Survival Impact of Adjuvant Chemotherapy for Resected Locally Advanced Rectal Adenocarcinoma

Accepted Manuscript Survival impact of adjuvant chemotherapy for resected locally advanced rectal adenocarcinoma Rebecca Y. Tay, Murtaza Jamnagerwalla, Malcolm Steel, Hui-Li Wong, Joseph J. McKendrick, Ian Faragher, Suzanne Kosmider, Ian Hastie, Jayesh Desai, Peter Gibbs, Rachel Wong PII:

S1533-0028(16)30205-5

DOI:

10.1016/j.clcc.2016.09.011

Reference:

CLCC 336

To appear in:

Clinical Colorectal Cancer

Received Date: 28 March 2016 Revised Date:

10 September 2016

Accepted Date: 22 September 2016

Please cite this article as: Tay RY, Jamnagerwalla M, Steel M, Wong H-L, McKendrick JJ, Faragher I, Kosmider S, Hastie I, Desai J, Gibbs P, Wong R, Survival impact of adjuvant chemotherapy for resected locally advanced rectal adenocarcinoma, Clinical Colorectal Cancer (2016), doi: 10.1016/ j.clcc.2016.09.011. 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 PAGE

TITLE Survival impact of adjuvant chemotherapy for resected locally advanced rectal

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adenocarcinoma

AUTHORS AND AFFILIATIONS

Rebecca Y Tay1, Murtaza Jamnagerwalla2, Malcolm Steel2, Hui-Li Wong3-4, Joseph J McKendrick1,5, Ian Faragher6, Suzanne Kosmider6, Ian Hastie7, Jayesh Desai7, Peter

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Gibbs3-4,6-7, Rachel Wong1,3,5. 1

Department of Medical Oncology, Eastern Health, Box Hill, Australia

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Department of Surgery, Eastern Health, Box Hill, Australia

3

Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

4

University of Melbourne, Melbourne, Australia

5

Monash University, Faculty of Medicine, Nursing and Health Sciences, Melbourne,

Australia 6

Western Health, Footscray, Australia

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The Royal Melbourne Hospital, Parkville, Australia

CORRESPONDING AUTHOR

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Rachel Wong, MBBS (Hons), FRACP

Eastern Health, Department of Medical Oncology

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Postal Address: PO Box 94, Box Hill 3128, Australia E-mail: [email protected]

CONFLICT OF INTEREST/DISCLOSURES: None

KEY WORDS Colorectal cancer; Surgery; Post-operative chemotherapy; Pathological complete response; Overall survival

Word count abstract: 280 Word count main text: 2760 1

ACCEPTED MANUSCRIPT MICROABSTRACT

The

benefit

of

adjuvant

fluoropyrimidine-containing

chemotherapy

following

preoperative chemoradiotherapy and surgical resection for locally advanced rectal cancer is uncertain. In this retrospective analysis, no significant relapse free or

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overall survival benefit was associated with adjuvant chemotherapy. However, in the subset of patients who did not achieve a pathological complete response to preoperative chemoradiotherapy, use of adjuvant chemotherapy resulted in a

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significant overall survival benefit.

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ACCEPTED MANUSCRIPT CLINICAL PRACTICE POINTS •

What is already known about this subject? o Adjuvant fluoropyrimidine-containing chemotherapy after preoperative chemoradiotherapy (CRT) and surgical resection for locally advanced

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rectal cancer (LARC) is an accepted standard of care. o The benefit of adjuvant chemotherapy is uncertain, particularly in the modern era whereby preoperative CRT is widely adopted.

o Patients who achieve a pathologic complete response (pCR) following

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preoperative CRT have less loco-regional recurrence and improved overall survival (OS). It is not clear if this subset of patients who already have an excellent prognosis, derive any further benefit from

•

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adjuvant chemotherapy.

What are the new findings?

o In this retrospective analysis:


Adjuvant chemotherapy was did not significantly impact relapse

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free survival compared to surveillance alone (HR 0.93; 95% CI: 0.58–1.51; p=0.78).


Adjuvant chemotherapy did not significantly impact OS benefit compared to surveillance alone (HR 0.62; 95% CI: 0.37–1.05;

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p=0.074).


Adjuvant chemotherapy was associated with a significantly

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improved OS benefit compared to surveillance alone (HR 0.49, 95% CI: 0.28-0.86, p=0.014) in the subset of patients who did not achieve a pCR to preoperative CRT.

