Disclosure Information
Kim, Tae Won
Relationships with Companies
Honoraria: Roche, Amgen, Merk Serono, Bayer, Sanofi
Research Fund:Merck Serono, AstraZeneca, Pfizer, Bayer, Sanofi
Long-term results of the ADORE trial:ADjuvant Oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) versus 5-fluorouracil and leucovorin (FL) after preoperative chemoradiotherapy and surgery for locally advanced REctal cancer
Yong Sang Hong 1, Sun Young Kim 1, Ji Sung Lee 2, Byung-Ho Nam 3, Jeong Eun Kim 1, Kyu-pyo Kim 1, Joon Oh Park 4, Young Suk Park 4, Ji Yeon Baek 5, Tae-You Kim 6, Keun-Wook Lee 7, Joong Bae Ahn 8, Kyung Hae Jung 1,
and Tae Won Kim 1 on behalf of ADORE investigators
2KIM, TAE WON
1 Asan Medical Center, University of Ulsan College of Medicine, Seoul; 2 Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul; 3 HERINGS, The Institute of Advanced Clinical and Biomedical Research, Seoul; 4 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; 5 National Cancer Center, Goyang; 6 Seoul National University Hospital, Seoul National University College of Medicine, Seoul; 7 Seoul National University Bundang Hospital,
Seoul National University College of Medicine, Seongnam; 8 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
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Treatment of Locally Advanced Rectal Cancer
Preoperative chemoradiotherapy
• Both pre- and post-operative oxaliplatin based chemotherapy improved disease-free survival,1 but is still investigating. At present, fluoropyrimidine (capecitabine or 5-fluorouracil) monotherapy is the current standard strategy during pre-operative chemoradiotherapy. 2-4
• Adjuvant FOLFOX after preoperative chemoradiotherapy was based on the extrapolation of results obtained for colon cancer patients. 5,6
cT3-4N0 or N+Clinical staging by Rectal MRI
Total Mesorectal Excision
Adjuvant Chemotherapy
Controversies for adjuvant chemotherapy
1 Rodel et al. Lancet Oncol 2015; 2 O’Connell et al. J Clin Oncol 2014; 3 Gerard et al. J Clin Oncol 2012; 4 Aschele et al. J Clin Oncol 2011; 5 Andre T, et al. NEJM 2004; 6 Haller D, et al. J Clin Oncol 2011
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4KIM, TAE WON
Study design and Rationale
Adjuvant FOLFOXOxaliplatinLeucovorin5-Fluorouracil
85 mg/m2 on day 1200 mg/m2 on day 1400 mg/m2 bolus on day 12400 mg/m2 CIV for 46 hours
Every 2 weeks X 8 cycles
Adjuvant FL
R
Leucovorin5-Fluorouracil
20 mg/m2/day from days 1 to 5380 mg/m2/day from days 1 to 5
Every 4 weeks X 4 cycles
Stratified by- ypStage (II vs III)- Participating centers
ypStage II (ypT3-4N0)
ypStage III (ypTanyN1-2)
Preoperative chemoradiotherapy
with fluoropyrimidines
Total Mesorectal
Excision
Screening procedure based on the postsurgical pathologic stages
Clinical practice according to the institutional standards
Key inclusion criteria• Preoperative chemoradiotherapy with fluoropyrimidines alone;
oxaliplatin or other combined regimens were not allowed.
• Total mesorectal excision (TME) was mandatory.• Curative surgery (no microscopic residual tumor), ≤ 8 weeks prior to randomization.
Exclude ypStage 0-I, or stage IV
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Statistical ConsiderationsPrimary endpoint: disease-free survival (DFS)
• This study was a randomised phase II trial based on the parallel concurrent historical comparison.
• Patients number was calculated based on the expected 3-year DFS for the FOLFOX arm was 78%, and was 70% for the FL arm, the historical control.
• 160 patients per treatment arm were required to ensure one-sided type I error of 5% and a power of 80%, after assuming an 8% of drop-out rate.
