Effect of Adjuvant Chemotherapy on Stage II Rectal Cancer Outcomes After Preoperative Short-Course Radiotherapy

Accepted Manuscript Impact of adjuvant chemotherapy on stage II rectal cancer outcomes following preoperative short course radiotherapy Jonathan M. Loree, MD, Hagen F. Kennecke, MD MHA, Daniel J. Renouf, MD MPH, Howard J. Lim, MD PhD, Michael M. Vickers, MD MPH, Caroline H. Speers, BA CHIM, Winson Y. Cheung, MD MPH PII:

S1533-0028(16)30051-2

DOI:

10.1016/j.clcc.2016.04.003

Reference:

CLCC 278

To appear in:

Clinical Colorectal Cancer

Received Date: 21 December 2015 Revised Date:

1 April 2016

Accepted Date: 27 April 2016

Please cite this article as: Loree JM, Kennecke HF, Renouf DJ, Lim HJ, Vickers MM, Speers CH, Cheung WY, Impact of adjuvant chemotherapy on stage II rectal cancer outcomes following preoperative short course radiotherapy, Clinical Colorectal Cancer (2016), doi: 10.1016/ j.clcc.2016.04.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Title: Impact of adjuvant chemotherapy on stage II rectal cancer outcomes following preoperative short course radiotherapy Article Type: Original study a

a

a

Authors: Jonathan M. Loree MD , Hagen F. Kennecke MD MHA , Daniel J. Renouf MD MPH , Howard J. Lim a

b

c

a

RI PT

MD PhD , Michael M. Vickers MD MPH , Caroline H. Speers BA CHIM , and Winson Y. Cheung MD MPH Affiliation List: a

th

Division of Medical Oncology, University of British Columbia, British Columbia Cancer Agency, 600 West 10

Avenue, Vancouver, British Columbia, V5Z 4E6, Canada b

SC

Division of Medical Oncology, University of Ottawa, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Box

911, Ottawa, Ontario, K1H 8L6, Canada

Cancer Control Research, Gastrointestinal Cancers Outcomes Unit Database, University of British Columbia, th

M AN U

c

British Columbia Cancer Agency, 600 West 10 Avenue, Vancouver, British Columbia, V5Z 4E6, Canada Address for Correspondence: Dr. Winson. Y. Cheung

Division of Medical Oncology – British Columbia Cancer Agency th

V5Z 4E6, Canada Telephone: 1-604-877-6000

TE D

600 West 10 Avenue Vancouver, British Columbia

E-mail: [email protected]

EP

Email addresses for other others:

Jonathan M. Loree ([email protected]), Hagen F. Kennecke ([email protected]), Daniel

AC C

J. Renouf ([email protected]), Howard J. Lim ([email protected]), Michael M. Vickers ([email protected]), Caroline H. Speers ([email protected]) Grants/Support: None Disclosures: None

Page 1 of 15

ACCEPTED MANUSCRIPT Micro Abstract The benefit of adjuvant chemotherapy in rectal cancer is controversial and recent studies have focused on outcomes after chemoradiotherapy. In this population-based cohort of pathologic stage II rectal cancer patients treated with preoperative short course radiotherapy, the addition of adjuvant chemotherapy does not appear to

RI PT

benefit most patients. Only those with multiple risk features had improved outcomes after adjuvant chemotherapy.

Abstract:

Background: Adjuvant chemotherapy (AC) is offered in stage II rectal cancer, but its use is controversial. We

SC

examined population-based outcomes of patients with pathologic stage II rectal cancer treated with AC following preoperative short course radiotherapy.

M AN U

Methods: We included patients diagnosed with pathologic stage II tumors between 1999 and 2009 in British Columbia. Disease-specific (DSS), relapse-free (RFS), and overall survival (OS) were assessed. Multivariate models adjusting for age, gender, ECOG, and high risk features (pT4, poor differentiation, <12 nodes removed, LVI, perineural invasion, or obstruction/perforation) were constructed.

Results: Of 851 patients reviewed, 330 received preoperative short course radiotherapy, of which 123 (37%)

TE D

received AC. Patients treated with AC were younger (median age 61 vs 73, P<0.0001), reported better ECOG (P<0.0001), and had more high risk features (P<0.0001).

