# Presentation: 709758

## ASCO/FDA Public Workshop onClinical Trials Endpoints inColorectal Cancer  

***Rectal Cancer Endpoints***
**November 12, 2003**

## Evolution of Adjuvant Treatment 

**Stage II/III Rectal Cancer (T3/T4, N+)**
***Surgical Treatment***
***+ Radiation Therapy or Chemotherapy***
***+ Post-operative Chemoradiation Therapy***
***+ Neoadjuvant Chemoradiation Therapy    ******	******  and Post-operative Chemotherapy***

## Proposed Rectal Cancer Endpoints 

***Local Control***
***Sphincter-Sparing Surgery***
***Pathologic Complete Response***

## Local-Regional Failure 

**“****In contrast to colon cancer, there is a significant risk of local-regional failure as the only or 1****st**** site of recurrence in patients with curative resected rectal cancer.”**
***Stage I ******	******5% to 10%***
***Stage II******	******up to 25% to 30%***
***Stage III******	******up to 50% or higher***

***NIH Consensus Conference on Adjuvant Therapy for Patients with Colon and Rectal Cancer, JAMA, Sept. 19, 1990***

## Local-Regional Failure Characteristics

**Main prognostic determinant is Stage**
**Local-Regional failure associated with significant morbidity**
**Major mode of failure**** ****(+/- distant metastases)**
** **
**Most failures within 2-3 yrs and               rare after 5 yrs**** ****(+/- distant metastases) **
**Successful salvage is rare**

## Post-Op ChemoRT vs Surgery 

***K. Hu and L. Harrison – Semin Surg Oncol 19:336-349, 2000***

| Trial | Treatment Arms | LF | DM | OS |
| --- | --- | --- | --- | --- |
| GITSG
7175
1975-80
202 pts | Surgery Alone
RT (40-48 Gy)
Chemo (MeCCNU/5FU)
Chemo + RT
 | 24%
20%
27%
11% | 34%
30%
27%
26% | 45%
52%
52%
67%
(5-yr DFS significant) |
| NSABP
R01
1977-86
555 pts | Surgery Alone
Chemo (MOF)
RT (46-47 Gy)
 | 25%
22%
26%
 | 26%
24%
31% | 43%
53%
41%
(Males:  
5-yr OS significant) |

## Post-Op ChemoRT vs Single Modality 

***K. Hu and L. Harrison – Semin Surg Oncol 19:336-349, 2000***

| Trial | Treatment Arms | LF | DM | OS |
| --- | --- | --- | --- | --- |
| NSABP
R02
1987-92
694 pts
 | Chemo (MOF or 5FU/LV)
Chemo + RT (50.4 Gy)
 | 13%
8%
(p=.02) |  | NS
(DFS &OS) |
| Mayo
NCCTG
1980-1986
204 pts | RT (45-50 Gy)
RT + Chemo (MeCCNU/Bolus 5FU) | 25%
14%

 | 46%
29%
  | 46%
53%
(5-yr Act p=.025) |

## Short-Term Pre-Op Radiotherapy vs Surgery Alone 

|  | Local Recurrence | 
OS | p-value |
| --- | --- | --- | --- |
| Swedish Rectal Cancer Trial 1987-1990 - NEJM 1997
1,168 pts  - Dukes A, B, and C
Short Course RT + Surgery 
vs Surgery Alone | 

11% 
27%
(5-yr FU) | 

58% 
48%
(5-yr) | LR
p<.001

OS
p<.001 |
| Dutch CRC Group Trial 
1996-2000 - NEJM 2001
1,861 pts - Dukes A, B, and C
Short Course RT + TME Surgery vs TME Surgery Alone | 

2.4%
8.2%
(2-yr) | 

82% 
82%
(2-yr) | LR
p<.001

OS
NS |

## Pre-Op vs Post-Op Chemoradiation

**NSABP R-03  – Low Accrual**
**Treatment-related toxicity similar**
**Sphincter-saving surgery **
**Pre-op Group (plan 31% to 50%) **
**Post-op Group (plan 33% vs 33% actual)**
** ****INT-0147 – Low Accrual**
** ****German Trial – CAO/ARO/AIO-94  **
**Results presented ASTRO – Oct. 2003**

## German Trial – CAO/ARO/AIO-94

** **

***800+ pts – T3/T4, N+ rectal cancer(CI 5-FU + 50.4 Gy)***

|  | Pre-Op | Post-Op | p-value |
| --- | --- | --- | --- |
| 5-yr Local Recurrence | 6% | 12% | p=.02 |
| 5-yr Distant Relapse | 35% | 39% | p=.52 |
| 5-yr DFS  | 59% | 55% | p=.23 |
| 5 –yr Overall Survival | 78% | 73% | p=.38 |
| Acute Grade 3/4 Tox | 30% | 30% | NS |
| Anastomotic Stenosis | 2.7% | 8.5% | p=.001 |
| Sphincter preserved
(188 – low lying tumors) | 39%
(pCR 8%) | 19% | p=.004 |

***U Penn Oncolink Report on Plenary Session Presentation – ASTRO 45******th******  Annual Meeting – Oct. 2003 -  R. Sauer et al – German Rectal Cancer Group***

## Pathologic Complete Response 

**Mix of Retrospective Series, Prospective Series, and Phase 2 Studies**
**Small Studies**
**Dependent on pathologic review/QA**
**Different ChemoRT regimens**
**Different Stages (usually T3, N+)**
**Range pCR 9% - 24****%**
**pCR associated with trends in decreased LR, increased sphincter-preserving surgery**

## Pathologic Assessment:  # Lymph Nodes & Outcome

| Nodal Status | # Nodes Analyzed | # Pts | 5-Yr Relapse-Free Survival | 5-Yr Survival
Rate |
| --- | --- | --- | --- | --- |
| Node Negative Pts | 0 and < 5
5 and < 9
9 and < 14
 14 | 127
138
129
133 | 37%
34%
26%
19% | 68%
73%
72%
82% |
| Node Positive Pts
 | 0 and < 6
6 and < 10
10 and < 15
 15 | 270
306
264
297 | 41%
49%
47%
46% | 61%
58%
57%
61% |

***J. Tepper et al, J Clin Oncol 19:157-163, 2001***

***Pathology Reports  with Information on ***
***Circumferential Margin Status <10% in this study***

***US GI Intergroup Adj. Trial INT-0114  ***
***(1,664 pts, pT3,T4 or Node+ Rectal Cancer)***

## Future US Phase III Trials:Rectal Cancer

**	****NSABP R-04  ****	****	****Pre-Op ChemoRT**
**	****Activation 2004****	****	****5-FU****	****	****	****	****	****	****	****	****	****Capecitabine**
**	****	****	****	****	**
**	****E3201   ****	****	****	****Post-Op ChemoRT**
**	****Activated 10/2003****	****	****5-FU/LV**
**	****	****	****	****	****	****CPT-11/5-FU/LV**
**	****	****	****	****	****	****Oxaliplatin/5-FU/LV**

## DISCUSSION

## Rectal Cancer EndpointsNeoadjuvant Therapy-Stage II/III Rectal Cancer

| Proposed Endpoint | Advantages | Disadvantages |
| --- | --- | --- |
| Local Control |  |  |
| Sphincter Preservation |  |  |
| Pathologic Complete Response |  |  |