Rectal Cancer: Is a Boost with IORT Necessary

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Rectal Cancer Is a Boost with IORT Necessary?

• Michael G. Haddock, MD
• Mayo Clinic
• ISIORT, Madrid 2008

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The question is not should we boost with IORT
but when should we boost with IORT
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Rectal CancerIORT

• Locally Advanced Rectal Cancer
• Recurrent Rectal Cancer in Pelvis
• Previously Irradiated
• Not previously Irradiated
• Recurrent rectal cancer in lymph nodes

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THE THEORY
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Tumor control probabilityRadiobiologic Axioms

• Surviving fraction of tumor cells is a function
  of radiation dose
• Functional radiation effects in normal tissues is
  related to dose
• The dose needed to obtain tumor control depends
  on the number of clonogens and may not be
  achievable in all cases with acceptable normal
  tissue effects

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Tumor Control Probability Adenocarcinoma of the
Breast
Dose Tumor control probability 5,000 cGy gt 90
subclinical 6,000 cGy 90 clinically positive
axillary nodes 2.5 - 3 cm 7,000 cGy 65 2-3 cm
primary 7,000 - 8,000 cGy 30 gt 5 cm
primary 8,000 - 9,000 cGy 56 gt 5 cm
primary 8,000 - 10,000 cGy 75 5 - 15 cm primary
200 cGy fractions Fletcher, J Radiol Electrol
56383, 1975
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Radiation Tolerance Doses
1-5 25-50 Volume or Organ Injury at
5 yrs TD 5 / 5 TD 5 / 5 length Esophagus Ulce
r, stricture 60-65 Gy 75 Gy 75 cm3
Stomach Ulcer,perforation 45-50 Gy 55 Gy 100
cm3 Intestine Ulcer, stricture 45-50 Gy 55
Gy 100 cm3 Colon Ulcer, stricture 55-60 Gy 75
Gy 100 cm3 Rectum Ulcer, stricture 55-60 Gy 75
Gy 100 cm3 Anus Ulcer, stricture 60-65 Gy 75
Gy Whole Liver Liver failure 35 Gy 75
Gy Whole Bile Ducts Stricture 50 Gy 70 Gy --
Gunderson and Martenson, Front Radiat Ther Oncol
23277, 1988
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Tumor Control ProbabilityTumor Volume Definitions

• Gross disease gt 108 tumor cells
• 1 cm3 109 tumor cells
• 10-100 gm tumor 1010 - 1011 cells
• Microscopic disease lt 108 tumor cells
• Clinical CR reduction to lt 108 cells
• Pathologic CR reduction to lt 106 cells
• Chemotherapy maximum reduction of about 3
  logs for solid tumors

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IORTGeneral Rationale

• able to treat small volume of tissue within IORT
  boost field
• can limit dose to sensitive normal organs such as
  small bowel
• can increase effective radiation dose

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Patient Selection Criteria IOERT

• Surgery alone unacceptable local control
• External beam dose gt 60 - 70 Gy for curative
  attempt
• IOERT at time of planned operative procedure
• IOERT EBRT would theoretically result in a more
  favorable therapeutic ratio between cure and
  complications
• IOERT boost is technically more feasible than
  brachytherapy
• No evidence of distant disease

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THE DATA NON-IORT APPROACHES FOR GROSS DISEASE
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EBRT for Gross Colorectal Cancer Mayo
Randomized Trial

• 44 patients with unresectable, residual or
  recurrent colorectal cancer
• 50 Gy in 25 fractions over 7 weeks
• Randomized to RT /- BCG
• Recurrence in RT field 28/31 (90)
• Bowel obstruction in 7 (16)
• No 5 year survivors

OConnell, IJROBP 81115-9, 1982
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EBRT for Gross Colorectal CancerPrimary Locally
Advanced

• 17 patients 1977-1984
• EBRT after subtotal resection
• 40-60 Gy (median 50 Gy)
• 7 patients with gross disease
• local failure 6/7 (86)
• one 5 year survivor

Schild, IJROBP 16(2) 459, 1989
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EBRT for Gross Colorectal CancerRecurrent
Locally Advanced

• 106 patients, 1981-1988, subtotally resected
  recurrent rectal cancer
• 37 pts EBRT (med. 50.4 Gy) without IORT
• 3 year local recurrence 93
• 5 year survival 5.6