In univariate analysis, AC was associated with

improved DSS (HR 0.58; 95%CI 0.36-0.94; P=0.028), RFS (HR 0.62; 95%CI 0.39-0.98; P=0.043) and OS (HR 0.42; 95%CI 0.30-0.59; P<0.0001). In multivariate analysis, these outcomes were not significant (DSS HR 0.83;

EP

95%CI 0.43-1.61; P=0.58; RFS HR 0.82; 95%CI 0.44-1.50; P=0.51; OS HR 0.62; 95%CI 0.37-1.03; P=0.064). Subgroup analysis suggests AC improved DSS (HR 0.25, 95%CI 0.07-0.89, P =0.033), RFS (HR 0.24, 95%CI

AC C

0.07-0.85, P =0.027), and OS (HR 0.22, 95%CI 0.069-0.70, P =0.011) only in patients with ≥2 high risk features. Conclusion: In this population-based cohort of stage II rectal cancer, AC did not improve outcomes in unselected patients. In a small subgroup of patients with ≥2 risk factors, we noted improved outcomes following AC use. Clinical Practice Points •

There is significant controversy surrounding the magnitude of benefit of adjuvant chemotherapy in rectal cancer, with many of the trials demonstrating benefit occurring in the era of post-operative radiation and prior to total mesorectal excision becoming a standard of care.

Page 2 of 15

ACCEPTED MANUSCRIPT •

Short course radiation continues to be used in many centers as it has similar survival outcomes compared to chemoradiation. There is currently a lack of evidence to support adjuvant chemotherapy following pre-operative short course radiation with the only trial assessing this question being closed early due to poor accrual. We aimed to determine pathologic stage II patients may lack benefit from adjuvant chemotherapy after

RI PT

•

pre-operative short course radiation. •

Using a population based cohort of all stage II rectal cancer patients referred to the British Columbia Cancer agency over a 10 year period, we demonstrate that most patients do not derive benefit from

SC

adjuvant chemotherapy. Our results suggest that only those patients with multiple high risk features have improved outcomes following fluoropyrmide chemotherapy and that a large proportion of patients may be

•

M AN U

over treated.

We suggest that the high risk features used in the colon cancer literature (pT4, poor differentiation, <12 nodes removed, LVI, perineural invasion, or obstruction/perforation) may be useful in helping to risk stratify stage II rectal cancer patients.

TE D

Key words:

AC C

EP

Risk factors, rectal neoplasms, chemoradiotherapy, locally advanced, colorectal

Page 3 of 15

ACCEPTED MANUSCRIPT Introduction: The treatment of locally advanced rectal cancer entails a multidisciplinary approach with patients receiving

a

combination

of

radiotherapy

(RT),

surgery,

and

chemotherapy.

Whether

long

course

chemoradiotherapy (CRT) or short course RT is used in the preoperative setting depends on regional practice

RI PT

patterns and patient/tumor characteristics. To date, no clinical trial has shown a difference in survival outcomes between the two strategies, but CRT is associated with greater tumor down staging.1–4 Following surgical resection, many patients are offered adjuvant chemotherapy (AC); however, the indications and benefit of postoperative AC remains controversial.

SC

A 2012 Cochrane review of 21 randomized controlled trials (RCTs) suggested that the addition of fluoropyrimidine AC following surgical resection improved overall (OS) and disease free survival (DFS) with 5

M AN U

hazard ratios (HRs) of 0.83 and 0.75, respectively. This review mostly included patients treated with postoperative RT which is no longer the standard of care due to evidence showing that RT given preoperatively provides superior local control, DFS, and toxicity profiles.

6,7

An updated meta-analysis in 2015 demonstrated that 8

for most patients treated with preoperative RT, the addition of AC did not improve outcomes. For patients treated with short course RT the evidence of benefit with AC is as yet unclear, with the only trial assessing this question 9

TE D

closed early due to poor accrual.

Despite a lack of evidence specific to rectal cancer treated with short course radiation, AC is still currently recommended by the National Comprehensive Cancer Network and the European Society of Medical Oncology in the post-operative management of stage II/III rectal cancer.

10,11

Further, stage II/III rectal cancers are frequently

EP

considered together in adjuvant trials, even though stage II tumors have a significantly lower risk of recurrence. Evidence in colon cancer suggests that not all patients with stage II disease benefit from AC and that high risk 10,12–14

These features include pT4 lesion, poor

AC C

features may help stratify patients into different risk groups.

differentiation, inadequate lymph node sampling (<12 regional lymph nodes removed), lymphovascular invasion (LVI), perineural invasion (PNI), and obstruction or perforation at diagnosis. Given the uncertainty surrounding the benefit of AC in rectal cancer and the lack of data regarding AC use following short course RT, we conducted a population-based analysis of patients at the British Columbia Cancer Agency (BCCA). The main goals were to 1) describe patterns of AC use in stage II rectal cancer following preoperative short course RT, 2) determine whether AC impacted disease-specific survival (DSS), relapse-free

