# Presentation: 108581

## Rectal Cancer: Advanced Technologies 

- Chris Willett, M.D.
- Department of Radiation Oncology
- Duke University Medical Center
- Durham, NC

## Gastric Intergroup 0116: RT Considerations

- 35% of initially submitted RT plans: Major deviations (2/3 undertreatment)
- 2 D Therapy: AP/PA

## Median Survival By Rx Arm And RT Compliance—All Patients

|  |  |  |  |  |
| --- | --- | --- | --- | --- |
| Treatment Arm | Per protocol | Variation Acceptable | Variation
Unacceptable | p-value for trend 
(1 sided) |
| 5FU  Arm
 | 1.50 yrs
 | 1.52 yrs
 | 1.18 yrs
  | 
   0.08 |
| n / (95% CI) | 117 /(1.28, 1.90) | 82 /(1.21,1.91) | 12 /(1.06,1.84) |  |
| 
Gem Arm
 | 
1.89 yrs | 
1.41 yrs | 
1.37 yrs |     

   0.03 |
| (n / 95% CI) | 99 /(1.54, 2.48)
 | 94 /(1.24,1.73) | 12 / (1.18, 2.37) |  |
|  |  |  |  |  |
|  |  |  |  |  |

##  Stage II/III Rectal Ca: 2006 Management 

- Preoperative EBRT +     5-FU Based ChT
- Surgery
- Adjuvant ChT

## Preoperative EBRT: Rectal Ca

- CTV: 45 Gy / 1.8 Gy Fx
- GTV: 50.4 (T3) – 54 Gy (T4) / 1.8 Gy Fx
- 3 Fields (PA and Laterals) or 4 Fields (AP/PA and Laterals)
- Minimize SB Tx: Prone / False Table Top / Bladder Distention

## T4 Rectal Cancer: 4 Fields

- M. Mohiuddin 2006

## Ph III German Trial (CAO/ARO/AIO-94)

- 	823 Pts. with cT3/T4 or N+ randomized to:
- Preop 5-FU and Leucovorin / EBRT and TME Surgery
- TME Surgery and Postop 5-FU and Leucovorin / EBRT (Stage II/III)

- NEJM 2004

## CAO/ARO/AIO-94 Trial: 5 Yr Results

|  | Pelvic
Failure
  (%) |  DM

  (%) |  DFS

  (%) |  OS

 (%) |
| --- | --- | --- | --- | --- |
| Preop Tx
(405 Pts) |    7* |   30 |   59 |   78 |
| Postop Tx
(392 Pts) |   11 |   34 |   55 |   73 |

## CAO/ARO/AIO-94 Trial: Results

|  | pCR
 (%) | Acute GI
  G 3/4
Toxicity
   (%) | Late G 3/4 GI Toxicity
     (%) | Sph
Preserv
Rate
(%) |
| --- | --- | --- | --- | --- |
| Preop Tx
(405 Pts) |    8* |    12 * |      13* |   39* |
| Postop Tx
(392 Pts) |    0 |    18 |       27 |   19 |

## CAO/ARO/AIO-94 Trial: Conclusions

- 	Preop ChT + EBRT vs Postop ChT+EBRT:
- Improved LC (93%)
- Distal Lesions: Enhanced Sphincter Preservation
- Less G3/4 Acute (12%) / Chronic GI Toxicity (18%)

## PMH Phase 2 Trials: Results

|   Dose   (Gy) | pCR (%) | 2 Yr LC (%) 

  |  2 Yr DFS (%) | Acute G3/4 Toxicity (%) |
| --- | --- | --- | --- | --- |
| 40(n=46) |     15 |   72 |   62 |   13 |
| 46(n=52) |     23 |   90 |   84 |     4 |
| 50(n=36) |     33 |   89 |   80 |   14 |

## Fox Chase Phase I Rectal Ca

| Dose (Gy): 45 Gy + 1.2 BID |    Downstaging |
| --- | --- |
| 54.6 (n=10) |         50% |
| 57 (n=7) |         57% |
| 61.8 (n=6) |         67% |

- 23 Pts: 4 pCR (17%)

## 	Rectal Ca: New Agents with EBRT

- Oral 5-FU: Capecitabine (TS inhibition)
- Irinotecan (topo I inhibitor)
- Oxaliplatin (inter & intra-strand DNA cross-links)
- Anti EGFR: Cetuximab, Gefitinib, Erlotinib
- Anti-VEGF: Bevacizumab