•

How might it impact on clinical practice in the foreseeable future? o Patients who fail to achieve a pCR to pre-operative CRT appear to derive the most benefit from the addition of adjuvant chemotherapy o This retrospective study suggests that in patients who do achieve a pCR, adjuvant chemotherapy offers no significant survival advantage and omitting adjuvant chemotherapy may be considered in this select

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ACCEPTED MANUSCRIPT group o Improved clinical and/or pathological markers of recurrence risk and adjuvant therapy benefit following preoperative CRT are required to identify those patients who will benefit most from adjuvant

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chemotherapy.

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ACCEPTED MANUSCRIPT ABSTRACT

Background: Recent

data

has

created

uncertainty

regarding

the

benefit

of

adjuvant

fluoropyrimidine-containing chemotherapy following preoperative chemoradiotherapy

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and surgical resection for locally advanced rectal cancer (LARC). In particular, patients with a pathologic complete response (pCR) may derive no benefit from adjuvant chemotherapy.

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Methods:

This is a retrospective analysis of patients with LARC, diagnosed between 1 January 2003 and 31 December 2014 at three Melbourne health services. Patients were

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identified from the ACCORD database, where a defined data set is prospectively collected on consecutive patients. Patient demographics, pCR rates, postoperative treatment, recurrence and survival were analysed.

Results:

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A total of 717 patients with LARC were identified, of whom 555 (77%) had received preoperative long-course chemoradiation followed by surgery. 452/555 patients (81%) subsequently received adjuvant fluoropyrimidine-based chemotherapy. At a median follow-up of 45.9 months, 95 (21%) patients in the adjuvant chemotherapy

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group and 20 (19%) in the surveillance group had relapsed. Five-year RFS was 77% in the adjuvant chemotherapy group and 71% in the surveillance group with no

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significant difference on univariate analysis (HR 0.93; 95% CI: 0.58–1.51; p=0.780). No significant impact on RFS was seen for either pCR or non-pCR patients. Fiveyear OS was 85% in the adjuvant chemotherapy group and 74% in the surveillance group with a non-significant trend towards OS benefit (HR 0.62; 95% CI: 0.37–1.05; p=0.074). A significant OS benefit favouring adjuvant chemotherapy was seen in the non-pCR subset of patients (HR 0.49, 95% CI: 0.28-0.86, p=0.014).

Conclusion: A high proportion of patients in this routine practice cohort received adjuvant chemotherapy following preoperative treatment and surgery for LARC. Adjuvant chemotherapy administration was associated with a significant improvement in 55

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year OS only in to patients with a non-pCR.

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ACCEPTED MANUSCRIPT INTRODUCTION

Locally advanced rectal cancer (LARC) is defined by either the presence of T3-4 and/or node positive disease in the absence of distal metastases. Patients with LARC are at risk of both local and distant recurrence.1 Preoperative combined

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chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is considered the current standard of care for patients with LARC.2,3 While this multimodality approach improves loco-regional control, sphincter preservation and may downstage

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disease, the impact on overall survival (OS) remains uncertain.4,5

Early adjuvant therapy trials, in the pre-TME era and when radiation was given postoperatively, demonstrated that adjuvant chemotherapy improved survival outcomes

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for patients with LARC.6,7 However, in the current era where concurrent CRT followed by TME is now widely adopted, the utility and survival benefit of adjuvant chemotherapy remains uncertain. Furthermore, the impact of chemotherapy may vary for different patient subsets. Patients who achieve a pathologic complete response (pCR) following preoperative CRT have less loco-regional recurrence and 11

It is not clear if these patients in particular, who already have

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improved OS.8, 9, 10

an excellent prognosis, derive any benefit from adjuvant chemotherapy. The widely variable pCR rates (9-27%) reported in the literature reflect the impact of the quality of pathological examination and possibly the timing of surgery following completion 11,12

This inconsistency does confound

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of preoperative therapy on this endpoint.

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cross study comparisons.

In Australia, adjuvant fluoropyrimidine-containing chemotherapy after preoperative CRT and surgical resection for LARC is an accepted standard of care. This retrospective analysis aims to assess patterns of adjuvant chemotherapy uptake in resected LARC following preoperative CRT and to report relapse-free and overall survival outcomes in patients receiving adjuvant chemotherapy compared to patients undertaking routine surveillance alone. Survival outcomes in the subsets of patients who derive a pCR and those without a pCR following preoperative CRT will also be reported.

