Collaboration for Clinical Trials: Colorectal Cancer · TNT = Total neoadjuvant therapy CT (FOLFOX) => 5FURT => TME Keeps the RT! Goal: decrease distant mets in “higher risk”

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




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]


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?


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!


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


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!


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


^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


=> CT x2m


>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]


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


=> CT x2m


>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



©2016 by American Society of Clinical Oncology https://commons.wikimedia.org/wiki/File:Thats_all_folks.svg

Documents

Collaboration for Clinical Trials: Colorectal Cancer · TNT = Total neoadjuvant therapy CT (FOLFOX) => 5FURT => TME Keeps the RT! Goal: decrease distant mets in “higher risk”