Phase II Timing of Rectal Cancer Response to ... II Timing of Rectal Cancer Response to Chemoradiation: Analysis of Radiotherapy (RT) Acknowledgement •Supported, in part, by NIH,

CR Thomas Jr., Y Chen, J Garcia-Aguilar,, K Avila, RM Krieg, EK Bergsland, AH Ko, P Chu, DD Smith,

DA Rothenberger, JM Hwang

OHSU Knight Cancer Institute (Portland, OR), Memorial Sloan-Kettering Cancer Center (New York, NY), UCSF Helen Diller

Family Comprehensive Cancer Center (San Francisco, CA), City of Hope (Duarte, CA), University of Minnesota (Minneapolis, MN)

Phase II Timing of Rectal Cancer

Response to Chemoradiation:

Analysis of Radiotherapy (RT)

Acknowledgement

• Supported, in part, by NIH, NCI R01 CA 090559 to J Garcia-Aguilar

Disclosure

• The authors have no conflicts of interest to disclose.

6 – 8 Weeks

Rectal Cancer Treatment Algorithm

uT1 (+/- uT2) well/mod diff., no LVI < 40% circumference < 6 ( ?8) cm from verge Mobile / non-fixed

uT2, N0

Non- fixed High risk uT1

uT3 or T4, N0 or uTany, N1

Metastatic disease

Consider local excision +/- postop radiation

Above anorectal ring, continent patient

Below anorectal ring, incontinent patient

Prep CMT (5FU/XRT)

Operate if potentially resectable liver metastases, otherwise for palliation only

LAR

APR



LAR

APR Consider tissue flap closure

Clinical Staging

History + Physical Endorectal ultrasound Rigid prostoscopy Colonoscopy Biopsy CT Chest/Abd/Pelvis

Surgical Therapy: Use of Neoadjuvant Therapy

Goal of therapy: pathologic complete response

Am J Surg 109:76-83, 1965

Surg Clin N Am 42:1219-34, 1962

6 – 8 Weeks

Rectal Cancer Treatment Algorithm

uT1 (+/- uT2) well/mod diff., no LVI < 40% circumference < 6 ( ?8) cm from verge Mobile / non-fixed

uT2, N0

Non- fixed High risk uT1

uT3 or T4, N0 or uTany, N1

Metastatic disease

Consider local excision +/- postop radiation



Prep CMT (5FU/XRT)

Operate if potentially resectable liver metastases, otherwise for palliation only

LAR

APR



LAR

APR Consider tissue flap closure

Clinical Staging

History + Physical Endorectal ultrasound Rigid prostoscopy Colonoscopy Biopsy CT Chest/Abd/Pelvis

Is It Time to Re-think the Rules?

TNT: Total Neoadjuvant Therapy Goal of therapy: pathologic complete response

Fernandez-Martos et al, J Clin Oncol 2010

Nilsson et al, BMC Cancer 13:279, 2013

Zhu et al, Radiation Oncology 8:130, 2013

Rationale for TNT in Rectal Cancer

●NAT allows for administration of

full dose systemic therapy, subclinical

extra-pelvic dx can be promptly treated,

downstaging of the primary can take place,

& increased likelihood for organ preser-

vation.

●Intensification or enhanced modulation of

radio-

Sensitization via the addition of more cytotoxic

Agents has proved challenging.

●Novel targeted therapeutics can be readily

assessed via an in-vivo assessment

Primary aims of overall study was to compare the impact

different CRT-to-surgery intervals on pCR, surgical

difficulty & morbidity.

XRT + 5FU

1 5 12 Recovery

Surgery

XRT + 5FU

1 5 12 Recovery

Surgery

XRT + 5FU

1 5 12 Recovery

Surgery

XRT + 5FU

1 5 12 Recovery

Surgery

10 16

10

10

16 14 20

16 14 20 24 18

FOLFOX (8) 1 5 9 13 3 7 11 15

1 5 9 3 7 11

FOLFOX (6)

1 5 3 7

FOLFOX (4)

1 3

FOLFOX (2)

FOLFOX (4)

FOLFOX (6)

FOLFOX (2)

MATERIALS & METHODS Primary aims of the present analysis is to describe the RT

parameters and possible impact on outcome

This trial was a phase 2 with sequential single-arm

Simon’s 2-stage mini-max designs of 306 Stage II-III RC pts (Groups 1-4).