Page 4 of 15

ACCEPTED MANUSCRIPT survival (RFS), and OS, and 3) determine if clinical features used to risk stratify stage II colon cancer patients may be applied to those with stage II rectal cancer. Methods: Description of the Study Setting

RI PT

The BCCA is a province-wide agency that delivers publicly funded cancer care to nearly 4.7 million people in British Columbia (BC), Canada. The agency is comprised of 5 comprehensive, regional cancer centers that provide a full range of oncologic care. The BCCA Gastrointestinal Cancer Outcomes Unit (GICOU) prospectively collects demographic, disease, treatment, and outcome-related data on all patients referred to the

SC

BCCA. As the sole provider of radiation services in BC, the BCCA GICOU database is able to reliably capture population-based data and outcomes for all cases of rectal cancer that received RT as part of their management.

M AN U

Description of the Patient Population

After obtaining approval from the institutional research ethics board, the GICOU database was queried for all patients diagnosed with rectal cancer between January 1, 1999 and December 31, 2009 who were treated with preoperative short course RT in the province of BC. Only patients with pathologic stage II rectal cancer (ypT3/ypT4 and ypN0) after short course RT and surgical resection were included. Individuals diagnosed with

Definitions of Treatment

TE D

prior malignancies except non-melanoma skin cancers within the past 5 years were excluded.

Short course RT was delivered at a dose of 2500 cGy in 5 fractions without concurrent chemotherapy. Patients were considered to have been treated with AC if they received ≥1 cycle of fluoropyrimidine

EP

chemotherapy post-operatively. During the time of the study, provincial treatment guidelines specified that 2

patients with stage II rectal cancer are offered 6 months of either 5-fluorouracil (5-FU), consisting of 400 mg/m 2

AC C

intravenous (IV) bolus followed by a continuous IV infusion of 2400 mg/m of 5-FU over 46 hours every 2 weeks, 2

or capecitabine at a dose of 1250 mg/m orally every 12 hours on days 1 to 14 of each 21 day cycle. Definitions of Key Covariates

The Eastern Cooperative Oncology Group (ECOG) performance status was used to characterize functional status of patients. This was ascertained from the patient’s chart within 1 month of referral to the BCCA.

15

Staging was based on the AJCC sixth edition cancer staging manual.

16

High risk features were defined

apriori as pT4 tumor, poor differentiation, inadequate (<12) lymph node sampling, LVI, PNI, and obstruction or

Page 5 of 15

ACCEPTED MANUSCRIPT perforation at diagnosis.

10,17

Tumor differentiation was assigned at time of initial diagnosis. CEA was assessed for

association with benefit from AC but not included as a high risk feature in models. Statistical Analysis Comparisons of clinical characteristics were performed using the Student t test for continuous variables 2

RI PT

and Fisher exact or χ test for categorical variables. DSS was defined as the interval from date of diagnosis to date of rectal cancer related death, RFS was defined as the interval from date of diagnosis to date of recurrence or death from rectal cancer, and OS was defined as the interval from date of diagnosis to date of death from any cause. DSS and RFS were considered co-primary end-points because they were less likely to be affected by

SC

competing causes of death unrelated to cancer. Patients who were alive at the time of last follow-up were censored. Survival distributions were plotted using the Kaplan-Meier method and compared using the log-rank

M AN U

test. Multivariate Cox proportional hazard models for DSS, RFS, and OS were constructed. Age, gender, and ECOG (0 and 1 vs ≥2) were entered into a stepwise forward selection, with AC as the main predictor variable. Patients were stratified by presence of high risk features due to the proportional hazards assumption not being satisfied. All other variables satisfied proportional hazards assumptions. Subgroup analysis was subsequently performed in subsets with >30 patients. Only patients with data for all variables in the models were included in

TE D

multivariate analysis. A two-sided p-value of <0.05 was considered significant. Analysis was performed with Graph Pad Prism software version 5.01 and SPSS version 14.0. Results: Baseline Characteristics

EP

Of 851 patients with pathologic stage II rectal cancer, 330 underwent preoperative short course RT. Within this population, 123 (37%) patients received AC. Ninety-one patients (74%) received 5-FU, 29 (24%)

AC C

capecitabine, and 3 (2%) alternate agents/combinations. As described in Table 1, patients treated with AC were younger (median age 61 vs 73, P<0.0001), reported better ECOG scores (P<0.0001), and were more likely to have high risk features (71% vs 34%; P<0.0001). There were no differences in tumor histology, margin status, rate of total mesorectal excision, or distance from anal verge between AC and non-AC patients. No single high risk feature was significantly different between groups, but preoperative CEA showed a trend towards being abnormal more frequently in those receiving AC (P=0.098). Median follow up was 8.57 years in the AC arm and 7.92 years in the non-AC arm. Median time from the completion of radiation until surgical resection was 8 days in the AC arm and 8 days in the non AC arm (P=0.91).

