Accepted Manuscript

Impact of delay in adjuvant oxaliplatin-based chemotherapy for stage III colon cancer

Renata D’Alpino Peixoto, Aalok Kumar, Caroline Speers, Daniel Renouf, Hagen F.Kennecke, Howard J. Lim, Winson Y. Cheung, Barbara Melosky, Sharlene Gill

PII: S1533-0028(14)00117-0

DOI: 10.1016/j.clcc.2014.10.002

Reference: CLCC 175

To appear in: Clinical Colorectal Cancer

Received Date: 10 August 2014

Revised Date: 16 October 2014

Accepted Date: 27 October 2014

Please cite this article as: D’Alpino Peixoto R, Kumar A, Speers C, Renouf D, Kennecke HF, Lim HJ,Cheung WY, Melosky B, Gill S, Impact of delay in adjuvant oxaliplatin-based chemotherapy for stage IIIcolon cancer, Clinical Colorectal Cancer (2014), doi: 10.1016/j.clcc.2014.10.002.

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Title: Impact of delay in adjuvant oxaliplatin-based chemotherapy for stage III

colon cancer

Authors: Renata D’Alpino Peixoto, Aalok Kumar, Caroline Speers, Daniel Renouf,

Hagen F. Kennecke, Howard J. Lim, Winson Y. Cheung, Barbara Melosky, Sharlene Gill

Division of Medical Oncology, University of British Columbia,

British Columbia Cancer Agency, Vancouver, Canada

Address Correspondences to:

Renata D’Alpino Peixoto, MD

British Columbia Cancer Agency

600 West 10th Avenue

Vancouver, BC, Canada, V5Z 4E6

Tel: 604.877.6000 ; Fax: 604.877.0585

Email: renatadalpino@gmail.com

Previously presented as a poster at 2014 ASCO Annual Meeting

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MicroAbstract

The belief that adjuvant chemotherapy (AC) for colon cancer must be commenced within

8 weeks is somewhat arbitrary. In our population-based study including 635 patients with

stage III colon cancer, we have analyzed the impact of delay in oxaliplatin-based AC

beyond 8 weeks on recurrence-free survival (RFS) and cancer-specific survival (CSS).

Administration of oxaliplatin-based AC beyond 8 weeks was not associated with inferior

outcomes.

Abstract

Background: Less than 8 weeks has been recommended as the optimal time to initiate

adjuvant chemotherapy (AC) based upon 2 meta-analyses suggesting worse survival with

delayed AC. However, neither study included patients treated with an oxaliplatin-based

chemotherapy. We aim to investigate the impact of delay in initiating oxaliplatin-based

chemotherapy on recurrence-free survival (RFS) and cancer-specific survival (CSS) for

stage III colon cancer.

Methods: Records of patients who initiated oxaliplatin-based AC for stage III colon

cancer between 2006 and 2011 at the British Columbia Cancer Agency were

retrospectively reviewed. Cox proportional models were used to analyze the impact of

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time to AC (TTAC) on RFS and CSS. TTAC was categorized into ≤ 8 weeks (G1) and >

8 weeks (G2).

Results: 635 pts were included (G1=291; G2=344). Median time from surgery to

initiation of AC was 8.3 weeks. At a median follow-up of 57.9 months, 176 patients

(27.7%) have recurred and 118 (18.6%) have died. 5-years RFS was 70.9% (95% CI

65.2-76.5) for G1 and 72.1% (95%CI 67.2-77) for G2. 5-years CSS was 82% for G1

(95% CI 87.09-76.91) and 82.8% for G2 (95% CI 78.30-87.30). On multivariate analysis,

delayed TTAC did not have prognostic significance on either RFS (HR = 1.08, p = 0.609)

or CSS (HR = 1.02, p = 0.893).

Conclusion: In our population-based study, TTAC following stage III colon cancer

resection did not have an impact on RFS or CSS. Contrary to most of the existing data

which is primarily based on 5-fluorouracil-based AC, delay of oxaliplatin-based AC

beyond 8 weeks did not appear to be associated with inferior outcomes.

Keywords: Colon cancer, adjuvant, chemotherapy, oxaliplatin, surgery

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Introduction

Colorectal cancer remains the third most commonly diagnosed malignancy with

approximately 136,830 new cases diagnosed annually in the United States. Despite recent

decline in death rates for CRC, it is still responsible for approximately 10% of all cancer-

related deaths in North America1. About one-third of all patients presenting with CRC

will have node-positive disease2 with five-year survival rates varying from 73% in stage

IIIA (T1-2 N1) to only 28% in stage IIIC disease (N2)3.