Pts were treated with CRT for 5-6 wks using continuous infusion 5-FU,

accrued in 4 groups.

Pts in Group 1 (n=81) received CRT alone & had TME surgery 6 wks later.

Pts in Groups 2 (n=76), 3 (n=74), & 4 (n=75) with evidence of clinical

response

4 wks after CRT received 2, 4, & 6 cycles of mFOLFOX-6, respectively.

Pts in Groups 2-4 had surgery 11-12, 14-15, & 18-20 wks after CRT,

respectively.

Tumor response was assessed by central pathology.

We analyzed the results of 194 pts with RT data of the total 231 pt

cohort accrued to Groups 1-3.

MATERIALS & METHODS

DEFINITION OF CLINICAL RESPONSE

CLINICAL COMPLETE RESPONSE (cCR): no visible abnormality or

completely healed scar

CLINICAL PARTIAL RESPONSE (cPR): ulceration without mass; mass

with or without ulceration that has reduced in size significantly compared to

pre-chemoradiation status.

CLINICALLY STABLE DISEASE (cSD): no significant tumor change

compared to pre-chemoradiation status.

CLINICALLY PROGRESSIVE DISEASE (cPD): increase in size

compared to pre-chemoradiation status.

DEFINITION OF PATHOLOGIC RESPONSE

Pathologic response will be determined by comparing tumor width and stage in the

surgical specimen with the same parameters as determined by pre-chemoradiation

ERUS or MRI

PATHOLOGIC COMPLETE RESPONSE (pCR): no residual tumor.

PATHOLOGIC PARTIAL RESPONSE (pPR): at least a 30% decrease in tumor

width (or in tumor length, in circumferential tumors).

PATHOLOGIC PROGRESSIVE DISEASE (pPD): at least a 20% increase in tumor


PATHOLOGIC STABLE DISEASE (pPD): Neither sufficient shrinkage to qualify for

partial response nor sufficient increase to qualify for progressive disease, as

compared with tumor width in the previous evaluation.

PATHOLOGIC DOWNSTAGE (pDS): pathologic stage lower than ERUS stage.

DEFINITION OF PATHOLOGIC RESPONSE Pathologic response will be determined by comparing tumor width and stage in the


ERUS or MRI


It is possible to have a pDS and not demonstrate a pPR or pCR, since the

response rate is calculated based on a combination of bulk and depth.

For example, if the tumor is stage II at baseline (T3N0). Patients are considered

to have a pPR if the tumor has shrunk at least 30% in one dimension. However,

the bulk of the tumor may respond in the rectal wall, but there may be residual

tumor cells left at depth (e.g. cells found in muscularis propria). In this case, the

tumor would still classified as stage II compared to baseline.

RESULTS: Institutional Accrual Summary SITE GROUP 1 GROUP 2 GROUP 3 GROUP 4 TOTAL (SG 1-4)

City of Hope 0 5 10 6 21

Cleveland Clinic n/a 2 3 0 5

Colon & Rectal Surg/Creighton 7 2 2 0 11

John Muir Health 6 10 5 1 22

Oregon Health & Science Univ. n/a 0 4 7 11

St. Joseph Hospital 1 13 8 1 23

Salem Hospital n/a n/a n/a 1 1

Univ. of Calgary 3 0 3 (temporarily closed)

UC @ Irvine 4 3 2 6 15

UCSF 14 10 2 7 33

Univ. of Chicago 4 0 8 3 15

Univ. of Minnesota 3 1 4 (no longer participating)

Univ. of South Florida 15 23 10 11 59

Univ of Vermont n/a 1 9 11 21

Washington University 9 3 4 6 22

Washington Hospital Center 7 3 7 16 33

Western Pennsylvania Hospital 2 0 2 (no longer participating)

Univ. of Southern California 6 0 6 (no longer participating)

TOTAL ACCRUAL 81 76 74 76 307

RESULTS: Accrual Summary

SG1 (n=81)

SG2 (n=76)

SG3 (n=74)

SG4 (n=76)

Ineligible 11 2 3 0

Non-protocol tx 6 1 1 3

Discontinued tx 2 3 2 5

Metastatic disease

1 2 0 0

Deaths on-study 1 1 1 0

Eligible for analysis

60 67 67 68

RESULTS: Accrual Summary

SG1 (n=81) SG2 (n=76) SG3 (n=74)

Ineligible 11 2 3

Non-protocol tx 6 1 1

Discontinued tx 2 3 2

Metastatic disease 1 2 0

Deaths on-study 1 1 1

Eligible for analysis 60 67 67

231 pts

194 pts

DEFINITION OF PATHOLOGIC RESPONSE

Pathologic response will be determined by comparing tumor width and stage in the


ERUS or MRI

PATHOLOGIC COMPLETE RESPONSE (pCR): no residual tumor.