Page 6 of 15

ACCEPTED MANUSCRIPT Survival Analysis As shown in Figure 1, patients treated with AC had improved DSS (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.36-0.94; P=0.028), RFS (HR 0.62; CI 0.39-0.98; P=0.043), and OS (HR 0.42; CI 0.300.59; P<0.0001) in univariate analysis. Median survival times were not reached for DSS or RFS; however, median

RI PT

OS was 11.71 years and 7.68 years in the AC and non-AC arms, respectively. Multivariate Model

Figure 2 summarizes the multivariate analysis for the entire cohort and subgroups. After adjusting for age, gender, ECOG, and the presence of any one high risk feature, the benefit of AC observed in univariate analysis

SC

did not persist for DSS (HR 0.83; CI 0.43-1.61; P=0.58), RFS (HR 0.82; CI 0.44-1.50; P=0.51), and OS (HR 0.62; CI 0.37-1.03; P=0.064). In subgroup analysis, however, those patients with ≥2 high risk features and received AC

M AN U

experienced improved DSS (HR 0.25; CI 0.070-0.89; P=0.033), RFS (HR 0.24; CI 0.065-0.85; P=0.027), and OS (HR 0.22; CI 0.069-0.70; P= 0.011) when compared to those who did not receive AC. Poor differentiation, distance to the anal verge (online supplement - Table 2) and inadequate lymph node sampling did not impact DSS, RFS or OS, while patients treated with AC who had LVI/PNI (HR 0.34; CI 0.14-0.88; P=0.026) or an elevated preoperative CEA (≥4 µg/L) (HR 0.23; CI 0.063-0.83; P=0.025) experienced improved OS, but not DSS

Discussion:

TE D

and RFS.

This study represents one of the largest population-based evaluations of AC in stage II rectal cancer after preoperative short course RT. Our findings indicate that only 37% of patients received AC and among these, the

EP

majority did not appear to derive significant benefit from fluoropyrimidine based AC. By considering clinical factors conventionally used to risk-stratify stage II colon cancer, we identified a subset of stage II rectal cancer patients,

AC C

specifically those with ≥2 high risk features, who experienced improved outcomes when treated with AC. A major challenge with interpreting the adjuvant rectal cancer literature is the heterogeneity in treatment options and differences in clinical trial designs. The introduction of total mesorectal excision and the transition from postoperative to preoperative RT delivery have improved rectal cancer outcomes but also made the interpretation of AC trials that preceded these advances challenging, particularly when the majority of these trials focused on those receiving CRT rather than short course RT.

6,7,18,19

Although most prior studies failed to

demonstrate any benefits from adjuvant fluoropyrimidines, the Adore and AIO-04 trials recently showed that the addition of adjuvant oxaliplatin to 5-FU improved DFS.

8,20,21

While no differences were detected among stage II

Page 7 of 15

ACCEPTED MANUSCRIPT cases specifically, the Adore study was a phase II trial with only a small sample of 123 stage II patients. Interestingly in the AIO-04 trial, patients with clinical N0 disease appeared to derive benefit from adjuvant oxaliplatin when compared to fluoropyrimidine alone, but pathologic N0 patients did not. Given that the data concerning benefits of oxaliplatin remain uncertain, certain jurisdictions, including BC,

RI PT

do not uniformly fund or provide access to adjuvant oxaliplatin for stage II rectal cancer patients. Therefore, our emphasis on evaluating the role of fluoropyrimidines is clinically relevant since the current standard of care for early stage rectal cancer in many centers continues to be fluoropyrimidines alone.

Unlike colon cancer, a noteworthy finding from our analysis is that AC benefit in rectal cancer was limited 10,11

This is in contrast to our understanding of colon cancer whereby the

SC

to those with ≥2 high risk factors.

presence of any one poor prognostic feature is sufficient to warrant the use of AC.