## RTOG 0012: CPT-11, 5-FU & RT Preop

**	****Phase II, Pts with cT3-T4 Disease **_**Randomized to**_**:**
**	****  ****CPT-11 + 5-FU & RT 50.4-54 Gy/1.8 Gy qd**
**	**
**	****  ****5-FU & RT 55.2-60 Gy/1.2 Gy bid**
- 			     ***Opened: February 2002***
***	******	******	******     ******Accrual: 100***
***	******	******	******     ******Closed: January 2003***

- R

- JCO 2006

##  RTOG 0012: Results

|  |   pCR
  (%) |   Acute 
 G 3⁄4 GI
 Toxicity
     (%) |   Late G 3/4
  GI Toxicity
      (%) |
| --- | --- | --- | --- |
|  EBRT / 5-FU   + CPT-11       (54 Pts) |    28 |      19 |        2.0 |
| EBRT / 5-FU
(52 Pts) |    28 |      13 |        2.0 |

## CALGB 89901 Phase I/II: Oxali, 5-FU & RT Preop

**	**

|  | M | T | W | Th | F | Sa | Su |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Oxal | X |  |  |  |  |  |  |
| 5FU | X | X | X | X | X | X | X |
| XRT | X | X | X | X | X |  |  |

**5FU 200mg/m****2****/d;  RT 50.4Gy; Oxali 30–60mg/m****2****/d**

**MTD = 60 mg/m2****, Gr 3 diarrhea**
**21/32 (66%) completed 6 cycles**
**26/32 (81%) completed 4 cycles**

- JCO 2006

## CALGB 89901: Results

|  |   pCR
  (%) |   Acute 
   G3/4
 Diarrhea
     (%) |   Late G 3/4
  GI Toxicity
      (%) |
| --- | --- | --- | --- |
|  EBRT / 5-FU   + Oxaliplatin         (Phase II– 32 Pts) |    25 |      37 |  No Comment |

## RTOG 0247: Cape, RT + Oxali or CPT-11 Preop

**	****Phase II, Pts with cT3-T4 Disease **_**Randomized to**_**:**
**	****Oxali**** (****50**** d 1, 8, 15, 22 & 29), ****Cape**** (****825 BID, 5 d**** per w) & RT 50.4 Gy/1.8 Gy qd**
**	**
**	****CPT-11**** (****50**** d1, 8, 22 & 29), ****Cape**** (****600 BID, 5 d**** per w) & RT 50.4 Gy/1.8 Gy qd**
- 			         ***Opened: February 2004***
***	******	******	******      ******Amended: March 2005***
***	******	******	******      ******Planned Accrual: 141***

**R**

## E5201 Preop INT Trial

**Preop**
** ****CMT***

**FOLFOX**

**S**
**U**
**R**
**G**

**Bevacizumab**

**±**

*** = bolus 5FU ± LV, CI, or capecitabine**

## NSABP R-04 Preop

**Capecitabine **
**(825 mg BID)**
**     ****50.4 Gy**
**     ****CI 5-FU **
**(225 mg/m2/d)**
**     ****50.4 Gy**

_**+**_** Oxaliplatin**
**   ****(60 mg/m2 qw)**

_**+**_** Oxaliplatin**
**   ****(60 mg/m2 qw)**

**  *****Stratify***
***• ******T2 vs. T3***
***• ******M vs. F***
***• ******SP vs. APR***

***n=1460***

## Rectal Ca: Preoperative Tx

- 	New Cytotoxic Agents + 5-FU during EBRT :
- 	Higher Rates of Acute GI Toxicity
- ? Rates of Late GI and other Toxicity

## Dose-Volume Relationship of Acute SB Toxicity

- 40 Rectal Ca Pts: EBRT (50.4 Gy) + 5-FU
- 3 D Tx Planning with SB excluding techniques – bladder distention, prone position, false table top.
- Correlate Acute SB Toxicity (Diarrhea/Pain) to Volume of SB Irradiated

- Baglan et al: Int J Rad Onc Biol Phy 2002

## Dose-Volume Relationship of Acute SB Toxicity

- 	40 Patients – Overall Toxicity Rates
- Grade 0: 7/40  (17.5%)
- Grade 1: 15/40 (37.5%)
- Grade 2: 8/40   (20%)
- Grade 3: 10/40 (25%)
- No Grade 4/5