Surgical resection followed by adjuvant chemotherapy (AC) is the standard of care for

patients with stage III colon cancer. The superiority of adding oxaliplatin to adjuvant 5-

fluorouracil (5-FU) and leucovorin (LV) backbone therapy after resection of stage III

colon cancer has been demonstrated in two pivotal randomized trials4,5 as well as in a

large retrospective study in the community setting6. While in both randomized trials

patients initiated AC within 8 weeks of surgical resection, the observational analysis

included patients whose chemotherapy was started within 120 days of surgical resection.

Nonetheless, outcomes were not compared according to time from surgery to initiation of

AC.

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The belief that AC for colon cancer must be commenced within 8 weeks is somewhat

arbitrary, and mainly based on clinical trial protocols in this setting4,5,7-9. However, it

remains unknown whether there is a true time cutoff beyond which adjuvant treatment is

of no value. In routine clinical practice, adherence to the 8-week time frame may be

difficult due to postoperative complications, delays in referral to medical oncologists, and

waiting lists to initiate chemotherapy10-13. As a consequence of those barriers to early

commencement of AC, medical oncologists are typically confronted with the dilemma of

whether they should consider AC beyond the customary 8-week window.

An association between delaying chemotherapy with LV-modulated 5-FU beyond 8

weeks and increased risk of recurrence and/or death has been suggested in some

retrospective analyses14-17. In addition, two meta-analyses have addressed the same

question. The first showed that delaying chemotherapy beyond 8 weeks was associated

with a significantly higher risk of death (relative risk 1.20, 95% confidence interval [CI]

1.15 to 1.26), although disease-free survival (DFS) was not significantly different18. The

second demonstrated that a 4-week increase in time to AC (TTAC) was associated with a

significant decrease in both overall survival (HR, 1.14; 95% CI, 1.10-1.17) and DFS (HR,

1.14; 95% CI, 1.10-1.18)19. So far, only one small retrospective study with 102 patients

has investigated the impact of delaying adjuvant FOLFOXon time to tumor recurrence20.

Time from surgery to AC was not a predictor of recurrence (p = 0.19), although there was

a non-significant trend toward higher risk of systemic recurrence when the delay in AC

initiation was longer than 12 weeks (p = 0.068).

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The aim of our study was to further investigate the impact of delay in initiating

oxaliplatin-based chemotherapy beyond eight weeks on recurrence-free survival (RFS)

and cancer-specific survival (CSS) in stage III colon cancer.

Methods

Characteristics of the Study Setting and Study Population

The British Columbia Cancer Agency (BCCA) is a provincial-based cancer control

program that is responsible for funding and providing cancer treatment to approximately

4.5 million residents in British Columbia, Canada. The agency is comprised of five

comprehensive, regional cancer centers that are distributed across different catchment

areas of the province so that access to care can be distributed as equitably as possible to a

diverse population, regardless of financial capabilities or geographical location. All of the

centers offer a full range of quality cancer services and programs including ambulatory

oncology clinics, chemotherapy suites, radiation facilities, surgical services, inpatient

units, palliative care, and the opportunity to participate in major oncology clinical trials

for the estimated 15,000 to 20,000 new patients who are referred to the BCCA annually.

The BCCA Gastrointestinal Cancers Outcomes Database prospectively collects

demographic, disease, treatment and outcome data for patients who reside in the province

at the time of their diagnosis of a gastrointestinal cancer and who are referred to the

BCCA for management. Various clinico-pathological factors are available from this

database, such as age, sex, performance status, tumor site and histology, date and type of

surgery performed, stage at diagnosis, extent of lymph node sampling, presence of

lymphovascular invasion (LVI) or perineural invasion (PNI), presentation with

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perforation of obstruction, details of systemic and radiation therapy received, and date of

relapse and death.

Records of patients who initiated AC with either 5-FU and LV or capecitabine plus

oxaliplatin for stage III colon cancer between 2006 and 2011 at the BCCA were reviewed.

Six-hundred and fifty-nine patients were identified through the BCCA Gastrointestinal

Cancers Outcomes Database. Twenty patients were excluded from the analysis due to

evidence of metastatic disease prior to embarking on chemotherapy while 14 patients

were excluded due to rectal primaries. The final cohort consisted of 635 patients. The

institutional review board of the BCCA approved this study.

Statistical analyses

TTAC was categorized into two groups: within 8 weeks (G1) and beyond 8 weeks (G2).

Differences in baseline characteristics between the two groups (G1 and G2) were

evaluated with descriptive statistics. Variations in baseline parameters across the different

groups (G1 and G2) were evaluated using the Chi-square test for categorical variables

and the F-test for continuous variables.

