American College Of Surgeons - Inspiring Quality: Highest Standards, Better Outcomes

CRP Investigator Webinar: Lower GI (NCCTG N1048, NRG-GI002, A021502)

CRP Investigator Webinar: Lower GI

A Surgical Investigators Meeting Webinar focusing on Ongoing Rectal Cancer Trials.

Sponsored by the ALLIANCE/American College of Surgeons Clinical Research Program

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Recorded October 5, 2017

Presentation Slides

Moderator: Y. Nancy You, MD MHSc, Education Committee, ACS CRP

Speakers: Martin Weiser, MD, FACS; Thom George, MD, FACP; Walter Peters, MD

Trials Covered: NCCTG N1048, NRG-GI002, and A021502

NCCTG N1048

A Phase II/III Trial of Neoadjuvant FOLFOX, with Selective Use of Combined Modality Chemoradiation Versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection with Total Mesorectal Excision

The ALLIANCE trial PROSPECT challenges the current treatment paradigm for rectal cancer. The PROSPECT trial attempts to individualize treatment by using radiotherapy selectively rather than reflexively.
The rationale for using radiation selectively in rectal cancer patients includes:

  • Better rectal cancer risk stratification—not all patients are at high risk for local recurrence
  • Minimize risk of short- and long-term toxicity
  • Enable more patients complete the prescribed multimodality regimen
  • Ability to move systemic therapy proximally to potentially reduce distant recurrence, which is the major threat to longevity

N1048/PROSPECT Trial Schema

PROSPECT Trial Schema

NRG GI002

Phase II Clinical Trial Platform of Sensitization Utilizing Total Neoadjuvant Therapy in Rectal Cancer

Outcomes for locally advanced rectal cancer (LARC) have been limited by inconsistent delivery of adjuvant therapy and ineffective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms. The experimental arms test a variety of sensitizers or hypotheses in a consistent high-risk patient population. Success of any given experimental arm will be determined by achievement of pathologic endpoints compared to the control arm.

Eligible patients/tumors are defined as meeting any one of the following criteria:

  • Distal location (as defined by measurement on MRI, ERUS/pelvic CT scan or palpable on digital rectal exam [DRE]): cT3-4 ≤ 5 cm from the anal verge, any N
  • Bulky: any cT4 with the majority of the untreated tumor < 12 cm from the anal verge or below the peritoneal reflection as determined by the treating surgeon, or evidence that the tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia on MRI or ERUS/pelvic CT scan
  • High risk for metastatic disease with 4 or more regional lymph nodes (cN2)
  • Not a candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy (as planned by the primary surgeon)

NRG GI-002 (TNT) Schema

NRG GI 002 Schema

ATOMIC (A021502)

Randomized Trial of Standard Chemotherapy Alone or Combined with Atezolizumab as Adjuvant Therapy for Patients with Stage III Colon Cancer and Deficient DNA Mismatch Repair

This randomized phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer. The PD-1/PD-L1 pathway acts to protect tumor cells from immune attack by T cells which can be circumvented by checkpoint inhibitors.

Key Inclusion Criteria

  • Histologically proven stage III colon adenocarcinoma
  • Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab
  • Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)
  • Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate
  • Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented in the operative report or otherwise confirmed by the surgeon; near or positive radial margins are acceptable so long as en bloc resection was performed. Proximal or distal margin positivity is not permitted.

Key Exclusion Criteria

  • No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e., ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
  • No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration

A021502 (ATOMIC) Schema

A021502 (ATOMIC) Schema

Estimated Enrollment : 700
Start Date: September 12, 2017
Estimated Study Completion Date : July 1, 2020

About the Speakers and Program

More about Martin R. Weiser, MD, FACS

Martin R. Weiser is vice-chair, education and faculty development, department of surgery, and Stuart H.Q. Quan Chair in colorectal surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

More about Thom George, MD, FACP

Thom George is a clinical investigator and educator with a focus on gastrointestinal malignancies. As medical director of the GI Oncology Program at the University of Florida, Dr. George oversees the treatment of all patients with GI malignancies.

More about Walter R. Peters, MD, MBA

Walter Peters is chief of the division of colon and rectal surgery and co-director of the Rectal Cancer Research and Treatment Center at Baylor University Medical Center in Dallas, TX. His research interests have included the development of minimally invasive surgical techniques for the treatment of colon and rectal cancer. He served as one of the inaugural co-chairs of the Community Oncology Committee of the Alliance for Clinical Trials in Oncology.

More about Y. Nancy You, MD MHSc, Education Committee, ACS CRP

Dr. You is associate professor, section of colorectal surgery, department of surgical oncology and medical director, Familial High Risk Gastrointestinal Cancer Clinic at the University of Texas MD Anderson Cancer Center. She is Vice-Chair, ACS CRP Education Committee.

More about ALLIANCE/ACS Clinical Research Program

The mission of the ALLIANCE/American College of Surgeons Clinical Research Program (ACS CRP) is to reduce the impact of cancer by increasing knowledge and awareness of new evidence and practice standards; increasing the participation of community oncology surgeons in cancer research and cancer care activities; developing and implementing evidence-based practices in surgical oncology; and creating opportunities for meaningful health services research.