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ACCEPTED MANUSCRIPT METHODS

Study population and data accrual

Data from three Melbourne health services; Eastern Health, Royal Melbourne

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Hospital and Western Health, collected within the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD) was utilised. ACCORD is a large multi-centre database where prospectively collected data on colorectal cancer

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patients is recorded.13

A search of ACCORD was performed to identify patients with LARC diagnosed between 1 January 2003 and 31 December 2014 who had received preoperative

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long-course CRT followed by resection of the primary tumour. For this population, the definition of LARC was restricted to T3-4 tumours within 12cm of the anal verge and/or node positive disease. In this select population, OS and relapse free survival (RFS) were analysed in patients who received adjuvant fluoropyrimidine-based chemotherapy compared to patients who had routine surveillance alone. Overall

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survival and RFS outcomes following adjuvant chemotherapy in the subset of patients who achieved pCR to preoperative treatment at the time of surgery was also evaluated.

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Data obtained from ACCORD included patient age, gender, performance status, tumour and nodal stage, uptake and completion of preoperative CRT and

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pathological response to preoperative treatment. pCR was defined as no residual viable tumour at pathological examination as reported by the local pathologist. Staging was based on American Joint Committee on Cancer criteria. Ethical approval was granted by the Eastern Health Ethics Committee (LR44/1314) and Biogrid Australia (201311/1).

Statistical analysis

Relapse free survival was calculated from date of diagnosis to first event (i.e. local recurrence or progression, distant recurrence or death from any cause). Overall survival was calculated from diagnosis to date of death. Patients were censored at 8

ACCEPTED MANUSCRIPT last follow-up. Multivariate analysis was conducted using Cox proportional hazard regression models, with manual backwards step-wise regression techniques applied to identify the independent predictors of OS and RFS. Results were reported as Hazard Ratios (HR) with associated 95% confidence intervals, with Kaplan-Meier curves prepared for OS and RFS, in order to calculate 3-year and 5-year OS and

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RFS rates. P-values of <0.05 were considered statistically significant. Statistical analysis was performed using Stata version 12.1 (StataCorp LP, Texas, USA).

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RESULTS

Patient demographics

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Between 1 January 2003 and 31 December 2014, a total of 1783 patients were diagnosed with rectal cancer at the participating hospitals. Metastatic disease was present in 302 patients (17%) at diagnosis. A further 585 patients were excluded due to early stage disease (T1-2, N0), and 179 patients were excluded due to insufficient staging information. A total of 717 (40%) patients were identified as having locally

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advanced disease. Of this population, 555 patients (77%) received preoperative long-course CRT, median dose, 50Gy for 5 weeks given with concurrent fluoropyrimidine, followed by resection of the primary tumour. A total of 509 patients (92%) completed the full preoperative CRT treatment course. Following surgery,

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452/555 (81%) patients received adjuvant fluoropyrimidine-based chemotherapy.

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103/555 patients (19%) received routine surveillance only. See Figure 1.

Patient demographics in the adjuvant chemotherapy and surveillance groups are listed in Table 1. Adjuvant fluoropyrimidine-based chemotherapy regimens included 5-fluorouracil/folinic acid, FOLFOX (folinic acid, fluorouracil, oxaliplatin) and singleagent capecitabine. As listed in Table 2, 5-fluorouracil +/- folinic acid was the most commonly utilised adjuvant chemotherapy regimen (93%, 419/452). Median time from surgery to commencement of adjuvant chemotherapy was 48 days. The full course of prescribed adjuvant chemotherapy was completed in 322/452 patients (71%). The primary reason for early cessation of adjuvant chemotherapy was toxicity (60/452, 13%), most commonly, diarrhoea or nausea and vomiting.

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ACCEPTED MANUSCRIPT Survival analysis

With a median follow up of 45.5 months, relapse was reported in 95 of 452 (21%) patients in the adjuvant chemotherapy group and 20 of 103 (19%) in the surveillance group. Univariate analysis indicated no statistically significant difference between the

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adjuvant chemotherapy group and the surveillance group (HR 0.93; 95% CI: 0.58– 1.51; p=0.780) (see Figure 2A), and was confirmed on multivariate analysis (HR 1.02; 95% CI: 0.62–1.68; p=0.944). Three-year RFS was 81% (95% CI: 76% to 84%) in the adjuvant chemotherapy group and 79% (95% CI: 67% to 87%) in the

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surveillance group. Five-year RFS was 77% (95% CI: 73% to 81%) in the adjuvant chemotherapy group and 71% (95% CI: 57% to 81%) in the surveillance group.