RFS was the primary end-point of the study and was measured from the date of surgery

to the date of first documented local or distant recurrence or last follow-up. Patients who

died before experiencing an event were censored at the date of death. CSS was measured

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from the date of surgery to the date of death due to underlying colon cancer. Deaths from

other causes were censored. The 5-years RFS and 5-years CSS were estimated for the

different groups using the Kaplan-Meier method. Differences in survival outcomes were

assessed with the log-rank test.

Multivariate Cox proportional hazards regression models were subsequently fitted to

evaluate the relationship of TTAC on RFS and CSS. The multivariate model was

constructed incorporating the significant prognostic factors found in the univariate

logrank test. They were expressed as hazard ratios (HR) and 95% confidence intervals

(95% CI) for relapse. All tests were two-sided where a p value of <0.05 was considered

statistically significant. SPSS (version 14.0) was used to conduct all of the statistical

analyses.

Results

A total of 635 patients were included in the analysis. Median age was 62 years (range 26

– 80) and 329 (51.8%) patients were male. Baseline characteristics are summarized in

Table 1.

Median lymph nodes examined and involved were 15 (range 3-98) and 3 (range 1-61),

respectively. Median TTAC was 8.3 weeks (SD 18.58) (Figure 1). 291 patients (45.8%)

commenced AC within 8 weeks (G1) while 344 (54.2%) had their AC started after 8

weeks (G2). Median TTAC was 49 days for G1 (range 26-56) and 68 days for G2 (range

57-201). Chemotherapy regimens included FOLFOX (n=564) and CAPOX (n=71).

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Demographic and clinical characteristics were well balanced between G1 and G2, except

for a predominance of poorly differentiated tumors and younger patients in G1 (Table 1).

No patients died during adjuvant chemotherapy.

At a median follow-up of 57.9 months, 176 pts (27.7%) have recurred and 118 (18.6%)

have died, 104 of them due to colon cancer. 5-years RFS and CSS for the entire cohort

was 71.6% (95% CI 67.88 – 75.32%) and 82.1%, respectively (95% CI 78.58-85.62).

On univariate analysis, higher T stage (T1/2 versus T3 versus T4), higher N stage,

poorly-differentiated grade, presence of LVI, presence of PNI, presentation with

obstruction and presentation with perforation were all significantly associated with worse

RFS (Table 2). Gender, age, presence of mucinous histology and TTAC were not

associated with poor RFS. There was no statistically significant difference in RFS

between G1 and G2 (p=0.604; HR=1.08; medians not reached in either group) (Figure 2).

5-years RFS was 70.9% (95% CI 65.2-76.5) for G1 and 72.1% (95%CI 67.2-77) for G2.

Similarly, CSS was not different according to TTAC (p=0.893; HR=1.02; medians not

reached in either group) (Figure 3). When exploring TTAC as a continuous variable,

results remained similar (CSS: HR=1.00, 95% CI 0.99-1.01, p=0.59; RFS: HR=1.00,

95% CI 0.99-1.01, p=0.461). T stage, N stage, perforation, grade, LVI, PNI and

mucinous features were significantly associated with CCS in univariate analysis (Table 3).

There was a trend towards worse CCS among older patients (p=0.051) and patients

presenting with obstruction (p=0.062). 5-years CCS was 82% for G1 (95% CI 87.09-

76.91) and 82.8% for G2 (95% CI 78.30-87.30).

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On multivariate analysis, T stage, N stage, LVI, obstruction and perforation were

identified as a poor prognostic factor for RFS (Table 2). TTAC did not have prognostic

significance (HR 1.03, p = 0.844). Age older than 65, higher T and N stage, perforation,

LVI and mucinous features were all associated with poor CCS in multivariate analysis

(Table 3). Similar to RFS, delayed AC was not associated with worse CCS (HR = 0.99,

95% CI 0.66-1.47, p=0.965).

Discussion

To the best of our knowledge, this is the largest retrospective study to evaluate the impact

of delayed oxaliplatin-based AC initiation beyond 8 weeks in resected stage III colon

cancer. Important findings have emerged from this retrospective study. First, we have

demonstrated that more than half of our patient population with a universal health

insurance program started AC after 8 weeks. Although large intergroup randomized trials

stipulate that AC commences within 8 weeks of surgery, longer delays are frequently

encountered in clinical practice. Second, in our population-based study TTAC did not

impact on either 5-years RFS or 5-years CCS. Contrary to most of the existing data which

is primarily based on 5-FU-based AC, delay of oxaliplatin-based therapy beyond 8 weeks

was not associated with inferior outcomes.