PATHOLOGIC PARTIAL RESPONSE (pPR): at least a 30% decrease in tumor


PATHOLOGIC PROGRESSIVE DISEASE (pPD): at least a 20% increase in tumor


PATHOLOGIC STABLE DISEASE (pPD): Neither sufficient shrinkage to qualify for

partial response nor sufficient increase to qualify for progressive disease, as

compared with tumor width in the previous evaluation.


RESULTS: Pathologic Response Summary

194 pts

resp Frequency Percent Cumulative

Frequency

Cumulative

Percent

pCR, pDS 49 26.20 49 26.20

pPR, pDS 92 49.20 141 75.40

pPR 46 24.60 187 100.00

RESULTS: Pathologic Response Summary

Stratified by Treatment Group

resp Group 1

(n=60)

Group 2

(n=67)

Group 3

(n=67)

TOTAL

pCR, pDS 11 17 21 49

pPR, pDS 27 31 34 92

pPR 16 19 11 46

TOTAL 54 67 66 187

-Pathologic Response Frequency Missing =7 pts

-All 7 of these pts are eligible for analysis

RESULTS: Total Dose Summary (Groups 1 – 4)

Total Dose

(cGy)

Frequency Percent Cumulative

Frequency

Cumulative

Percent

4500 14 5.86 41 5.86

5040 139 58.16 153 64.02

5400 86 35.98 239 100.00

RESULTS: Total Dose Summary (Groups 1 – 3)

Total Dose

(cGy)

Frequency Percent Cumulative

Frequency

Cumulative

Percent

4500 12 6.25 12 6.25

5040 112 58.33 124 64.58

5400 68 35.42 192# 100.00

*Excluding group=4 #Frequency Missing = 2

RESULTS: Total Dose Summary

Stratified by Treatment Group

Total Dose

(cGy)

Group 1 Group 2 Group 3 TOTAL

4500 10 0 2 12

5040 40 32 40 112

5400 13 31 24 68

TOTAL 63 63 66

192

Evaluation of the association between pathology response and

other covariates.

We used three-level pathology response (1=“pCR, pDS” ;

2=”pPR, pDS”; 3=”pPR”).

Statistical method: Chi-square test or Fisher’s exact test was

used to assess the general association between two categorical

variables. In addition, Cochrane Mantle-Haenszel test was used

to evaluate test of linear trend for two ordered categorical

variables (e.g., pathology response and total dose).

Result: The pathology response is not associated with total dose

(p = 0.2311, fisher’s exact test) overall, and no evidence of linear

trend (p=0.4662, CMH test).

RESULTS: Response by Total Dose Summary


Response 4500 cGy 5040 cGy 5400 cGy TOTAL

pCR, pDS 5 28 15 48

pCR, pDS 2 49 38 89

pPR 2 28 15 45

TOTAL 9 105 68

182*

*Frequency Missing = 12

When fitting a logistic regression model that includes the

interaction term of total dose and group, the term is not

significant (p=0.6462), suggesting the effect of total dose on the

pathology response is not significantly different for different

groups.

Nevertheless, we assess the association between total dose and

pathology response within each group.

The pathologic response is not associated with total dose for

Group 1 (p = 0.4610, Fisher’s exact test) nor Group 2 (p =

0.7823, chi-square test).

For Group 3, the distribution of pathologic response differs by

dose levels (p = 0.0365, Fisher’s exact test). The contingency

table for Group 3 is shown on the following slide.



Response 4500 cGy 5040 cGy 5400 cGy TOTAL

pCR, pDS 2 12 7 21

pCR, pDS 0 17 16 33

pPR 0 10 1 11

TOTAL 2 39 24

65*


Group 3

There is not linear trend observed for pathology

response and total dose within each group.

RESULTS: Response by IMRT Summary

Overall, the pathology response is also not associated with IMRT

(p = 0.4318, Chi-square test).

