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, MA4Roswell 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 post-operative 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 follow-

up– 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 cancerN=5785

Stage II-III rectal cancer patientsN=1441

Did not receive neoadjuvant therapy

N=299 (27%)

Did receive neoadjuvant therapy

N=810 (73%)

Stage II-III rectal cancer patients with 9 months

follow-up N=1109

Received adjuvant therapyN=651 (80%)

Did not receive adjuvant therapy

N=159 (20%)

Not seen by Med Onc

N=21 (13%)

Seen by Med OncN=88 (55%)

UnknownN=50 (31%)

Chemo recommended / discussedN=52 (59%)

UnknownN=10 (11%)

Chemo not recommended N=26 (30%)

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 2-sided 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)

ResultsReasons 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*

FFF

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

Pathologic Stage

Unable to stage

Stage 0 Stage 1 Stage 2 Stage 3 Total

Unable to stage N=31

0 (0%) 3 (10%) 6 (19%) 10 (32%) 12 (39%) 31 (4%)

Stage IIN=252

7 (3%) 66 (26%) 72 (29%) 58 (23%) 49 (19%) 252 (31%)

Stage IIIN=527

17 (3%) 79 (15%)* 140 (27%) 117 (22%) 174 (33%) 527 (65%)

Total N=810

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

Pathologic Stage

Complete Responders

(Stage 0)

Downstaged Upstaged No change NA

Unable to stage N=31

3 (10%) NA NA NA 28 (90%)

Stage IIN=252

66 (26%) 72 (29%) 49 (19%) 58 (23%) 7 (3%)

Stage IIIN=527

79 (15%) 257 (49%)* NA 174 (33%) 17 (3%)

Total N=810

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%)

SummaryIn 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, 0.16-

0.90, p=0.03)– Lack of closure of ileostomy/colostomy (OR, 0.54; 95% CI, 0.33-

0.87, 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-morbidities2. Patients’ lack of acceptance of the necessary 6-month treatment

• The reason for patient refusal is not recorded in NCCN database3. Benefit of aCTX in locally advanced rectal cancer is not definitive

and may be a reason for variability among NCCN institutions4. 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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