Secondary endpoints
• Adverse events• Patterns of failure• Overall survival• Quality of life
The 3-year DFS, adverse events, and quality of life were reported at ASCO 2014 #3502 and published.1
1 Hong et al. ASCO 2014 #3502, Lancet Oncol 2014
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Patient Disposition
10 consent withdrawal4 ineligible 12 consent withdrawal
321 patients randomly assigned(ypT3-4N0 or ypTanyN1-2)
160 allocated to FOLFOX 161 allocated to FL
146 received FOLFOX 149 received FL
First patient in: Nov 2008
Last patient in: Jun 2012
Data cut-off for primary outcomes: Dec 2013
Data cut-off for long-term results: Jan 2018
Median follow-up: 74.1 months (IQR, 56.2 – 88.0)
* From 6 participating centers in Korea
Intent-to-treat (ITT)population
Safety population
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1 Hong et al. ASCO 2014 #3502, Lancet Oncol 2014
65 events at cut-off39 deceased
46 events at cut-off32 deceased
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Patient Characteristics (1)FOLFOX(n=160)
FL(n=161)
Age (years), median (range) 55 (27–81) 54 (25–79)
Age ≥ 65 31 19.4% 24 14.9%
GenderMale 118 73.8% 116 72.0%
Female 42 26.3% 45 28.0%
ECOG performance status0 26 16.3% 30 18.6%
1 134 83.8% 131 81.4%
Distance of the primary tumorfrom the anal verge
≤ 4 cm 48 30.0% 45 28.0%
4 ~ 8 cm 81 50.6% 89 55.3%
> 8 cm 31 19.4% 27 16.8%
Tumor differentiationWell differentiated 13 8.1% 20 12.4%
Moderately differentiated 133 83.1% 130 80.7%
Poorly differentiated /signet ring cell / mucinous 11 6.9% 9 5.6%
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Patient Characteristics (2)FOLFOX(n=160)
FL(n=161)
Preoperative radiotherapyDose (cGy), median (IQR) 5,000 (5,000–5,040) 5,000 (5,000–5,040)
Duration (weeks), median (IQR) 5.1 (4.9–5.7) 5.0 (4.6–5.4)
Concurrent chemotherapy during preoperative radiotherapy
5-Fluorouracil ± leucovorin 107 66.9% 108 67.1%
Capecitabine 46 28.8% 43 26.7%
UFT 7 4.4% 10 6.2%
Interval between end of preoperative chemoradiotherapy and surgery (weeks), median (IQR) 7.0 (6.1–8.0) 7.0 (6.0–8.0)
Type of surgery
Abdominoperineal resection 24 15.0% 24 14.9%
Low anterior resection 135 84.4% 135 83.9%
Hartmann’s procedure 1 0.6% 2 1.2%
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Patient Characteristics (3)FOLFOX(n=160)
FL(n=161)
ypStage
ypStage II 58 36.3% 65 40.4%
ypStage III 102 63.8% 96 59.6%
Lymphovascular invasion
Absent 120 75.0% 120 74.5%
Present 37 23.1% 41 24.5%
missing 3 1.9% 0 0%
Grade of tumor regression
Total regression 5 3.1% 2 1.2%
Near total regression 31 19.4% 22 13.7%
Moderate regression 85 53.1% 84 52.2%
Minimal or no regression 38 23.8% 52 32.3%
missing 1 0.6% 1 0.6%
Time from surgery to randomization (weeks), median (IQR) 3.4 (3.0 – 4.3) 3.6 (3.1 – 4.6)
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Treatment Exposure and Adverse Events
Treatment Exposure
FOLFOX(n=146)
FL(n=149)
Completed planned cycles 141 (96.6%) 141 (94.6%)
Relative dose intensity
5-FU bolus 86.6% 95.0%
5-FU continuous infusion 87.6% -
Oxaliplatin 93.2% -
Grade 3 or 4 Adverse Events
FOLFOX(n=146)
FL(n=149)
p value
Hematologic
Leucopenia 12 8.2% 8 5.4% 0.363
Neutropenia 52 35.6% 38 25.5% 0.076
Febrile neutropenia 1 0.7% 4 2.7% 0.371
Thrombocytopenia 1 0.7% 0 0% 0.495
Anemia 0 0.0% 1 0.7% 1.000
Non-hematologic
Nausea 2 1.4% 1 0.7% 0.620
Vomiting 1 0.7% 1 0.7% 1.000
Stomatitis 0 0.0% 2 1.3% 0.498
Diarrhea 2 1.4% 4 2.7% 0.684
Sensory neuropathy 1 0.7% 0 0% 0.495
p value calculated by Fisher’s exact test
1 Hong et al. ASCO 2014 #3502, Lancet Oncol 2014
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Disease-free survival, ITT population
