Collaboration for Clinical Trials: Colorectal Cancer
Jeff Letzer, DO Hematology/Oncology MidMichigan Physician Group April 25, 2016 Physicians Group April 25, 2016
Volunteering on the First Day of Work
April 25, 2016
http://www.klowns-in-my-koffee.com/2010_09_01_archive.html
Expanding Opportunities for Our Cancer Patients @MMH
Current clinical trials program @MMH; need for more trials!
PROSPECT = largest colorectal cancer treatment trial @UofM
Prognosis of locally advanced rectal cancer (LARC) Can we divide into 2 different risk groups and tx differently?
Current Tx LARC
PROSPECT Design
??? being asked
Why it makes sense for our patients who are eligible
More to come @MMH for ALL of our cancer patients in terms of clinical trial options
ASCO: “Our Nation’s Path to Conquering Cancer”
Don S. Dizon et al. JCO 2016;34:987-1011
©2016 by American Society of Clinical Oncology
ASCO: “Our Nation’s Path to Conquering Cancer”
Don S. Dizon et al. JCO 2016;34:987-1011
©2016 by American Society of Clinical Oncology
MidMichigan Health: Open Trials (3.27.16)
5 breast cancer trials
1 second-line NSC lung cancer trial
UofM Open Colorectal Trials (3.27.16)
ECOG E7208: Ph II (irinotecan & cetuximab, +/-Ramucirumab in WT metastatic CR-CA following progression on bevacizumab-based tx; N= 89/147)
SWOG S0820: 1o and 2o prevention trial with Eflornithine & Sulindac (N= 1488)
SWOG S1316: +/- surgery in malignant bowel obstruction
SWOG S1406: Ph II (irinotecan & cetumixmab, +/- Vemurafenib in BRAF mutant met CR-CA (N= 93/105)
NCCTG N1048 [PROSPECT]: Ph II/III, Locally advanced, operable rectal ca; SELECTIVE use of RT (N= 509/1060)
Rectal Cancer Staging: Locally Advanced
Stage II
T3 N0
T4 N0
Stage III
T1-4b N1 [1-3 LN]
T1-4b N2 [4+ LN]
NCCN Guidelines Version 1.2016 Staging Rectal Cancer. https://www.macmillan.org.uk/information-and-support/bowel-cancer/colon/treating/treatment-decisions/Understanding-your-diagnosis/staging-and-grading.html
[T4 = penetrates to visceral peritoneum (a) or invades contiguous organs (b)]
PROSPECT: Interested in a Lower Risk Subset that is Potentially Operable (LAR)
Stage II
T3 N0
T4 N0
Stage III
T1-4b N1 [1-3 LN]
T1-4b N2 [4+ LN]
NCCN Guidelines Version 1.2016 Staging Rectal Cancer. https://www.macmillan.org.uk/information-and-support/bowel-cancer/colon/treating/treatment-decisions/Understanding-your-diagnosis/staging-and-grading.html
T2-3
cN2= 1+ cm LN’s x 4 on MRI/EBUS
Operable LARC: NCCN: T3N0 or Tany N1-2
Neoadjuvant CRT [Category I]
Cape/5FU-RT
Then surgery
Then more chemo (5FU v FOLFOX)
NCCN Guidelines Version 1.2016
NCCN: T3N0 or Tany N1-2 (Operable)
Category 1
NCCN Guidelines Version 1.2016
CRT TME CHEMO
Locally Advanced (II/III) Rectal Ca: Standard Results with Neoadj CMT
German study (Sauer et al), R-03, R-04
LRR (local recurrence rate)
6-11%
DFS (2-11y)
60-82%
Roh JCO 27:5124-5130. O'Connell JCO 32:1927-1934. Sauer NEJM 004;351:1731-40.
Locally Advanced (II/III) Rectal Ca: Standard Results with Neoadj CMT
German study (Sauer et al), R-03, R-04
LRR (local recurrence rate)
6-11%
DFS (2-11y)
60-82%
However, not all LARC have the same px! There are lower and higher risk groups that have different px’s, both in terms of LRR and DFS
Roh JCO 27:5124-5130. O'Connell JCO 32:1927-1934. Sauer NEJM 004;351:1731-40.
Rectal Ca: 5 Year Survival and Relapse Rates by Stage
Gunderson et al. Gastrointest Cancer Res 2:25–33. ©2008
PMC full text: Gastrointest Cancer Res. 2008 Jan-Feb; 2(1): 25–33.