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Multiple reasons exist to support the early initiation of AC. Prior mice models have

demonstrated that the removal of a primary tumor may lead to early accelerated growth

of micrometastases as well as the stimulation of angiogenesis due to the release of

circulating growth factors21-24. In addition, surgery may suppress cytotoxic T-cell and

natural killer cell activity, enabling the growth of micrometastases25,26. Mathematical

modeling has suggested that the drug sensitivity of tumors is related to their spontaneous

mutation rate, which is obviously a function of time27. Moreover, the effectiveness of a

given chemotherapeutic regimen is inversely proportional to the tumor burden,

suggesting that delaying AC initiation could be detrimental due to increasing tumor size28.

An important question that arises from the current study is why delayed time to 5-FU

based adjuvant chemotherapy was associated with inferior survival in previous studies

but not when oxaliplatin was added to a fluoropyrimidine backbone. It is possible that the

addition of oxaliplatin to a fluoropyrimidine may better eradicate micrometastatic disease

which would otherwise be insensitive to fluoropyrimidine alone at a certain tumor burden.

Another interesting finding was the fact that older patients had similar RFS when

compared to younger ones in the multivariate analysis. However, they had shorter CSS.

We believe that older patients are less likely to undergo metastasectomy or more intense

chemotherapy in the palliative setting.

Clinical data from TTAC in tumor sites other than colon cancer show conflicting results.

While a recent retrospective analysis showed poorer outcomes in high-risk breast cancer

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patients who initiated AC after 60 days29, a study including 1032 patients with lung

cancer showed no impact of TTAC on OS30. Another study in pancreatic cancer showed

that TTAC did not influence OS31. Those disparities in conjunction with our study reveal

that findings from mice or mathematical models are not always reflected in clinical

practice. Because randomized trials evaluating TTAC are unlikely to be undertaken, we

are left with theoretical premises and population-based studies.

The current study has limitations inherent to its retrospective nature. However,

randomized controlled trials to specifically address the question whether delayed AC

compromises outcomes may be considered unethical, highlighting the importance of

population-based data. TTAC is not independent of patient and tumor characteristics, and

therefore an analysis of the impact of TTAC on long-term outcomes may be confounded

by measured and unmeasured covariates. Measured covariates have been adjusted for

through a Cox regression model. However, unmeasured confounders may have an

influence on TTAC as well. There were fewer poorly-differentiated tumors in the G2. Although

tumor differentiation was not a prognostic factor in the present study, this imbalance might have

diminished the ability to detect survival differences between the groups. In addition, we have not

collected information on comorbidities. Although it is reasonable to assume that patients

with comorbid conditions may have increased postoperative complications and recovery

time, thereby leading to delayed TTAC, or may be at higher risk of death from any cause,

we did not consider this to be an important potential confounder in our study since we

reported the results in terms of RFS and CSS.

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In the current study data on either time of hospitalization after surgery or rates of

postoperative complications were not collected. Moreover, we have not analyzed time

from surgery to referral, time from referral to medical oncologist consult or

chemotherapy waitlist. However, reasons for a delay in TTAC have been already

described in previous studies and may be attributed to patient factors such as

postoperative complications or comorbid conditions or health-system logistic factors

including delays in referral or wait times10-13. In addition, we have not determined a time

cut-off beyond which benefit of AC is lost. Because only a small number of patients

received AC after 12 weeks, we could not explore whether such a delay would have an

impact on 5-years RFS or CSS. The elapsed time from surgery beyond which the

increasing tumor burden will eventually surpass the curative potential of the AC remains

to be determined.

In conclusion, our results demonstrate that those patients who initiated oxaliplatin-based

adjuvant chemotherapy beyond the customary 8 weeks had similar 5-year RFS and CCS

when compared to patients who had their chemotherapy started earlier.

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Table 1 – Baseline characteristics

Variable

Total

N=635 (%)

G1

N=291 (%)

G2

N=344 (%)

p value

Age 62 (median) 61 (median) 62.5 (median) 0.002

Gender Female

Male

306 (48.2)

329 (51.8)

141 (48.5)

150 (51.5)

165 (48)

179 (52)

0.902

T stage T1/2

T3

T4

83 (13.1)

418 (65.8)

134 (21.1)

44 (15.1)

187 (64.3)

60 (20.6)

39 (11.3)

231 (67.2)

74 (21.5)

0.371

N stage N1

N2

382 (60.2)

253 (39.8)

176 (60.5)

115 (39.5)

206 (59.9)

138 (40.1)

0.878

Obstruction Yes

No

67 (10.6)

568 (89.4)

29 (10)

262 (90)

38 (11)

306 (89)

0.659

Perforation Yes

No

26 (4.1)