10

While univariate analysis

M AN U

showed a difference in outcomes for the entire cohort based on AC receipt, this finding likely reflects selection bias since patients who received AC were younger, had lower ECOG, and potentially experienced less comorbidity burden than non-AC patients. Upon controlling for known prognostic factors in the multivariate analysis, the survival differences for the entire cohort were no longer significant. Unfortunately, we were unable to correct for patient comorbidities, chemotherapy completion rates/dose intensity, or the reason patients in the non-AC arm

influenced outcomes.

TE D

did not undergo AC as this information was not available for the entire cohort. These factors may have also

It is also important to note that we were unable to evaluate each high risk factor individually because of limited statistical power. Prior literature suggests that pT4 disease may derive the most benefit from AC in stage II

EP

colon cancer, but there were only 6 patients with pT4 rectal tumors in the current study.

22

This is likely because

these patients underwent CRT instead of RT alone and thus were excluded from our analysis. Despite this

AC C

limitation, our sample size of 330 patients is one of the largest population-based studies assembled for stage II rectal cancer following short course RT. This is further strengthened by the long follow up of nearly 8 years in both study arms.

While this analysis addresses an important question regarding stage II rectal cancer, it cannot be extrapolated to patients treated with CRT, where tumor down staging makes it difficult to assess a patient’s true nodal status. Over 20% of patients treated with CRT with clinical N0 disease staged prior to preoperative therapy have undetected mesorectal nodal involvement.

23

We used pathologic staging as it more accurately reflects nodal

status. Following short course radiotherapy, there can be tumor down staging, but this is typically in the setting of

Page 8 of 15

ACCEPTED MANUSCRIPT delayed surgery.

24,25

In our study patients had surgical resection a median of 8 days following RT and likely had

minimal downstaging, resulting in a more accurate assessment of nodal risk.

26

In patients who are clinically node

negative, the preferential use of short course RT could confirm node negative status and thus avoid AC if no high risk features are present. If CRT was employed in the same clinical scenario, there may be more trepidation about

RI PT

withholding AC due to a lack of confidence in accurate mesorectal staging. Due to the timing of our cohort, some patients were likely classified as stage II that would classified as th

stage IIIA or IIIB in the 7 edition of AJCC. We were unable to retrospectively review pathology specimens to determine the number of patients affected by this change. These patients could have tumor deposits in the

SC

subserosa, mesentery, or non peritonealized pericolic or perirectal tissues without regional nodes and would now 27

receive a nodal score of N1c. . In addition, patients who had a delayed time from RT until surgery, may have had

M AN U

some tumor/nodal down staging. The inclusion of these patients is a confounding factor that we were unable to control. Both of these groups would be at an elevated risk of recurrence compared to other stage 2 patients and may have confounded our results if we had shown benefit to AC. Given that we failed to show AC provided benefit even with the inclusion of these high risk patients, we believe most stage II patients lack benefit from AC. In summary, much of the literature supporting AC use in rectal cancer is from studies that included post5

TE D

operative RT or preoperative RT given concurrently with chemotherapy. The only RCT assessing the benefit of 9

AC following preoperative short course RT failed to fully accrue. This population-based study provides evidence that fluoropyrimidine AC following preoperative short course RT is of limited benefit in stage II rectal cancer in the absence of clinicopathologic risk factors, but it may confer improved outcomes in patients with a ≥2 high risk

EP

features. As with stage II colon cancer, a risk-stratified approach in the management of stage II rectal cancer may

AC C

minimize unnecessary use of fluoropyrimidine AC.

Disclosures:

The authors have no conflicts of interest to declare.

Page 9 of 15

ACCEPTED MANUSCRIPT References: 1.

Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04. J. Clin. Oncol. 2012;30(31):3827-33.

2.

RI PT

doi:10.1200/JCO.2012.42.9597.

Siegel R, Burock S, Wernecke K, et al. Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the

3.

SC

Berlin Cancer Society. BMC Cancer 2009;9:50. doi:10.1186/1471-2407-9-50.

Bujko K, Nowacki MP, Nasierowska-Guttmejer a., Michalski W, Bebenek M, Kryj M. Long-term results of a

M AN U

randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br. J. Surg. 2006;93:1215-1223. doi:10.1002/bjs.5506. 4.

Latkauskas T, Pauzas H, Gineikiene I, et al. Initial results of a randomized controlled trial comparing clinical and pathological downstaging of rectal cancer after preoperative short-course radiotherapy or longterm chemoradiotherapy, both with delayed surgery. Color. Dis. 2012;14:294-298. doi:10.1111/j.1463-

5.

TE D

1318.2011.02815.x.

Petersen S, Harling H, Kirkeby L, Mocellin S. Postoperative adjuvant chemotherapy in rectal cancer operated for cure . ( Review ). 2012;(3).