Suzuki, Cancer 75939-52, 1995
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THE DATA NON-IORT APPROACHES FOR MICROSCOPIC
DISEASE
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EBRT for Microscopic Rectal CancerMayo Results

• 17 patients 1977-1984
• EBRT after subtotal resection
• 40-60 Gy (median 50 Gy, 1 pt gt 52 Gy)
• 10 patients with microscopic disease
• local failure 7/10 (70)
• local controls 45, 50 and 50 Gy
• three 5 year survivors (30)

Schild, IJROBP 16(2) 459, 1989
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Locally Advanced Rectal CancerEBRT Chemotherapy
Study EBRT Dose Results PMH 40-50 Gy, 2.5
Gy / fx LF 91, 5 yr OS 2 Mayo 50 Gy in 7
weeks LF 28 / 31 (90) RTOG 76-16 45 - 70 Gy 40
2 yr OS 45 - 60 Gy 5-FU/MeCCNU 64 local
failure
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Unresectable Rectal CancerPreoperative EBRT
Surgery
Series Resectability Local Relapse
Rate after Resection U Oregon 20 / 40
(50) 45 23 / 60 (38) 52 MGH 18 / 25
(72) 43 Tufts 33 / 44 (75) 36
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Subtotally Resected Rectal CaResults of
Postoperative EBRT
LF vs. residual Series Microscopic Gross A.
Einstein 2 / 13 (15) 9 / 18 (50) MGH 9 / 30
(30) 13 / 23 (57)
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EBRT for Microscopic Rectal CancerMGH Results
Dose in Gy vs. Local Failure (EBRT) Residual lt
50 50-60 gt 60 Totals Volume No. () No.
() No. () Gross 2/3 5 /11 (45) 6/9 (67) 12/23
(57) Micro 0/1 8/20 (40) 1/9 (11) 9/30
(30) Early death due to PS
Allee, I.J.R.O.B.P. 1171171, 1989
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Primary Locally Advanced Colorectal Cancer

• IORT Data

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Unresectable Primary Colorectal Cancer can be
Cured with Multimodality Therapy

• Kellie L, Mathis, M.D.
• John H. Pemberton, M.D.
• Heidi Nelson, M.D.
• Michael G. Haddock, M.D.
• Leonard L. Gunderson, M.D.

Submitted to Annals of Surgery, 2008
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Background

• Fixation to critical structures may deem tumor
  unresectable

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Background

• Unresectable CRC treated with EBRT alone 5yr
  survival lt10

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Demographics and Tumor Characteristics

• 1981 to 2006
• 146 patients, 65 male
• Median Age - 58 years (range 19 - 89)
• Primary Tumor
• Rectum 106 (73)
• Colon 40 (27)

Mathis, Submitted to Annals of Surgery, 2008
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Neo/Adjuvant Therapy

• External Beam Radiation Therapy
• Pre-Op 124 (85)
• Post-Op 20 (14)
• None 2 ( 1)
• Median Dose (Gy) 50.4 (range 16-93)
• 5FU-based chemo with EBRT
• Yes 131 (90)
• No 15 (10)

Mathis, Submitted to Annals of Surgery, 2008
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Surgical Procedure

• Rectum
• APR (66), LAR (26), other (8)
• Colon
• R hemi (40), sigmoid/LAR (40), other (20)
• Structures resected en bloc
• ovary (20), uterus (15), bladder (13), vagina
  (10), prostate (10), ureter (8), small bowel (4),
  other (15)
• Structures resected for mets
• Liver (11), Adrenal (2), Ovary (1), Pancreas (1)

Mathis, Submitted to Annals of Surgery, 2008
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Surgical Procedure

• Final Margins
• Negative (R0) 100 (68)
• Micro positive (R1) 28 (19)
• Gross positive (R2) 18 (12)
• IORT in all
• Dose range 7.5 to 25 Gy

Mathis, Submitted to Annals of Surgery, 2008
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30-day Complications

• Mortality 0
• Morbidity
• Leak/Abscess/Fistula 5
• SBO 4
• Wound 4
• Dehiscence 1
• Ureteral Injury 1
• 15 complications in 12 patients (8)

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gt30-day Complications

• Peripheral Neuropathy 28
• SBO 20
• Ureteral obstruction 18
• Wound infection/breakdown 13
• Fistula 11
• Bladder dysfunction 10
• Sexual dysfunction 9
• Enteritis/proctitis 5
• Abscess 5
• 119 complications in 77 patients (53)

