Download Use In Stage II/III Rectal Cancer Patients

Postoperative Adjuvant Chemotherapy
(CTX) Use In Stage II/III Rectal Cancer
Patients (Pts) Treated With Neoadjuvant
Therapy: A National Comprehensive
Cancer Network (NCCN) Analysis
P. Khrizman1, J. C. Niland2, A. ter Veer2, D. Milne3, K.
Bullard Dunn4, W. E Carson III5, P.F. Engstrom6, S. Shibata2,
J. M. Skibber7, M. R. Weiser8, D. Schrag3, A.B. Benson III1
1Robert
H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL
2City of Hope Comprehensive Cancer Center, Los Angeles, CA
3Dana-Farber Cancer Institute, Boston, MA
4Roswell Park Cancer Institute, Buffalo, NY
5The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH
6Fox Chase Cancer Center, Philadelphia, PA
7The University of Texas MD Anderson Cancer Center, Houston, TX
8Memorial Sloan-Kettering Cancer Center, New York, NY
Abstract
•
Background: Practice guidelines recommend that patients who receive neoadjuvant chemotherapy
and radiation (nCRT) for locally advanced rectal cancer complete postoperative systemic
chemotherapy irrespective of tumor downstaging.
•
Methods: We used the NCCN Colorectal Cancer (CRC) Database which tracks longitudinal care for
patients treated at 8 specialty cancer centers* to evaluate how frequently rectal cancer patients
treated with nCRT receive postoperative systemic chemotherapy. We examined patient and tumor
characteristics associated with adjuvant chemotherapy (aCTX) in a multivariable logistic regression
model.
•
Results: Between September 2005 and February 2010, 1,441 pts with stage II/III rectal cancer were
enrolled. Of these, 810 pts received nCRT and were included in the analysis. Of these, 159 pts (20%)
did not receive any aCTX. For those seen by a medical oncologist, the most frequent reason
chemotherapy was not recommended was due to co-morbid illness (54%) and the most frequent
reason chemotherapy was not received even though it was recommended or discussed was due to
patient refusal (73%). Pts who were more likely to have no aCTX administered included: age 75+
(OR=11.4, p<0.0001), ECOG PS ≥ 1 (OR=3.1, p=0.0009), on Medicaid or indigent (OR=3.6, p=0.02),
complete pathologic response (cPR; OR=2.4, p=0.02), abnormal CEA post-operatively (OR=2.2,
p<0.0001), unavailable CEA post operatively (OR=3.4, p<0.0001), presence of re-operation/wound
infection (OR=2.7, p=0.03), and no closure of ileostomy/colostomy (OR=1.9, p=0.01).
•
Conclusion: Even at specialty cancer centers, a sizeable minority of rectal cancer patients treated with
curative intent nCR do not complete postoperative chemotherapy. Strategies to foster adherence to
the third and final component of curative intent treatment are necessary.
8 specialty cancer centers include: City of Hope Cancer Center (CHCC), Dana-Farber Cancer Center (DFCC), Fox Chase Cancer Center (FCCC), Memorial
Sloan-Kettering Cancer Center (MSKCC), Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at the Ohio State University (OSU), Robert H.
Lurie Cancer Center at Northwestern University (Lurie), Roswell Park Cancer Institute (RPCI), and University of Texas MD Anderson Cancer Center (MDA)
Introduction
• In 2009 there were an estimated 40,870 new cases of rectal
cancer diagnosed in the United States.
• Treatment strategies for stage II/III rectal cancer patients have
evolved over the past two decades to include neoadjuvant
chemoradiation (nCRT) followed by surgery and postoperative adjuvant chemotherapy (aCTX).
• Combinations of such treatment modalities have been shown
to prolong the overall survival (OS) as well as decrease the
local recurrence rates.
Introduction
• NCCN Colorectal Cancer Outcomes Database Project was
initiated in 2005
– Goal: evaluate the outcomes of cancer care, practice patterns
and adherence to evidence-based guidelines
– Participants: 8 of the 21 NCCN cancer centers
• Recent published analysis: Using ASCO/NCCN quality
measures, low mean concordance rates were demonstrated
among participating NCCN centers for aCTX in clinical stage
II/III rectal cancer within 9 months of diagnosis.