Copyright/License ► Request permission to reuse
Table 2
Rectal cancer pooled analysis: Survival and relapse rates by stage of disease.
Stage 5-yr survival Relapse Stage
Risk of relapse TN MAC OS(%) DFS(%) Local(%) Distant(%) Dukes TNM
Low T1N0 A ~90 ~90 ≤ 5 ~10 A I
T2N0 B1 ~90 ~90 ≤ 5 ~10 A I
Intermediate T1-2N1 C1 81 74 6 15 C IIIA
T3N0 B2 74 66 8 19 B IIA
Moderately high T1-2N2 C1 69 62 8 26 C IIIC
T4N0 B3 65 54 15 28 B IIB
T3N1 C2 61 50 11 34 C IIIB
High T3N2 C2 48 39 15 45 C IIIC
T4N1 C3 33 30 22 39 C IIIB
T4N2 C3 38 30 19 50 C IIIC
Modified from Gunderson et al.11
Stage of disease based on surgical and pathologic findings at the time of resection
Survival: Unadjusted Kaplan-Meier estimates
Data derived from prior publications, as low-risk patients were not eligible for the three phase III trials in the
pooled analysis
Abbreviations: DFS = disease-free survival; MAC = modified Aster-Coller; OS = overall survival; TNM =
tumor, node, metastasis.
*
* †
‡
*
†
‡
Can We Rearrange Gunderson Data to Find a Group With Low LRR But Inadequate Cure Rate?
Gunderson et al. Gastrointest Cancer Res 2:25–33. ©2008
PMC full text: Gastrointest Cancer Res. 2008 Jan-Feb; 2(1): 25–33.
Copyright/License ► Request permission to reuse
Table 2
Rectal cancer pooled analysis: Survival and relapse rates by stage of disease.
Stage 5-yr survival Relapse Stage
Risk of relapse TN MAC OS(%) DFS(%) Local(%) Distant(%) Dukes TNM
Low T1N0 A ~90 ~90 ≤ 5 ~10 A I
T2N0 B1 ~90 ~90 ≤ 5 ~10 A I
Intermediate T1-2N1 C1 81 74 6 15 C IIIA
T3N0 B2 74 66 8 19 B IIA
Moderately high T1-2N2 C1 69 62 8 26 C IIIC
T4N0 B3 65 54 15 28 B IIB
T3N1 C2 61 50 11 34 C IIIB
High T3N2 C2 48 39 15 45 C IIIC
T4N1 C3 33 30 22 39 C IIIB
T4N2 C3 38 30 19 50 C IIIC
Modified from Gunderson et al.11
Stage of disease based on surgical and pathologic findings at the time of resection
Survival: Unadjusted Kaplan-Meier estimates
Data derived from prior publications, as low-risk patients were not eligible for the three phase III trials in the
pooled analysis
Abbreviations: DFS = disease-free survival; MAC = modified Aster-Coller; OS = overall survival; TNM =
tumor, node, metastasis.
*
* †
‡
*
†
‡
Rectal Ca: 5 Year Survival and Relapse Rates by Stage: Risk Stratification Inferred from PROSPECT!
Gunderson et al. Gastrointest Cancer Res 2:25–33. ©2008
Risk Stage DFS% Local Relapse %
Distant %
Low T1-2N0 ~90 < 5 ~10
Intermediate T1-2N1 T3N0 T3N1
74 66 50
6 8 11
15 19 34
High T1-2N2 T4N0 T3N2 T4N1 T4N2
62 54 39 30 30
8 15 15 22 19
26 28 45 39 50
RTME +/- Neoadjuvant RT (5x5): The Dutch
TME Study: Decreased LRR
Kapiteijn E et al. N Engl J Med 2001;345:638-646.
RTME +/- Neoadjuvant RT (5x5): The Dutch
TME Study: No Survival Diff!
Kapiteijn E et al. N Engl J Med 2001;345:638-646.