11KIM, TAE WON
% d
isea
se-f
ree
100
80
60
40
20
0
FOLFOX
FL
12010896847260483624120
Months, disease-free survivalNumber at risk
FL 161 114 99 91 82 72 51 29 12 2 0
FOLFOX 160 131 108 103 97 81 61 37 15 1 0
FOLFOX (n=160) FL (n=161)
Events 46 65
6-year DFS rate 68.2% 56.8%
Crude HR (95% CI) 0.63 (0.43 – 0.92), p=0.018
Stratified HR (95% CI) * 0.63 (0.43 - 0.93), p=0.018* Stratified by predefined stratification factors (ypStage and participating centers)
∆11.4%
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Disease-free survival, ypStage III%
dis
ease
-fre
e100
80
60
40
20
012010896847260483624120
Months, disease-free survival
FOLFOX
FL
Number at risk
FL 96 60 53 49 41 33 27 17 8 1 0
FOLFOX 102 83 68 63 58 46 37 23 8 0 0
FOLFOX (n=102) FL (n=96)
Events 35 47
6-year DFS rate 63.2% 48.3%
Crude HR (95% CI) 0.58 (0.37 – 0.90), p=0.014
Stratified HR (95% CI) * 0.59 (0.38 - 0.92), p=0.019* Stratified by predefined stratification factors (ypStage and participating centers)
∆14.9%
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Disease-free survival, ypStage II
FOLFOX
FL
% d
isea
se-f
ree
100
80
60
40
20
012010896847260483624120
Months, disease-free survivalNumber at risk
FL 65 54 46 42 41 39 24 12 4 1 0
FOLFOX 58 48 40 40 39 35 24 14 7 1 0
FOLFOX (n=58) FL (n=65)
Events 11 18
6-year DFS rate 77.8% 69.5%
Crude HR (95% CI) 0.67 (0.32 –1.42), p=0.293
Stratified HR (95% CI) * 0.64 (0.30 - 1.36), p=0.245
* Stratified by predefined stratification factors (ypStage and participating centers)
∆8.3%
Number of patient Stratified HR 95% CI p value p value for
interaction
ITT population 321 0.63 0.43 – 0.93 0.018
Gender 0.798
Male 234 0.62 0.39 – 0.98 0.039
Female 87 0.69 0.34 - 1.39 0.297
Age 0.903
< 65 years 266 0.64 0.42 – 0.97 0.034
≥ 65 years 55 0.60 0.21 – 1.67 0.325
Pathologic stage 0.856
ypStage II 123 0.64 0.30 – 1.36 0.245
ypStage III 198 0.59 0.38 – 0.92 0.019
Pathologic T stage 0.939
ypT0-2 48 0.61 0.19 – 2.00 0.415
ypT3-4 273 0.58 0.39 – 0.88 0.010
Pathologic N stage 0.167
ypN0 123 0.70 0.33 – 1.50 0.362
ypN1a 72 1.27 0.55 – 2.92 0.574
ypN1b 63 0.35 0.14 – 0.83 0.017
ypN2 63 0.47 0.22 – 0.99 0.048
Subgroup analysis for disease-free survival (1)
0.1 0.2 0.5 1 2 4
Favours FOLFOX Favours FL
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Subgroup analysis for disease-free survival (2)
0.1 0.2 0.5 1 2 4
Favours FOLFOX Favours FL
KIM, TAE WON
Number of patient Stratified HR 95% CI p value p value for
interaction
Location of Tumor 0.444
≤ 4 cm 93 0.59 0.31 – 1.12 0.107
4 ~ 8 cm 170 0.78 0.44 – 1.36 0.380
> 8 cm 58 0.37 0.14 – 1.01 0.052
Tumor differentiation 0.296
Well differentiated 33 0.42 0.09 – 1.98 0.272
Moderately differentiated 263 0.74 0.48 – 1.14 0.174
Poorly differentiated/mucinous/signet ring cell 20 0.28 0.08 – 0.97 0.045
Grade of tumor regression 0.297
Total or near total regression 60 0.95 0.39 – 2.33 0.908
Moderate regression 169 0.72 0.42 – 1.23 0.230
Minimal or no regression 90 0.40 0.19 – 0.85 0.016
Lymphovascular invasion 0.285
Absent 240 0.55 0.34 – 0.88 0.013
Present 78 0.86 0.44 – 1.69 0.662
Perineural invasion 0.282
Absent 241 0.53 0.33 – 0.86 0.010
Present 77 0.84 0.43 – 1.63 0.598
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Overall survival, ITT population
FOLFOX
FL
% s
urvi
ved
100
80
60
40
20
012010896847260483624120
Months, overall survivalNumber at risk
FL 161 144 137 126 120 104 79 50 22 2 0
FOLFOX 160 146 139 134 123 105 79 48 23 1 0
FOLFOX (n=160) FL (n=161)
Events 32 39
6-year OS rate 78.1% 76.4%
Crude HR (95% CI) 0.80 (0.50 – 1.27), p=0.338
