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
Above anorectal ring, continent patient
Below anorectal ring, incontinent patient
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
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
Above anorectal ring, continent patient
Below anorectal ring, incontinent patient
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
width (or in tumor length, in circumferential tumors).
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
surgical specimen with the same parameters as determined by pre-chemoradiation
ERUS or MRI
PATHOLOGIC DOWNSTAGE (pDS): pathologic stage lower than ERUS stage.
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
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
width (or in tumor length, in circumferential tumors).
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.
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
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.
RESULTS: Response by Total Dose Summary
RESULTS: Response by Total Dose Summary
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*
*Frequency Missing = 2
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*
*Frequency Missing = 7
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
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 X
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 4 (data not presented today) Total No. enrolled 76
Treatment Completed
-Completed surgery 71
FOLFOX-6 Compliance (eligible pts completing treatment thru surgery)
-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
Treatment in Progress
-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