609 (95.9)

9 (3.1)

282 (96.9)

17 (4.9)

327 (95.1)

0.241

Grade Well/moderately

Poorly

518 (81.6)

117 (18.4)

227 (78)

64 (22)

291 (84.6)

53 (15.4)

0.033

LVI Yes 260 (40.9) 166 (57) 209 (60.8) 0.343

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No 375 (59.1) 125 (43) 135 (39.2)

PNI Yes

No

87 (13.7)

548 (86.3)

247 (84.9)

44 (15.1)

301 (87.5)

43 (12.5)

0.339

Mucinous features Yes

No

39 (6.1)

596 (93.9)

270 (92.8)

21 (7.2)

326 (94.8)

18 (5.2)

0.300

TTAC ≤ 8 weeks

> 8 weeks

291 (45.8)

344 (54.2)

___________ ____________ _______

* LVI = lymphovascular invasion; PNI = perineural invasion; TTAC = time to adjuvant

chemotherapy

Table 2 - RFS

Variable Univariate Multivariate

HR 95% CI p HR 95% CI p

Age ≤ 65

> 65

Ref

1.11

0.82-1.50

0.496 ------- -------------

-

-------

Gender Female

Male

Ref

0.82

0.61-1.10

0.191 ------- -------------

-

-------

T stage T1/2 Ref

<0.001 Ref

0.002

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T3

T4

2.69

5.42

1.36-5.32

2.68-10.98

2.13

3.34

1.07-4.24

1.60-6.94

N stage N1

N2

Ref

2.11

1.56-2.84

<0.001 Ref

1.75

1.28-2.38

<0.001

Obstruction No

Yes

Ref

2.18

1.47-3.22

<0.001 Ref

1.73

1.16-2.57

0.007

Perforation No

Yes

Ref

3.40

2.03-5.69

<0.001 Ref

2.28

1.32-3.94

0.003

Grade

Well/moderately

Poorly

Ref

1.44

1.01-2.05

0.042 Ref

1.11

0.77-1.61

0.562

LVI Yes

No

Ref

1.89

1.41-2.54

<0.001 Ref

1.45

1.04-2.01

0.026

PNI Yes

No

Ref

1.69

1.16-2.47

0.006 Ref

1.00

0.66-1.51

0.98

Mucinous features No Ref 0.320 ------- ------------- -------

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Yes

1.33

0.75-2.34

-

Time surgery-chemo ≤ 8 weeks

> 8 weeks

Ref

1.08

0.80-1.45

0.604 Ref

1.03

0.76-1.39

0.844

Table 3 – Cancer-specific survival

Variable Univariate Multivariate

HR 95% CI p HR 95% CI p

Age ≤ 65

> 65

Ref

1.47

0.99-2.16

0.051

1.53

1.03-2.29

0.035

Gender Female

Male

Ref

0.74

0.50-1.09

0.129 ------

-

-------------- -------

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

T stage T1/2

T3

T4

Ref

3.18

8.31

1.15-8.76

2.96-23.29

<0.001 Ref

2.32

4.79

0.83-6.46

1.65-13.83

0.001

N stage N1

N2

Ref

2.76

1.85-4.11

<0.001 Ref

2.06

1.36-3.13

0.001

Obstruction No

Yes

Ref

1.71

0.97-3.02

0.062 Ref

1.28

0.71-2.30

0.403

Perforation No

Yes

Ref

3.67

1.96-6.88

<0.001 Ref

2.26

1.14-4.48

0.02

Grade

Well/moderately

Poorly

Ref

2.08

1.36-3.17

0.001 Ref

1.36

0.86-2.14

0.176

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

LVI Yes

No

Ref

2.42

1.63-3.60

<0.001 Ref

1.63

1.05-2.52

0.026

PNI Yes

No

Ref

2.07

1.30-3.30

0.002 Ref

1.15

0.69-1.93

0.572

Mucinous features No

Yes

Ref

2.49

1.39-4.46

0.002 Ref

2.11

1.15-3.88

0.016

TTAC ≤ 8 weeks

> 8 weeks

Ref

0.97

0.66-1.43

0.893 Ref

0.99

0.66-1.47

0.965

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Figure 1 – Distribution of TTAC in weeks

Figure 2 – Recurrence free survival curve by time from surgery to initiation of

chemotherapy

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

Figure 3 – Cancer-specific survival curve by time from surgery to initiation of

chemotherapy

-- ≤ 8 weeks

-- > 8 weeks

MANUSCRIP

T

ACCEPTED

ACCEPTED MANUSCRIPT

-- ≤ 8 weeks

-- > 8 weeks