6.

Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality therapy improves disease-free

EP

survival in patients with carcinoma of the rectum: NSABP R-03. J. Clin. Oncol. 2009;27(31):5124-30.

7.

AC C

doi:10.1200/JCO.2009.22.0467.

Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J. Clin. Oncol. 2012;30(16):1926-33. doi:10.1200/JCO.2011.40.1836.

8.

Breugom AJ, Swets M, Bosset J-F, et al. Adjuvant chemotherapy after preoperative (chemo)radiotherapy and surgery for patients with rectal cancer: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;2045(14):1-8. doi:10.1016/S1470-2045(14)71199-4.

9.

Breugom AJ, van Gijn W, Muller EW, et al. Adjuvant chemotherapy for rectal cancer patients treated with

Page 10 of 15

ACCEPTED MANUSCRIPT preoperative ( chemo ) radiotherapy and total mesorectal excision : a Dutch Colorectal Cancer Group ( DCCG ) randomized phase III trial †. Ann. Oncol. 2015;(October 2013):1-6. doi:10.1093/annonc/mdu560. 10.

Schmoll HJ, Van Cutsem E, Stein A, et al. Esmo consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann. Oncol.

RI PT

2012;23(10):2479-2516. doi:10.1093/annonc/mds236. 11.

Network NCC. Rectal Cancer. NCCN Clin. Pract. Guidel. Oncol. - Rectal Cancer 2015.

12.

O’Connor ES, Greenblatt DY, Loconte NK, et al. Adjuvant Chemotherapy for Stage II Colon Cancer With

13.

SC

Poor Prognostic Features. J. Clin. Oncol. 2011;29(25):3381-3388. doi:10.1200/JCO.2010.34.3426. Kumar A, Kennecke HF, Renouf DJ, et al. Adjuvant chemotherapy use and outcomes of patients with high-

14.

M AN U

risk versus low-risk stage II colon cancer. Cancer 2015;121(4):527-534. doi:10.1002/cncr.29072. Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J. Clin. Oncol. 2004;22(10):1797-1806. doi:10.1200/JCO.2004.09.059. 15.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative

TE D

Oncology Group. Am. J. Clin. Oncol. 1982;5(6):649-55. Available at:

http://www.ncbi.nlm.nih.gov/pubmed/7165009. Accessed January 18, 2015. 16.

Greene F, Page D, Fleming I, et al., eds. American Joint Committee on Cancer Staging Manual. 6th ed.

17.

EP

New York, New York: Springer-Verlag; 2002.

Benson AB, Schrag D, Somerfield MR, et al. American Society of Clinical Oncology recommendations on

AC C

adjuvant chemotherapy for stage II colon cancer. J. Clin. Oncol. 2004;22(16):3408-3419. doi:10.1200/JCO.2004.05.063. 18.

Kapiteijn E, Putter H, Van De Velde CJH. Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br. J. Surg. 2002;89(9):11421149. doi:10.1046/j.1365-2168.2002.02196.x.

19.

Heald R, Moran B, Ryall R, Sexton R, MacFarlane J. Rectal cancer. The Basingstoke Experience of Total Mesorectal Excision, 1978-1997. Arch. Surg. 1998;133:894-899.

20.

Hong YS, Nam B-H, Kim K-P, et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and

Page 11 of 15

ACCEPTED MANUSCRIPT leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an open-label, multicentre, phase 2, randomised controlled trial. Lancet. Oncol. 2014;2045(14):1-9. doi:10.1016/S1470-2045(14)70377-8. 21.

Rödel C, Graeven U, Fietkau R, et al. Oxaliplatin added to fluorouracil-based preoperative

RI PT

chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer ( the German CAO / ARO / AIO-04 study ): final results of the multicentre , open-label , randomised , phase 3 trial. Lancet Oncol. 2015;16:979-989.

Kumar A, Kennecke HF, Renouf DJ, et al. Adjuvant chemotherapy use and outcomes of patients with high-

SC

22.

risk versus low-risk stage II colon cancer. Cancer 2015;121(4):527-534. doi:10.1002/cncr.29072. Guillem JG, Díaz-González J a., Minsky BD, et al. cT3N0 rectal cancer: Potential overtreatment with

M AN U

23.

preoperative chemoradiotherapy is warranted. J. Clin. Oncol. 2008;26(3):368-373. doi:10.1200/JCO.2007.13.5434. 24.