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Relapse PatternsPrimary Advanced Colorectal Ca

• Median follow-up 3.7 years
• Central Relapse 3 ( 2)
• Local Relapse 19 (13)
• Regional Relapse 6 ( 4)
• Distant Relapse 68 (47)
• 5-yr survival for all pts 52
• 5-yr survival for M1 pts 43

Mathis, Submitted to Annals of Surgery, 2008
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Cause-Specific Overall
Survival Survival

• 59 at 5 years

• 52 at 5 years

Mathis, Submitted to Annals of Surgery, 2008
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Primary Colorectal IOERT - MayoDisease Control
Patients Local Relapse Distant Relapse at
risk Actuarial Actuarial Treatment (no.) 3
yr 5 yr 3 yr 5 yr External (EBRT) 17 76 76
59 59 EBRT IOERT 146 10 14 43 49
LF range 3-15 mo DF range 3-17 mo Schild,
IJROBP 16459, 1989. Mathis, submitted to
Annals of Surgery, 2008
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Summary

• No operative mortality and low perioperative
  morbidity
• Excellent local disease control
• Long term survival is possible (52 5-yr)
• Resectable M1 patients curable (43 5-yr)
• Significant long-term complications

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Conclusions

• Aggressive multimodality therapy can result in
  long-term survival of patients with unresectable
  primary colon and rectal cancers
• Future efforts should focus on decreasing
  long-term disabilities and reducing rates of
  distant metastases

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Locally Recurrent Colorectal Cancer

• IORT Data

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Locally Recurrent Rectal Cancer Palliative
Resection IOERT

• 106 patients 1981-1988 palliative resection
  with no extrapelvic disease
• 42 had IOERT as component of treatment
• IOERT dose 15 - 20 Gy in 39/42
• EBRT in 41 patients
• Gross residual in 34/42 (81)
• Microscopic residual in 8/42 (19)

Suzuki, Cancer 75939, 1995.
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Recurrent Rectal Palliative Resection
Multivariate Analysis of Survival Prognostic
Factors
Multivariate analysis Factor considered P
value IORT (yes vs. no) lt 0.05 Symptoms lt
0.05 Fixation lt 0.05 Male vs. Female lt
0.05 Mayo Surgery vs. elsewhere lt 0.05
Suzuki, Cancer 75939, 1995.
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Recurrent Rectal Palliative Resection Disease
Relapse vs. Prognostic Factors and IOERT
IOERT EBRT No IOERT Disease
Status Disease Status No. pts 3 yr LR 3 yr
DM 3 yr LR 3 yr DM Gross residual 34 40 62 9
3 55 Pain 30 45 63 92 49 Fixation F0-F1
25 26 55 87 51 F2 14 60 65 91 37 Tota
l 42 40 60 93 54
Suzuki, Cancer 75939, 1995.
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Recurrent Rectal Palliative Resection Survival
vs. Prognostic Factors and IOERT
IOERT EBRT No IOERT No.
pts Survival No.pts Survival 3 yr 3
yr Gross residual 34 44 61 15 Pain 30 43
50 19 Fixation F0-F1 25 52 20 37 F2 14 3
6 18 24 F3 3 - 21 0 Total 42 43 6
2 18
Suzuki, Cancer 75939, 1995.
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Patient Population Recurrent Colorectal IOERT

• Study period Apr 1981 - Jan 2008
• 607 patients
• Male 369 (61)
• Female 238 (39)
• Median age 62 yrs, range 21-87
• Primary site
• Colon 180 (30)
• Rectum 427 (70)

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Surgery Recurrent Colorectal IOERT

• Maximum resection prior to IOERT
• Disease status at time of IOERT
• Gross residual 156 (26)
• Microscopic residual 224 (37)
• Negative margin 226 (37)

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Docking Recurrent Colorectal IOERT
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IOERT Dose Recurrent Colorectal IOERT
Median IORT Range Group Dose (cGy) R0 1250
cGy 750 - 2500 R1 1500 cGy 1000 - 2500 R2 2000
cGy 1000 - 3000 Prior RT 1750 cGy 1000 - 3000 No
prior RT 1250 cGy 750 - 2500 All 1500 cGy 750
- 3000
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Analysis Endpoints Recurrent Colorectal IOERT

• Follow-up pts followed until death or for a
  median of 44 mos for 194 survivors
• endpoints evaluated
• local relapse in EBRT field
• central relapse in IOERT field
• distant relapse
• survival