Response Non-IMRT IMRT TOTAL

pCR, pDS 43 6 49

pCR, pDS 74 18 92

pPR 40 6 46

TOTAL 157 30 187*


RESULTS: Response by IMRT Summary

Overall, the pathology response is also not associated with IMRT (p = 0.4318,

Chi-square test).

When fitting a logistic regression model that includes the interaction term of

IMRT and Group, the term is not significant (p=0.8814), suggesting the effect

of IMRT on the pathologic response is not significantly different for different

Groups.

Association between IMRT and pathologic response within each Group was

assessed.

The pathology response is not associated with IMRT for Group 1 (p = 0.8047,

Fisher’s exact test), Group 2 (p = 0.3895), nor Group 3 (p = 0.8450).

When treating elapse day as a continuous variable, it is not significantly

associated with pathology response (p = 0.5169) overall, and within each group

(p = 0.3605 for group 1 ; p = 0.2948 for group 2; p = 0.3806 for group 3).

Categorization of the elapse day may be considered.

RESULTS: Response by Elapsed Days Summary

When treating Elapsed Days as a continuous variable, it is not significantly

associated with pathologic response (p = 0.5169) overall, nor within each

Group (p = 0.3605 , Group 1 ; p = 0.2948, Group 2; p = 0.3806, Group 3).

RESULTS Primary aims of the present analysis was to describe the RT parameters and

impact on outcome for Groups 1-3

At the time of this analysis, 194 pts (M:F, 57%:43%; median age 56 yrs, range 20-87 yrs)

had RT information available.

Pts were pre-CRT stage II 23% & III 77%.

The median & range RT dose was 50.4 & 28-54 Gy, respectively.

Thirty five percent (n=68) received a total RT dose of 54 Gy.

IMRT was documented in approximately 18% of patients.

Median, mean, and range of total elapsed days of RT in 190 pts with available information

was 40, 41, & 29-79, respectively.

RT interruption occurred in 35% of the pts, with the most common reasons being

holidays (33%) & non-heme toxicity (17%).

Following delivery of 45 Gy (n=192) to initial pelvic field, 58% (n=112) & 35% (n=68)

received boost RT to 50.4 & 54 Gy, respectively.

Pre-CRT clinical stage:

T2=8%, T3=89%, T4=3%

N0=23%, N1=70%, N2=7%, Nx=<1%.

Post-CRT (pathologic) stage:

ypT0=28%, ypTis=2%, ypT1=8%, ypT2=26%, ypT3=34%, ypT4=2%

ypN0=79%, ypN1=12%, ypN2=9%

ypStage 0=30%, ypStage I=27%, ypStage II=22%, ypStage III=21%.

New Directions/Successor Trial

Randomized Phase II trial testing the efficacy of 2 neoadjuvant chemotherapy schedules in maximizing the proportion of pts with distal LARC who are cured without standard radical surgery.

Randomized Phase II trial testing the efficacy of 2 neoadjuvant chemotherapy schedules in maximizing the proportion of pts with distal LARC who are cured without standard radical surgery.

SPECIFIC AIMS

• To evaluate 3-yr RFS for in pts receiving induction neoadjuvant or consolidative neoadjuvant chemotherapy, chemoradiotherapy, & selective non-operative mgt, vs standard historical controls managed with chemoradiotherapy, TME, & adjuvant chemotherapy

• To compare outcomes between pts in both study arms, with respect to organ preservation rates, compliance with treatment & adverse events

• To measure PRO (functional) & QoL in pts with distal LARC treated with neoadjuvant chemotherapy, chemoradiotherapy, & non-operative mgt, compare to pts treated with TME

• To investigate the diagnostic performance of conventional & DW-MRI in identifying pts with distal LARC treated with neoadjuvant chemotherapy & chemoradiotherapy, who may benefit from non-operative mgt.

New Directions/Successor Trial

Conclusions

A multi-institutional phase II trial in pts with locally advanced rectal cancer

who receive neoadjuvant CRT followed by consolidation chemotherapy (TNT)

& increasing interval of delayed surgery is feasible.

Pathologic response is not associated with total dose per inter- or intra-

Group

comparison.

Pathologic response is not associated with IMRT per inter- or intra-Group

comparison.

Elapsed Days (total) as a continuous variable, it is not significantly associated

with pathologic response per inter- or intra-Group comparison.

