeting accrual goals (102/100 patients). Replacement study will be a randomized phase II study examining Oxaliplatin vs Irinotecan with Capecitabine and radiation therapy administered preoperatively for patients with clinical T3 and T4 tumors. Protocol discussed and suggestions made to finalize prior to submission to headquarters.

Liver

1. Stereotactic Treatment for Primary and Metastatic Hepatic Malignancies. Protocol written. Image Guided Radiation Therapy Committee is evaluating.

Anal Carcinoma

1. RTOG 9811: Accrual is excellent at 393/650 patients.

GASTROINTESTINAL CANCER COMMITTEE (June, 2002)

Christopher G. Willett, M.D., Chair

1. REVIEW OF CURRENT PROTOCOLS:

2. REVIEW OF REPLACEMENT TO RTOG 97-04: Proposed study is randomized phase II employing Gemcitabine followed by radiation therapy and Gemcitabine with additional Gemcitabine with and without ras peptide vaccine. LOI just reviewed from NCI raised concerns regarding availability of vaccine and assays. Conference call will be arranged to discuss this with NCI.

3. REVIEW OF REPLACEMENT TO RTOG R 00-12: Drs. Meropol and Anne discussed concept of randomized phase II study evaluating preoperative radiation therapy with Capecitabine and Oxaliplatin versus preoperative radiation therapy with Capecitabine and Irinotecan for patients with clinical T3 or T4 rectal cancer. Consensus reached on study and protocol will be drafted.

4. Dr. Katz and Dr. Dawson are near completion of a protocol evaluating stereotactic irradiation of hepatic tumors. Protocol will be circulated and has approval of the committee.

5. REVIEW OF REPLACEMENT OF RTOG 0020: Dr. Crane updated concept of Bevacizumab and Capecitabine with radiation therapy for locally advanced pancreatic cancer. A phase I study is to be initiated at MD Anderson and Dr. Crane will update at next meeting. Dr. Rich presented a concept of Xyotac (a polymeric taxane) that his collaborators are planning to investigate with radiation therapy and pancreatic cancer.

6. Dr. Zakris presented a phase II protocol from the AIDS Consortium evaluating Amifostine with radiation therapy and Cisplatin and 5-FU. Dr. Kachnic will work with Dr. Zakris on this protocol.

GASTROINTESTINAL CANCER COMMITTEE (January, 2002)

Christopher G. Willett, M.D., Chair

1. Accrual For Current GI Trials:

a. RTOG 97-04 Pancreas: 455/518
b. RTOG 98-11 Anal Canal: 292/650
c. RTOG 99-04 Gastric: 15/49
d. RTOG 00-12 Rectal: 43/100
e. RTOG 00-20 Pancreas: 9/154
f. RTOG 01-13 Esophagus: 2/84
g. RTOG 01-14 Gastric: 11/94

2. Membership was encouraged to open new trials and initiate accrual.

3. The replacement trial for RTOG 97-04 (adjuvant pancreas) will be a randomized phase II trial evaluating postoperative irradiation and concurrent Gemcitabine with and without ras peptide vaccine. The study has strong support from CTEP. A draft of protocol is written and will be distributed shortly.

4. RTOG 10-18 Phase II Esophageal Cancer Protocol: Induction ChT and ChT/EBRT with surgery reserved for salvage is written and will be distributed.

5. Three concepts presented for potential successor studies for RTOG 00-20 Pancreas (locally advanced ds). C. Crane: Bevacizumab with xeloda and radiation therapy. D. Raben: Iressa with Taxol and radiation therapy. T. Rich: Celecoxib with xeloda and radiation therapy. These investigators are initiating pilots and will report back to the committee with their initial experience.

6. S. Wong presented neoadjuvant concept for xeloda with radiation therapy for rectal cancer. There will be a conference call within the next month to address replacement study for RTOG 00-12.

7. A phase II protocol utilizing conformal irradiation for primary and metastatic hepatic malignancies by Alan Katz and Paul Okunieff was approved. Draft of protocol is written.

8. Paula Kim presented information of the PanCan group which is a resource for physicians and patients with pancreatic cancer.

9. Carolyn Hoban of Variagenics presented data of gene array technology potentially predictive of late effects associated with radiation therapy.

10. David Ilson of Memorial Sloan Kettering Cancer Center updated their experience with CPT-11 and Cisplatin and radiation therapy of esophageal cancer. Preliminary data demonstrated minimal toxicity with initial good response. This group is pursuing a Phase II study.