Side Effects of Radiation: Bowel Function in
Eligible Patients Without a Stoma (Dutch)
K.C.M.J. Peeters et al. JCO 2005;23:6199-6206
©2005 by American Society of Clinical Oncology
Dutch TME Trial: Fecal Incontinence (N= 339, >5 Year FU: Retro Analysis)
Lange, et al. British Journal of Surgery 2007; 94: 1278–1284
Additional Side Effects from RT in Rectal Ca
SBO
2.5 x higher risk with RT (13 v 5%; Swedish, German)
Perineal wound complication
29 v 18% (Dutch)
Sexual dysfx
Higher in RT
Weiser M. Locally Advanced Rectal Cancer: Time for Change? ASCO 2016 Ed Program
Rectal Ca: 5 Year Survival and Relapse Rates by Stage: Risk Stratification Inferred from PROSPECT!
Gunderson et al. Gastrointest Cancer Res 2:25–33. ©2008
Risk Stage DFS% Local Relapse %
Distant %
Low T1-2N0 ~90 < 5 ~10
Intermediate T1-2N1 T3N0 T3N1
74 66 50
6 8 11
15 19 34
High T1-2N2 T4N0 T3N2 T4N1 T4N2
62 54 39 30 30
8 15 15 22 19
26 28 45 39 50
PROSPECT (N1048)
Preoperative Radiation Or Selective Preoperative radiation and Evaluation before Chemotherapy and TME
= CT alone or CT + RT in Pts with localy advanced rectal cancer undergoing Surgery
Ie, Can we omit RT for good responders to neoadjuvant CT?
N1048 Protocol. Schrag D. Neoadjuvant/Adjuvant Chemotherapy for Stage II/III Rectal CancerASCO 2016 Ed Program
Randomize
FOLFOX x 3m
Tumor regress >20%
LAR/TME
R0: CT x 3m R1/2: 5FU-RT
=> CT x2m
Tumor not regressing
>20%
5FU-RT
LAR/TME
CT x 4m
N1048 Protocol
PR
OSP
ECT
LARC: Ways to Improve Efficacy
HOW TO TRY TO IMPROVE DFS/CURE RATES? = GIVE OUR BEST CHEMO RIGHT AWAY!
PROSPECT
Aggressive CT (FOLFOX) upfront, then Surgery/TME, then more chemo
CT (FOLFOX) => TME => CT
Goal: decrease distant mets in “lower risk” LARC => ^OS
TNT = Total neoadjuvant therapy
CT (FOLFOX) => 5FURT => TME
Keeps the RT!
Goal: decrease distant mets in “higher risk” LARC => ^OS
Weiser M. Locally Advanced Rectal Cancer: Time for Change? Schrag D. Neoadjuvant/Adjuvant Chemotherapy for Stage II/III Rectal CancerASCO 2016 Ed Program. Chau, et al. J Clin Oncol 2006;24:668-674.
Mosaiq Colon Ca Trial: Kaplan-Meier 10y overall survival (OS) in the
intent-to-treat population according to (C) N1 stage III, and (D) N2
stage III: FOLFOX v LV5FU2
Thierry André et al. JCO 2015;33:4176-4187
©2015 by American Society of Clinical Oncology
^6% ^13%
Locally Advanced Rectal Ca: Why PROSPECT Makes Sense
Aggressive chemo ALONE, FIRST
Avoids delays ass’d with traditional neoadjuvant CRT
~18 week delay before aggressive chemo!
30% of pts due for “adjuvant” aggressive chemo either do not end up getting the chemo, or have dose reductions due to, myelosuppression a/w pelvic RT!
FOLFOX in the adjuvant setting (after TME) is not clearly superior to 5FU
The use of dose-reduced 5FU + OX concurrent with RT (before TME) is not clearly superior to 5FU, and is more toxic (thus may need to give full-dose FOLFOX alone first!)
Weiser M. Locally Advanced Rectal Cancer: Time for Change? ASCO 2016 Ed Program. Cercek et al. JCO 2010;28;15S. Schrag D. Neoadjuvant/Adjuvant Chemotherapy for Stage II/III Rectal Cancer. 2015 ASCO Ed Program.
LARC: Ways to Decrease Morbidity
HOW TO TRY TO DECREASE MORBIDITY?
PROSPECT: Try to avoid RT
an attempt to substitute modern chemotherapy for chemoradiation!
Try to avoid Surgery (in pts responding well to CRT)
Weiser M. Locally Advanced Rectal Cancer: Time for Change? Schrag D. Neoadjuvant/Adjuvant Chemotherapy for Stage II/III Rectal CancerASCO 2016 Ed Program
Gunderson: Rectal Pooled Analysis: 5-Year Local Relapse Rates by Risk Group and Treatment: A
Subset in Which RT may not be needed?