Pettersson D, Holm T, Iversen H, Blomqvist L, Glimelius B, Martling a. Preoperative short-course radiotherapy with delayed surgery in primary rectal cancer. Br. J. Surg. 2012;99(4):577-583.

25.

TE D

doi:10.1002/bjs.7796.

Pettersson D, Lörinc E, Holm T, et al. Tumour regression in the randomized Stockholm III Trial of radiotherapy regimens for rectal cancer. Br. J. Surg. 2015;102(8):972-978. doi:10.1002/bjs.9811.

26.

Marijnen BC a M, Nagtegaal ID, Kranenbarg EK, Hermans J, Velde CJH Van De, Leer JWH. No

EP

Downstaging After Short-Term Preoperative Radiotherapy in Rectal Cancer Patients. J. Clin. Oncol.

27.

AC C

2001;19(7):1976-1984.

Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A, eds. American Joint Committee on Cancer Staging Manual. 7th ed. New York, New York: Springer-Verlag; 2009. Available at: http://www.springer.com/us/book/9780387884400.

Figure Captions: Figure 1. Kaplan-Meier survival curves demonstrating (A) disease-specific, (B) relapse-free, and (C) overall survival.

Page 12 of 15

ACCEPTED MANUSCRIPT

Figure 2. Multivariate analysis of (A) disease-specific, (B) relapse-free, and (C) overall survival.

Footnotes for figure 2:

AC C

EP

TE D

M AN U

SC

No. = number, HR = hazard ratio, CI = confidence interval.

RI PT

Abbreviations: LVI= lymphovascular invasion, CEA = carcinoembryonic antigen, AC = adjuvant chemotherapy,

Page 13 of 15

ACCEPTED MANUSCRIPT Table 1. Baseline population characteristics.

Median Age at Diagnosis (Years) ≥70 Years Old Male Median time from Radiation to Surgery Any High Risk Feature Any 2 High Risk Features

Adjuvant Chemotherapy (N=123) No. %

No Adjuvant Chemotherapy (N=207) No. %

61 25 79

73 124 131

87 23

Range (33-84) 20.3% 64.2% 8 days 70.7% 18.7%

71 32 4 16

57.7% 26.0% 3.3% 13.0%

66 62 35 44

Range (28-95) 59.9% 63.3% 8 days 34.3% 16.9%

<0.0001 <0.0001 0.86 0.91 <0.0001 0.68

31.9% 30.0% 16.9% 21.3%

<0.0001

203 4

98.1% 1.9%

0.82

71 35

3 4

M AN U

T Category

SC

ECOG 0 1 ≥2 Unavailable

121 2

98.4% 1.6%

P-value

RI PT

Baseline Characteristic

Regional Lymph Nodes Removed During Surgery <12 Regional Lymph Nodes Removed ≥12 Regional Lymph Nodes Removed Well Differentiated Moderately Differentiated Poorly Differentiated

58.5% 41.5%

111 96

53.6% 46.4%

0.39

6 92 18

4.9% 74.8% 14.6%

17 167 20

8.2% 80.7% 9.7%

0.21

17 72 31

13.8% 58.5% 25.2%

21 126 55

10.1% 60.9% 26.6%

0.60

97 13 109

90.9% 11.8% 88.6%

158 31 178

83.6% 16.4% 86.0%

11

8.9%

27

13.0%

119 4

96.7% 3.3%

197 10

95.2% 4.8%

0.49

28 55

22.8% 44.7%

60 73

29.0% 35.3%

0.098

6 117 12 111

4.9% 95.1% 9.8% 90.2%

13 194 31 176

6.3% 93.7% 15.0% 85.0%

TE D

Tumor Differentiation

72 51

Distance from Anal Verge Upper Rectum (11-15 cm) Mid Rectum (5.1-10.9 cm) Distal Rectum (≤5 cm)

Surgery Details

AC C

EP

TME Completed TME Not Completed Microscopic Margins >1 mm Microscopic Margins Positive or ≤1 mm

0.28 0.28

Tumor Histology

Adenocarcinoma Mucinous Adenocarcinoma

Preoperative CEA CEA ≥4 ng/mL CEA <4 ng/mL

Other High Risk Features Perineural Invasion Present Perineural Invasion Absent Lymphovascular Invasion Present Lymphovascular Invasion Absent

0.78 0.23 Page 14 of 15

ACCEPTED MANUSCRIPT Clinical Obstruction / Perforation at Diagnosis

4

3.3%

4

1.9%

0.70

No. = number, ECOG = Eastern Cooperative Oncology Group Performance Status,

AC C

EP

TE D

M AN U

SC

RI PT

T= TNM Tumor Score, CEA = carcinoembryonic antigen, TME = total mesorectal excision