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Overall Survival Recurrent Colorectal IOERT
Survival median 36 months 1 year 90 2 year 70 5
year 30 10 year 16
100
80
Survival ()
60
40
20
0
3
5
7
10
0
Years
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Survival- Univariate AnalysisRecurrent
Colorectal IOERT
Group 5 yr S P value Group 5 yr S P
value Colon 34 0.07 R0 46 lt0.001 Rectum 28 R1
27 R2 16 No prior RT 34 0.07 systemic
CT 40 0.03 Prior RT 26 No systemic CT 28 No
prior CT 34 0.08 After 3/3/97 36 lt0.001 Prior
CT 27 Before 3/3/97 25 Age lt 61.5
yrs 31 0.09 CT with EBRT 32 0.02 Age gt 61.5
yrs 29 No CT with EBRT 22
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Survival- Multivariate AnalysisRecurrent
Colorectal IOERT

• Group Multivariate P value
• R0 vs R1 vs R2 lt 0.0001
• No prior Chemo 0.0004
• Treatment after 3/3/97 0.012
• Colon vs. rectum 0.065
• Systemic chemo 0.075
• Age lt 61.5 0.122
• CT with EBRT 0.400
• Prior EBRT 0.897

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Survival Recurrent ColorectalR0 vs. R1 vs R2
Survival R0 R1 R2 median 51 mo 35 mo 27 mo 1
year 94 90 82 2 year 80 69 56 5
year 46 27 16 10 year 25 18 4
100
80
Survival ()
60
40
R0 (n 227)
p lt 0.0001
20
R1 (n 224)
R2 (n 156)
0
3
5
7
10
0
Years
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Survival - Recurrent Colorectal CaTreatment Era
After 3/3/97 (n 304)
Survival Before 3/3/97 After 3/3/97 median 32
mo 43 mo 1 year 84 95 2 year 63 71 5
year 25 78 10 year 12 -
100
80
Survival ()
60
40
p lt0.001
20
Before 3/3/97 (n 303)
0
3
5
7
10
0
Years
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Survival - Recurrent Colorectal Ca Systemic
chemotherapy
Survival chemo no chemo median 50 mos 34 mos 1
year 100 88 2 year 82 67 5 year 40 28 10
year 10 16
Years
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Survival - Recurrent Colorectal Ca Prior
chemotherapy
No prior chemo (n 242)
Survival prior chemo no chemo median 35 mos 42
mos 1 year 89 91 2 year 67 73 5
year 27 34 10 year 14 18
100
80
Survival ()
60
40
20
Prior Chemo (n 365)
p 0.08
0
3
5
7
10
0
Years
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Disease Control - Recurrent Colorectal Ca
Endpoint CC LC DC crude 87 74 51 1
year 96 92 78 2 year 90 80 56 5
year 82 62 38 10 year 78 57 36
100
central control
80
local control
Disease Control ()
60
40
distant control
20
0
3
5
7
10
0
Years
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Local Control Recurrent Colorectal Ca Prior
EBRT
Endpoint Prior RT No Prior RT 1 year 90 94 2
year 73 85 5 year 49 70 10 year 49 63
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Local ControlRecurrent Colorectal Ca R0 vs R1
vs R2
Endpoint R0 R1 R2 1 year 97 88 92 2
year 85 78 76 5 year 74 56 49 10
year 71 56 33
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Local Control Recurrent Colorectal Ca -
Treatment Era
Local Control Before 3/3/97 After 3/3/97 1
year 90 94 2 year 76 84 5 year 57 66 10
year 52 -
100
80
After 3/3/97 (n 304)
Survival ()
60
Before 3/3/97 (n 303)
40
p 0.01
20
0
3
5
7
10
0
Years
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Distant ControlRecurrent Colorectal Ca R0 vs
R1 vs R2
Endpoint R0 R1 R2 1 year 86 72 76 2
year 69 49 47 5 year 47 38 27 10
year 47 38 17
100
80
Local Control ()
60
R0 (n 227)
40
R1 (n 224)
20
p lt 0.0001
R2 (n 156)
0
3
5
7
10
0
Years
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Distant Control Recurrent Colorectal Ca -
Treatment Era
Endpoint Before 3/3/97 After 3/3/97 1
year 73 84 2 year 50 63 5 year 34 43 10
year 31 -
100
80
Survival ()
60
After 3/3/97 (n 304)
40
p 0.0007
Before 3/3/97 (n 303)
20
0
3
5
7
10
0
Years
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IOERT Related Severe Toxicity Recurrent
Colorectal Cancer