A successor trial will evaluate 3-yr RFS comparing induction vs

consolidation

systemic therapy, prospectively evaluate organ preservation non-operative

dx management, measure pt-related functional outcomes, and investigate the

predictive utility of DW-MRI for resectable rectal cancer

Supported, in part, by NIH, NCI R01 CA090559 to Julio Garcia-Aguilar

Thank you for your attention

EXAMPLE OF PARTIAL RESPONSE WITHOUT

DOWNSTAGING

The response rate is calculated based on a combination of bulk and depth.

For example, let's say the tumor is stage II at baseline (T3N0). Patients are

considered to have a pPR if the tumor has shrunk at least 30% in one

dimension. However, the bulk of the tumor may respond in the rectal wall,

but there may be residual tumor cells left at depth (e.g. cells found in

muscularis propria). In this case, the tumor would still classified as stage II

compared to baseline.

In another case, if the tumor was staged at T3N1 at baseline (nodes positive

on imaging), and upon final path review residual tumor cells are found in

the muscularis propria but all nodes are negative, then the tumor would be

considered down-staged in this case.

RESULTS: Enrollment Summary for Group 2 Total No. enrolled xx

Treatment Completed

-Completed surgery xx

FOLFOX-6 Compliance (eligible pts completing treatment thru surgery)

-Completed all 6 cycles FOLFOX-6 xx

-Completed < 6 but > 1 cycles FOLFOX-6 x

-Did not start FOLFOX-6 due to toxicity/SAE x

-Did not start FOLFOX-6 due to other reason x

-Declined treatment x

-Treatment status unknown x

TOTAL xx

Treatment in Progress

-Undergoing neoadjuvant treatment (CRT or FOLFOX-6) x

-Treatment status unknown x

Removed from Study

-Ineligible @ baseline x

-Declined surgery (TME) x

-Treatment deviation x

-Disease progression x

-Death x

TOTAL x

RESULTS: Enrollment Summary for Group 3 Total No. enrolled XX

Treatment Completed

-Completed surgery XX


-Completed all 6 cycles FOLFOX-6 XX

-Completed < 6 but > 1 cycles FOLFOX-6 X

-Did not start FOLFOX-6 due to toxicity/SAE X

-Did not start FOLFOX-6 due to other reason X

-Declined treatment X

-Treatment status unknown X

TOTAL X


-Undergoing neoadjuvant treatment (CRT or FOLFOX-6) X

-Treatment status unknown X

Removed from Study

-Ineligible @ baseline X

-Declined surgery (TME) X

-Treatment deviation X

-Disease progression X

-Death X

TOTAL X

RESULTS: Enrollment Summary for Group 4 (data not presented today) Total No. enrolled 76

Treatment Completed

-Completed surgery 71


-Completed all 6 cycles FOLFOX-6 20

-Completed < 6 but > 1 cycles FOLFOX-6 4

-Did not start FOLFOX-6 due to toxicity/SAE 1

-Did not start FOLFOX-6 due to other reason 2

-Declined treatment 2

-Treatment status unknown 43

TOTAL 71


-Undergoing neoadjuvant treatment (CRT or FOLFOX-6) 0

-Treatment status unknown 0

Removed from Study

-Ineligible @ baseline 0

-Declined surgery (TME) 4

-Treatment deviation 1

-Disease progression 0

-Death 0

TOTAL 5

1. Summary table for pathology response (before further categorization)

PATH_RE

SP

Frequency Percent Cumulativ

e

Frequency

Cumulativ

e

Percent

pCR, pDS 49 25.26 49 25.26

pDS 1 0.52 50 25.77

pPR 46 23.71 96 49.48

pPR, pDS 92 47.42 188 96.91

pSD 4 2.06 192 98.97

pSD, pDS 2 1.03 194 100.00

We used the further categorization as show below to make the pathology

response three levels: 1=“pCR, pDS” ; 2=”pPR, pDS”; 3=”pPR”.

After categorization, the summary table for the pathology response is shown

as the follows:

resp Frequency Percent Cumulative

Frequency

Cumulative

Percent

pCR, pDS 49 26.20 49 26.20

pPR, pDS 92 49.20 141 75.40

pPR 46 24.60 187 100.00

Documents

Phase II Timing of Rectal Cancer Response to ... II Timing of Rectal Cancer Response to Chemoradiation: Analysis of Radiotherapy (RT) Acknowledgement •Supported, in part, by NIH,