Introduction
• We report an analysis of various socio-demographic and
clinical variables from the cohort of locally advanced, clinical
stage II/III, rectal cancer patients included in the NCCN
Outcomes Database as an effort to determine the significant
factors that would predict the use of aCTX following standard
nCRT and surgery
Patients
• Eligibility criteria:
– Age 18 or older
– Clinical diagnosis of locally
advanced rectal cancer who
received or did not receive
aCTX within 9 months of
diagnosis
– Histologies
such
as
adenocarcinoma, mucinous,
colloid, and signet ring
features included
• Exclusion criteria:
– Single or multiple diagnoses of
colon cancer
– Stage I and IV rectal cancer
– Recurrent disease
– No follow up
– Lack of clinical staging
– Less than 9 months of followup
– Lack of documentation of
administration of neoadjuvant
therapy and/or surgery
Methods
• Baseline patient information in the NCCN database:
–
–
–
–
–
socio-demographic characteristics
insurance status
co-morbidities (using Charlson index)
ECOG performance status (PS)
household income.
• Medical records were systematically reviewed at 4, 8, 12
months, and then yearly to document treatment and
recurrence information
Methods
• 4-month assessment documentation:
–
–
–
–
–
–
–
–
–
–
–
clinical and pathologic TNM staging
histology
tumor location
distance from the anal verge
# of lymph nodes examined and involved with tumor
grade at diagnosis and primary surgery
presence/absence of lymphovascular invasion
Presence/absence of perineural invasion
margin involvement (proximal, distal, radial)
CEA level prior to and after surgery
surgical procedures and complications
Patients with clinical stage II/III rectal cancer and administration
of adjuvant chemotherapy
All pts with colorectal cancer
N=5785
Stage II-III rectal cancer
patients
N=1441
Stage II-III rectal cancer
patients with 9 months
follow-up
N=1109
Did not receive neoadjuvant
therapy
N=299 (27%)
Did receive neoadjuvant
therapy
N=810 (73%)
Did not receive adjuvant
therapy
N=159 (20%)
Not seen by Med
Onc
N=21 (13%)
Seen by Med Onc
N=88 (55%)
Chemo not recommended
N=26 (30%)
Received adjuvant therapy
N=651 (80%)
Unknown
N=50 (31%)
Chemo recommended /
discussed
N=52 (59%)
Unknown
N=10
(11%)
Statistical Methods
• The association between receipt of adjuvant therapy and each
parameter was assessed independently in a univariate logistic
regression model
– An independent variable was created for whether the patient
had been downstaged or upstaged
– 52 of the patients (6%) were excluded from the
downstaged/upstaged analysis (unable to stage)
Statistical Methods
• Parameters found to be potentially associated with adjuvant
therapy, based on a P value ≤ 0.20, were included in the initial
multivariate model, along with variables known to be clinically
associated with adjuvant therapy, and defined a priori
• The final multivariate model includes those predictors with a 2sided P value < 0.05 and the control variables defined a priori
(clinical TNM stage and NCCN cancer center)
• Point estimates of the multivariate model were reported as odds
ratios (ORs) and 95% confidence intervals (CIs) for each OR
Results
Reasons CTX was not recommended (26 of 88 patients)
– Co-morbid illness (14 patients)
– Advanced age & co-morbid illness (2 patients)
– Therapy not indicated (5 patients)
– Recurrence before treatment decision reached (2 patients)
– Death before treatment decision reached (1 patient)
– Unknown reason (2 patients)
Results
Reasons CTX was recommended but was not
administered (52 of 88 patients):
• Declined treatment (38 patients)
• Recurrence prior to treatment administration (6 patients)
• Treatment not administered at 12 month assessment (2
patients)
• Death before treatment administration (1 patient)
• Transferred out (1 patient)