Page 15 of 15

ACCEPTED MANUSCRIPT

Table 2. Subgroup analysis

Subgroup

OS Events/Patients Without Event

OS HR (95% CI)

Pvalue

DSS Events/Patients Without Event

DSS HR (95% CI)

All Patients (N=270)

109/161

0.62 (0.37-1.03)

0.064

55/215

0.83 (0.43-1.61)

0.58

Age <70 (N=152)

38/114

0.49 (0.26-0.94)

0.032

21/131

0.64 (0.27-1.51)

Age ≥ 70 (N =118)

71/47

0.69 (0.32-1.49)

0.35

34/84

1.12 (0.43-2.90)

Elevated pre-operative CEA (≥4µg/L) (N =76)

33/43

0.23 (0.063-0.83)

0.025

16/60

0.48 (0.12-2.01)

Any High Risk Feature (N=188)

85/103

0.63 (0.36-1.10)

0.10

43/145

Low Risk (N =82)

24/58

0.54 (0.16-1.84)

0.32

≥2 High Risk Features (N=49)

27/22

0.22 (0.069-0.70)

0.011

Poorly Differentiated Tumor (N =34)

16/18

0.49 (0.13-1.92)

0.31

Lymphovascular or Perineural Invasion (N=51)

26/25

0.34 (0.14-0.88)

0.026

< 12 nodes removed (N=154)

71/83

0.60 (0.32-1.11)

Upper Rectum (11-15 cm) (N =33)

11/21

0.21 (0.042-1.06)

Mid Rectum (5-10.9 cm) (N =164)

70/94

Distal Rectum (<5 cm) (N=68)

26/42

RFS Events/Patients Without Event

RFS HR (95% CI)

Pvalue

61/209

0.82 (0.44-1.50)

0.51

0.31

25/127

0.59 (0.27-1.30)

0.19

0.82

36/82

1.45 (0.59-3.57)

0.42

0.32

17/59

0.47 (0.12-1.93)

0.30

0.85 (0.41-1.74)

0.65

46/142

0.94 (0.47-1.89)

0.86

12/70

0.39 (0.078-1.97)

0.26

15/67

0.50 (0.13-1.91)

0.31

16/32

0.25 (0.070-0.89)

0.033

16/32

0.24 (0.065-0.85)

0.027

9/25

0.53 (0.13-2.18)

0.37

9/25

0.52 (0.13-2.12)

0.37

15/36

0.60 (0.20-1.79)

0.36

15/36

0.56 (0.19-1.64)

0.29

37/117

0.74 (0.34-1.61)

0.44

40/114

0.81 (0.28-2.31)

0.69

0.059

4/28

0.27 (0.025-2.85)

0.27

4/28

0.27 (0.025-2.92)

0.28

0.95 (0.53-1.71)

0.86

35/129

1.51 (0.68-3.33)

0.31

38/126

1.59 (0.74-3.40)

0.24

0.23 (0.066-0.82)

0.024

15/53

0.28 (0.059-1.30)

0.10

18/50

0.35 (0.098-1.28)

0.11

RI PT

SC

M AN U

TE D

EP

AC C

0.10

Pvalue

OS = overall survival, DSS = disease specific survival, RFS = relapse-free Survival, HR = hazard ratio

ACCEPTED MANUSCRIPT 100 80 60

20

Adjuvant Chemotherapy (n = 123) P = .0278

0 0

Percent Survival

B

No Adjuvant Chemotherapy (n = 207)

5

Years 123 207

100 131

80 60 40

15

20

1 3

0 0

TE D

Adjuvant Chemotherapy (n = 123) No Adjuvant Chemotherapy (n = 207)

P = .0426

5

123 207

93 120

EP

0 0

10

15

20

1 3

0 0

Years 23 14

100

Percent Survival

AC C

C

23 15

100

20

Number at Risk Adjuvant Arm No Adjuvant Arm

10

M AN U

Number at Risk Adjuvant Arm No Adjuvant Arm

RI PT

40

SC

Percent Survival

A

80 60 40 20

Adjuvant Chemotherapy (n = 123) No Adjuvant Chemotherapy (n = 207)

P < .0001

0 0 Number at Risk Adjuvant Arm No Adjuvant Arm

5

10

15

20

1 3

0 0

Years 123 207

100 131

23 15

ACCEPTED MANUSCRIPT

SC

RI PT

A

AC C

C

EP

TE D

M AN U

B