S + RT S + CT
T1-2/N1 (n= 355) 7 5
T3/N0 (n= 1058) 12 11
T3/N1 (n= 881) 13 17
Leonard L. Gunderson et al. JCO 2004;22:1785-1796
Locally Advanced Rectal Ca: Why PROSPECT Makes Sense (cont.)
Modern chemo is effective in downstaging dz, allowing for more R0 resections without RT!
6/7 pts @MSK had >90% shrinkage with neo FOLFOX
TNT in high-risk LRC (N= 77; UK): Radiologic RR = 88% with neo FOLFOX
Avoids overtreating cII/III
German Rectal Trial: 18% who went straight to TME had stage I disease!!!
Weiser M. Locally Advanced Rectal Cancer: Time for Change? ASCO 2016 Ed Program. Cercek et al. JCO 2010;28;15S. Schrag D. Neoadjuvant/Adjuvant Chemotherapy for Stage II/III Rectal Cancer. 2015 ASCO Ed Program.
Randomize
FOLFOX x 3m
Tumor regress >20%
LAR/TME
R0: CT x 3m R1/2: 5FU-RT
=> CT x2m
Tumor not regressing
>20%
5FU-RT
LAR/TME
CT x 4m
N1048 Protocol
PR
OSP
ECT
PROSPECT: Eligibility by Stage (Operable)
Stage II
T3 N0
T4 N0
Stage III
T1-4b N1 [1-3 LN]
T1-4b N2 [4+ LN]
NCCN Guidelines Version 1.2016 Staging Rectal Cancer. https://www.macmillan.org.uk/information-and-support/bowel-cancer/colon/treating/treatment-decisions/Understanding-your-diagnosis/staging-and-grading.html
T2-3
cN2= 1+ cm LN’s x 4 on MRI/EBUS
PROSPECT: Other Eligibility
Surgical candidate for SSS (sphincter-sparing surgery) rather than APR upfront!
SSS = LAR (low anterior resection) with TME (total mesorectal excision
N1048 Protocol. https://openi.nlm.nih.gov/detailedresult.php?img=PMC3075139_crg0002-0175-f03&req=4. Up To Date 4.23.16
Randomize
FOLFOX x 3m
Tumor regress >20%
LAR/TME
R0: CT x 3m R1/2: 5FU-RT
=> CT x2m
Tumor not regressing
>20%
5FU-RT
LAR/TME
CT x 4m
N1048 Protocol
PR
OSP
ECT
PROSPECT: Objectives
Primary [non-inferiority]
R0 rate
TLR = time to local recurrence
Seconday [non-inferiority]
pCR
Overall survival
Tertiary
QOL
Genetics
N1048 protocol
PROSPECT: Multiple Genetics Testing
MIP = molecular inversion probe array
Mass spectrometry-based genotyping
To identify immune markers for response to neoadjuvant tx
To identify novel immune targets in rectal ca
To study various germline genetic variants
To study chemo and CRT effects on anti-tumor immunity
N1048 protocol
Chinese FOWARC Neoadjuvant LARC Trial
5FU-RT (N= 165)
FOLFOX-RT (N= 165)
FOLFOX (NO RT) (N= 165)
R0 90% 88% 91%
Post-op Anastomotic Leakage
24 19 6
Post-op Infection of Incision
26 30 9
Deng, et al. Journal of Clinical Oncology, 2015 ASCO Annual Meeting (May 29 - June 2, 2015). Vol 33, No 15_suppl (May 20 Supplement), 2015: 3500 © 2015 American Society of Clinical Oncology
Expanding Opportunities for Our Cancer Patients @MMH
Current clinical trials program @MMH; need for more
PROSPECT = largest colorectal cancer treatment trial @UofM
Prognosis of LARC
Current Tx LARC
PROSPECT Design
??? being asked
Why it makes sense for our patients who are eligible
More to come @MMH for ALL of our cancer patients in terms of clinical trial options vis-à-vis UofM/NCI
ASCO: “Our Nation’s Path to Conquering Cancer”
Don S. Dizon et al. JCO 2016;34:987-1011
©2016 by American Society of Clinical Oncology https://commons.wikimedia.org/wiki/File:Thats_all_folks.svg