• 66 (11) pts experienced 98 ? grade 3 IOERT
  related toxicities
• GI fistula/obstruction 7 (1)
• soft tissue (abscess/fistula/fibrosis) 42 (7)
• neuropathy 18 (3)
• ureteral obstruction 18 (3)
• other 11 (2)

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IOERT Related Neuropathy Recurrent Colorectal
Cancer

• IOERT related neuropathy in 94 pts (15)
• grade 1 32 pts (5)
• grade 2 43 pts (7)
• grade 3 18 pts (3)

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IOERT Related Neuropathy Recurrent Colorectal
Cancer
IOERT Dose

• 1250 cGy gt 1250 cGy
• any neuropathy 9 21
• Grade 1 3 7
• Grade 2 4 10
• Grade 3 1 4

P 0.0003
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Recurrent Colorectal CancerResults of Salvage
EBRT
Survival Relapse (crude)
No. Pts Median 5 yr Local Distant Netherlands 76
14 mo 5 68 41 Australia 39 18 mo 9 82 49
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Recurrent Colorectal CancerMayo IOERT results
Survival Relapse (3 yr)
No. Pts Median 5 yr Local Distant Suzuki
No IOERT 64 17 mo 7 93 54 IOERT 42 30
mo 19 40 60 Gunderson No prior EBRT 123 28
mo 20 25 64 Prior EBRT 51 23 mo 12
55 71 Current series No prior EBRT 359 37
mo 32 20 57 Prior EBRT 248 35
mo 26 49 49
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Conclusions Recurrent Colorectal Cancer

• Significant long term survival (30)
• R0 resection associated with better disease
  control and survival
• Multimodality curative intent approach is
  indicated in selected patients
• Long term survival with non-IORT regimens is poor
  or not reported

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Conclusions Recurrent Colorectal Cancer

• Distant relapse remains main pattern of failure
  (62 at 5 years)
• Nerve is dose limiting for IOERT
• Higher frequency and severity with IOERT dose gt
  1250 cGy
• Multimodality curative intent approach is
  indicated in selected patients

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Nodal RelapseColorectal Cancer

• IORT Data

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IOERT for Colorectal Nodal MetsPatient Population

• 48 patients with nodal disease
• 8 primary unresectable
• 2 rectal ACA with PA nodes
• 38 recurrent in nodes

Haddock, Int J Radiat Oncol Biol Phys 56966-73,
2003
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IOERT for Colorectal Nodal MetsSurvival and
Disease Free Survival
Survival Disease free survival
Survival
median 35 mos. 34 5 yr
Years
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IOERT for Colorectal Nodal MetsSurvival by
amount of residual
1.0
0.9
0.8
0.7
0.6
Survival
43
0.5
0.4
P 0.010
0.3
10
0.2
0.1
0.0
0
1
2
3
4
5
Years
72
IOERT for Colorectal Nodal MetsFreedom from
Disease Relapse
93
Central Control
1.0
0.9
0.8
Local Control
84
0.7
0.6
Distant Control
Freedom from Failure
0.5
54
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
Years
73
IOERT for Colorectal Nodal MetsLocal control by
residual
91
1.0
0.9
Microscopic residual 38 pts
0.8
P 0.013
0.7
47
0.6
Freedom from local failure
0.5
Gross residual 10 pts
0.4
0.3
0.2
0.1
0.0
0
1
2
3
4
5
Years
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IOERT for Colorectal Nodal MetsIOERT related
toxicity

• IOERT related toxicity
• none 41 pts (85)
• grade 1 2 pts (4)
• grade 2 3 pts (6)
• grade 3 2 pts (4)

Haddock, Int J Radiat Oncol Biol Phys 56966-73,
2003
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IOERT for Colorectal Nodal Mets Conclusions

• Colorectal cancer pts with advanced nodal mets
  are curable with combined modality therapy
  including IOERT
• Survival and disease control rates are highest in
  patients without gross residual
• 43 5 yr survival with microscopic residual
• 91 local control with microscopic residual

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ConclusionsWhen is IORT boost indicated?

• Primary locally advanced disease with high
  likelihood of R1 or R2 resection
• Locally recurrent disease
• Isolated local relapse
• Local relapse with controllable metastatic
  disease
• Nodal relapse

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The End