• Unknown reason (4 patients)
Characteristics of N=810 clinical stage II/III rectal cancer
patients who presented to NCCN institutions between
September 2005 and February 2010 and received neoadjuvant
therapy*
F
F
F
Characteristics of N=810 clinical stage II/III rectal cancer
patients who presented to NCCN institutions between
September 2005 and February 2010 and received neoadjuvant
therapy*
**
*Table includes statistically significant variables only
**52 of the patients (6%) were excluded from the downstaged/upstaged analyses, as these patients either
had clinical TNM stage = unable to stage OR pathologic TNM stage = unable to stage
Factors associated with receiving adjuvant therapy for patients with
stage II/III rectal cancer
Factors associated with receiving adjuvant therapy for patients
with stage II/III rectal cancer
Clinical and pathologic staging of cohort
Clinical
Stage
Unable to
stage
N=31
Stage II
N=252
Stage III
N=527
Total
N=810
Pathologic Stage
Unable to
stage
Stage 0
Stage 1
Stage 2
Stage 3
Total
0 (0%)
3 (10%)
6 (19%)
10 (32%)
12 (39%)
31 (4%)
7 (3%)
66 (26%)
72 (29%)
58 (23%)
49 (19%)
252 (31%)
17 (3%)
79 (15%)*
140 (27%)
117 (22%)
174 (33%)
527 (65%)
24 (3%)
148 (18%)
218 (27%)
185 (23%)
235 (29%) 810 (100%)
Proportion of patients in cohort that were complete
responders, downstaged, upstaged, or had no change
in staging
Clinical
Stage
Unable to
stage N=31
Stage II
N=252
Stage III
N=527
Total
N=810
Pathologic Stage
Complete
Responders
(Stage 0)
3 (10%)
Downstaged
Upstaged
No change
NA
NA
NA
NA
28 (90%)
66 (26%)
72 (29%)
49 (19%)
58 (23%)
7 (3%)
79 (15%)
257 (49%)*
NA
174 (33%)
17 (3%)
148 (18%)
329 (41%)
49 (6%)
232 (29%)
52 (6%)**
* 257 of the Stage III patients (49%) were downstaged (117 pts from Stage III to II and 140 pts from Stage III to I)
** 52 of the patients (6%) were excluded from the downstaged/upstaged analyses, as these patients either had
clinical TNM stage=unable to stage OR pathologic TNM stage=unable to stage
Summary
• 20% of patient cohort did not receive aCTX
• For patients seen by a medical oncologist, the most frequent
reason aCTX was not recommended was due to co-morbid
illness (54%)
• For patients seen by a medical oncologist, the most frequent
reason aCTX was not received although it was recommended
or discussed was due to patient refusal (73%)
Summary
In a multivariable model, significant factors associated with
decreased administration of aCTX included:
– Age >75 (OR, 0.09; 95% confidence interval (CI), 0.03-0.26,
p<0.0001)
– ECOG PS > 1 (OR, 0.33; 95% CI, 0.18-0.61, p=0.0009)
– Abnormal/unknown CEA value after surgery (OR, 0.46; 95% CI,
0.23-0.92, p<0.0001)
– Patients on Medicaid or indigent (OR, 0.28; 95% CI, 0.13-0.61,
p=0.02)
– Center of treatment (OR, 0.43; 95% CI, 0.21, 0.87, p=0.05)
– Patients with clinical to pathologic complete response (OR, 0.42;
95% CI, 0.22-0.79, p=0.02)
– Re-operation and/or wound infection (OR, 0.37; 95% CI, 0.160.90, p=0.03)
– Lack of closure of ileostomy/colostomy (OR, 0.54; 95% CI, 0.330.87, p=0.01)
Discussion
• The reasons patients inconsistently receive aCTX for locally
advanced rectal cancer include:
1. Reluctance to recommend aCTX to patients with co-morbidities
2. Patients’ lack of acceptance of the necessary 6-month treatment
•
The reason for patient refusal is not recorded in NCCN database
3. Benefit of aCTX in locally advanced rectal cancer is not definitive
and may be a reason for variability among NCCN institutions
4. No conclusive evidence to define the optimal aCTX regimen or the
optimal subgroups of patients to treat, which can result in
variability in physician recommendations
Discussion
• The focus on tumor biology and patient selection
generates additional data to foster adherence to
aCTX guidelines
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