GASTROINTESTINAL CANCER COMMITTEE (November, 2001)

Christopher Willett, M.D., Chair

1. Dr. Willett thanked members of the Strategy Committee as well as RTOG membership for their support and enormous effort for the RTOG grant submission which was highly successful.

2. Dr. Steve Swisher reviewed the planned single arm phase II study of chemoradiation for "operable" esophageal cancer with surgery reserved for salvage. The study will employ an induction cycle of 5-FU, cisplatin, and paclitaxel to be followed by external beam irradiation (50.4 Gy) with 5-FU and cisplatin. The protocol will be written shortly and will proceed for final review.

3. Dr. Ross Abrams reviewed the various options for replacement studies for RTOG 94-05. After considerable discussion, it was elected to proceed with a Phase II study evaluating concurrent Gemcitabine with external beam irradiation as well as maintenance Gemcitabine for patients undergoing resection. A conference call will be arranged for further discussions of the next replacement study.

4. Dr. Paul Okunieff presented a concept of conformal 3-D irradiation of patients with metastatic lesions to the liver. The goal would be to employ a chemoradiation approach with radiation therapy based on 3-D guidelines of tumor to liver. The concept was approved and the protocol will be written and submitted for review.

5. Dr. Lisa Kachnic re-presented a concept of preoperative chemoradiation of "favorable" rectal cancer. The concept was approved and protocol to be written and submitted for review.

GASTROINTESTINAL CANCER COMMITTEE (June, 2000)

Christopher Willett, M.D., Chair

1. Esophageal Cancer

The CALGB Intergroup trial for patients with operative esophageal cancer was closed this past year due to poor accrual. Discussions regarding potential replacement studies were initiated. Dr. Michael Haddock from Mayo Clinic and Drs. Bruce Minsky and David Kelsen from Memorial Sloan Kettering presented concepts. Investigators were encouraged to formally submit concepts and a conference call will be arranged to discuss a potential replacement study.

2. Pancreatic Cancer

a. RTOG 9704 will meet its accrual goals in approximately a year and discussions regarding a replacement study were initiated. In the adjuvant setting, there is limited data evaluating the use of concurrent gemcitabine with postoperative radiation therapy for patients with resected pancreatic cancer. A phase II study will be written by Dr. Ross Abrams developing this concept as well as the use of a farnesyl transferase inhibitor administered concurrently and after chemoradiation.

b. There was agreement by the committee to join ECOG in supporting a neoadjuvant study proposed by Dr. John Hoffman for patients with marginally resectable pancreatic cancer. This randomized phase II study will examine two treatment arms. One will be radiation therapy and concurrent gemcitabine followed by resection or induction cis-platin and gemcitabine followed by radiation therapy and concurrent gemcitabine followed by resection.

3. Biliary Cancer

A phase II study of preoperative chemoradiation for patients with biliary cancer was presented by Dr. Rich. This study will be a joint effort with the EORTC and will evaluate the efficacy of chronomodulated 5-FU infusion with 50.4 Gy of preoperative radiation therapy.

4. Gastric Cancer

A randomized phase II studies for patients with resected high risk gastric cancer evaluating two taxol based regimens with irradiation has been written. Dr. Chris Crane discussed potential approaches to incorporating image based three dimensional conformal irradiation into this and future studies. Dr. Crane will write an addendum to this protocol with guidelines for conformal irradiation.

5. Rectal Cancer

a. Dr. Neil Meropol discussed again his protocol for patients with rectal cancer. A randomized phase II study was approved employing two treatment arms. The first is a preoperative irradiation (50.4 Gy) with capecitabine followed by capecitabine and irinotecan after surgery or preoperative irradiation (50.4 Gy) with eniluracil/5-FU followed by eniluracil/5-FU/irinotecan after surgery. TS, TP, and DPD levels from the pretreatment rectal cancer biopsies will be correlated to pathological response rate, local control, and survival outcome.

b. Dr. John Skibber presented a concept evaluating a preoperative chemoradiation approach for patients with early clinical stage (T1, T2) rectal cancer. There will be strict entry criteria into the study (clinical and radiologic staging as well as only favorable histologic features. The concept was approved and Dr. Skibber will write the protocol.

c. Dr. Chris Crane presented background and a concept evaluating the use of Cox 2 inhibitors with chemoradiation for patients with recurrent rectal cancer. Preliminary data will be obtained from a pilot study to be run by Dr. Crane at the MD Anderson Cancer Center.