## Dose-Volume Relationship of Acute SB Toxicity

| Dose (Gy) | Threshold V | G3 SB Toxicity |
| --- | --- | --- |
|       5 |      500 | 45% (10/22) |
|     10 |      300 | 53% (10/19) |
|     15 |      150 | 50% (10/20) |
|     20 |      145 | 53% (10/19) |
|     25 |      140 | 59% (10/17) |
|     30 |      140 | 59% (10/17) |
|     35 |      135 | 59% (10/17) |
|     40 |      125 | 59% (10/17) |

## Volume Effect: Acute SB Toxicity

| V15 (cm3) |    # Pts | G0-2 SB Toxicity | G3 SB Toxicity |
| --- | --- | --- | --- |
| <150 |      20 |    100% |    0% |
| 150-299 |      20 |    70% |    30% |
| ≥ 300 |      20 |    30% |    70% |

## Dose-Volume Relationship of Acute SB Toxicity

- 41 Rectal Ca Pts: EBRT (45 Gy) + 5-FU/Leucovorin
- All 3 D Tx Planning
- Correlate Acute SB Toxicity (Diarrhea) to Volume of SB Irradiated

- Tho et al: Int J Rad Onc Biol Phy 2006

## Dose-Volume Relationship of Acute SB Toxicity

|  | Diarrhea<G2
Median SB V | Diarrhea ≥G2
Median SB V |
| --- | --- | --- |
| V5 |      24 | 276 |
| V10 |      16 | 274 |
| V15 |      4 | 194 |
| V20 |      0 | 94 |
| V30 |      0 | 70 |
| V35 |      0 | 64 |
| V40  |      0 | 54 |
| >V42.75 |      0 | 23 |

## Rectal Ca: 3-D

## Rectal Ca: IMRT

## Slide 30

## IMRT in Rectal Ca: Reduction in Bowel Dose

- Royal Marsden: 5 Patients with Locally Advanced Rectal Ca
- Dosimetric Comparison of 3-D Conformal Radiation Therapy to IMRT
- No Clinical Data

- Int J Rad Onc Biol Phy 2006

## IMRT: Reduction in V of Bowel Irradiated to High Dose

|  | Mean
Dose (Gy) | V50
(%) | V45(%) | V40 (%) |
| --- | --- | --- | --- | --- |
| 3 D
CRT | 27.1 | 6.4 | 26.4 | 31.4 |
| IMRT 
9 Field | 28.3 | 2.6 | 9.0 | 21.6 |
| IMRT
5 Field | 28.2 | 2.2 | 8.2 | 21.0 |

## IMAT in Rectal Ca: Reduction in Bowel Dose

- Ghent Hospital: 7 Patients with Locally Advanced Rectal Ca (4 Pre and 3 Post)
- Dosimetric Comparison of 3 D Conformal Radiation Therapy to IMAT
- No Clinical Data

## IMAT: Reduction in V of Bowel Irradiated to High Dose

|  | Mean
Dose (Gy) | V90
(%) | > V15 
(%) |
| --- | --- | --- | --- |
| 3 D
CRT | 17.0 | 19.1 | 45.6 |
| IMAT 
 | 12.4 | 6.6 | 33.0 |

## IMRT in Rectal Ca: Reduction in Bowel Dose

- 8 Patients (Glasgow) with Locally Advanced Rectal Ca
- Dosimetric Comparison of 3-D Conformal Radiation Therapy to IMRT
- No Clinical Data

- Int J Rad Onc Biol Phy 2006

## IMRT in Rectal Ca: Reduction in Bowel Dose

- With the use of IMRT vs. 3 D CRT: Statistically significant reduction in Median dose (5.08 Gy) and Mean dose (3.15 Gy) to Small Bowel

- Int J Rad Onc Biol Phy 2006

## Conclusions

- GI Toxicity (Acute and Late): Important Consideration
- Toxicity will increase with new agents with template of EBRT (50 Gy) + 5-FU
- Dosimetric plans show reduction in Bowel irradiation with IMRT vs. 3 D CRT
- No Clinical Data
- Clear Need for Phase II Trials with IMRT