Stratified HR (95% CI) * 0.73 (0.45 - 1.19), p=0.210
* Stratified by predefined stratification factors (ypStage and participating centers)
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Subgroup analysis for overall survival (1)
0.1 0.2 0.5 1 2 4
Favours FOLFOX Favours FL
KIM, TAE WON
Number of patient Stratified HR 95% CI p value p value for
interactionITT population 321 0.73 0.45 – 1.19 0.210
Gender 0.748
Male 234 0.69 0.40 – 1.22 0.203
Female 87 0.83 0.33 – 2.09 0.690
Age 0.923
< 65 years 266 0.75 0.44 – 1.26 0.271
≥ 65 years 55 0.70 0.20 – 2.46 0.576
Pathologic stage 0.800
ypStage II 123 0.83 0.33 – 2.10 0.691
ypStage III 198 0.72 0.41 – 1.25 0.242
Pathologic T stage 0.414
ypT0-2 48 1.31 0.26 – 6.62 0.741
ypT3-4 273 0.65 0.39 – 1.07 0.093
Pathologic N stage 0.303
ypN0 123 0.82 0.30 – 2.19 0.688
ypN1a 72 1.44 0.48 – 4.28 0.514
ypN1b 63 0.42 0.11 – 1.53 0.188
ypN2 63 0.42 0.18 – 0.96 0.040
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Subgroup analysis for overall survival (2)
0.1 0.2 0.5 1 2 4
Favours FOLFOX Favours FL
KIM, TAE WON
Number of patient Stratified HR 95% CI p value p value for
interaction
Location of tumor 0.429
≤ 4 cm 93 0.52 0.22 – 1.23 0.137
4 ~ 8 cm 170 1.01 0.52 – 1.97 0.981
> 8 cm 58 0.53 0.15 – 1.87 0.325
Tumor differentiation 0.286
Well differentiated 33 0.73 0.15 – 3.68 0.707
Moderately differentiated 263 0.87 0.49 – 1.52 0.615
Poorly differentiated/mucinous/signet ring cell 20 0.27 0.07 – 1.03 0.055
Grade of tumor regression 0.111
Total or near total regression 60 2.17 0.56 – 8.33 0.260
Moderate regression 169 0.91 0.43 – 1.89 0.790
Minimal or no regression 90 0.42 0.19 – 0.98 0.043
Lymphovascular invasion 0.931
Absent 240 0.69 0.37 – 1.29 0.244
Present 78 0.73 0.33 – 1.60 0.432
Perineural invasion 0.109
Absent 241 0.53 0.28 – 1.02 0.058
Present 77 1.22 0.57 – 2.62 0.615
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Patterns of recurrenceFOLFOX
(n=160)
FL(n=161)
Events 46 28.8% 65 40.4%
Locoregional recurrence 7 4.4% 15 9.3%
Distant metastasis 41 25.6% 53 32.9%
Lung 27 16.9% 33 20.5%
Liver 9 5.6% 17 10.6%
Lymph node 6 3.8% 13 8.1%
Bone 2 1.3% 6 3.7%
Peritoneum 1 0.6% 2 1.2%
Other * 2 1.3% 3 1.9%
Sum of distant metastases
1 organ 36 22.5% 38 23.6%
2 organs 4 2.5% 11 6.8%
≥ 3 organs 1 0.6% 4 2.5%* Other sites of metastasis included the brain (1), bladder (1), ovary (1), pleura (1) and abdominal wall (1)
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Treatment after recurrence
Initial treatment after recurrenceFOLFOX
(n=46)
FL(n=65)
Surgery of curative intent 19 41.3% 28 43.1%
Radiofrequency ablation 3 6.5% 4 6.2%
Stereotactic radiosurgery 1 2.2% 0 0%
Surgery of palliative intent 2 4.3% 5 7.7%
Palliative chemotherapy only 16 34.8% 20 30.8%
No treatment or lost to follow-up 5 10.9% 8 12.3%
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Conclusion
• Adjuvant FOLFOX demonstrated disease-free survival improvements compared with FL, in pathologic ypStage II-III patients after preoperative chemoradiotherapy with fluoropyrimidines alone and surgery.
• Subgroup analyses might provide potential candidates of adjuvant oxaliplatin-based chemotherapy in these patients.
KIM, TAE WON
• Selection of adjuvant chemotherapy should be considered based on the postoperative pathologic stages after preoperative chemoradiotherapy and surgery.
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Special Thanks
To all the patients and their families
To Sanofi Korea for providing study drugs and funds
To the investigators and research coordinators at the 6 institutions in Korea
KIM, TAE WON
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