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Death was reported in 65 of 452 (14%) patients in the adjuvant chemotherapy group and 18 of 103 (17%) in the surveillance group. Whilst adjuvant chemotherapy was associated with numerically better OS outcomes than the surveillance group (HR 0.62; 95% CI: 0.37–1.05; p=0.074, see Figure 3A), the survival outcomes were not statistically significantly better than for patients not receiving treatment. This was

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also confirmed on multivariate analysis (HR 0.67; 95% CI: 0.39–1.13; p=0.133, see Table 3). Three-year OS was 92% (95% CI: 89% to 94%) in the adjuvant chemotherapy group and 87% (95% CI: 76% to 93%) in the surveillance group, while five-year OS was 85% (95% CI: 81% to 89%) in the adjuvant chemotherapy group

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and 74% (95% CI: 59% to 83%) in the surveillance group. Median RFS and OS has

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not been reached in either group.

An assessment of interaction effects between the variables of treatment group (i.e. adjuvant chemotherapy versus surveillance) and pCR status indicated a presence of an interaction (p=0.071), thus sub-group analysis by pCR status was required.

In a subset analysis comparing survival outcomes according to pathological response to preoperative treatment; 127 (23%) patients of the 555 patients offered preoperative long-course CRT achieved a pCR while 405 patients (73%) did not achieve pCR. Response is unknown in 23 patients (4%). Of the 127 patients who achieved pCR, 97 patients (76%) received adjuvant fluoropyrimidine-based chemotherapy and 30 patients (24%) had routine surveillance only. Of the 405 10

ACCEPTED MANUSCRIPT patients who failed to achieve a pCR, 333 patients (82%) received adjuvant chemotherapy and 72 patients (18%) had surveillance alone.

There was no difference found in the Kaplan-Meier curves in the pCR subgroup for RFS (HR 1.37; 95% CI: 0.30-6.31, p=0.683, see Figure 2B) or OS (HR 1.87; 95% CI:

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0.42-8.21, p=0.409, see Figure 3B), which was also confirmed on multivariate analysis.

For the non-pCR sub-group group, whilst there was no difference between the

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adjuvant chemotherapy and surveillance groups for RFS (HR 0.84, 95% CI: 0.501.40, p=0.502, see Figure 2C). There was a noted statistically significant difference in OS with those in the adjuvant chemotherapy group having improved survival

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outcomes when compared to the surveillance group (HR 0.49, 95% CI: 0.28-0.86, p=0.014, see Figure 3C). Although, this statistical significance was not maintained upon multivariate analysis (HR 0.57, 95% CI: 0.32-1.01, p=0.055) after adjusting for age which was also associated with OS (p<0.001), see Table 4.

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Three-year OS in the non-pCR group was 93% (95% CI: 89% to 95%) and 83% (95% CI: 70% to 91%) in the adjuvant and surveillance groups, respectively. Fiveyear OS was 85% (95% CI: 79% to 89%) in the adjuvant chemotherapy group and

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66% (95% CI: 49% to 79%) in the surveillance group

Subsequent lines of therapy

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Loco-regional recurrence was reported in 14/95 (15%) and 8/20 (40%) patients in the adjuvant chemotherapy and surveillance groups respectively. Distal metastatic disease was reported in 88/95 (93%) in the adjuvant group with 37 patients offered metastatic resection. In the surveillance group, 14/20 (70%) patients relapsed with distal metastatic disease with 7 patients proceeding to metastatic resection.

First line chemotherapy in the metastatic setting was offered to 70/88 (80%) relapsed patients in the adjuvant chemotherapy group and 13/14 (93%) in the surveillance group. Further lines of chemotherapy are detailed in Table 5.

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ACCEPTED MANUSCRIPT Of the 65 deaths occurred that occurred in the adjuvant chemotherapy group, 41/65 (63%) were attributed to recurrent rectal cancer and 24/65 (37%) to other causes. In the surveillance group, an equal number of deaths were attributed to rectal cancer

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and other causes (9/18, 50% each group)

DISCUSSION

This retrospective analysis evaluated utilisation of adjuvant fluoropyrimidine-based

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chemotherapy and survival outcomes in resected LARC following preoperative CRT. In this cohort, a high proportion of patients in local routine practice (81%) receive adjuvant chemotherapy. With a median follow up period of 45.9 months, adjuvant

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chemotherapy did not significantly impact RFS, however a non-significant trend towards improved 5 year OS was detected. A statistically significant improvement in 5-year OS was found in patients without a pCR.

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This analysis suggests that patients who do not achieve a pCR to preoperative CRT derive the most OS benefit from the addition of adjuvant chemotherapy, demonstrated by a marked 5-year absolute survival benefit of 22% (85% vs 66%). Although numbers are small, the addition of adjuvant chemotherapy did not result in

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CRT.

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any survival advantage in patients who had achieved pCR following preoperative

An interesting observation to arise from this retrospective data is the discordance between RFS and OS benefit observed within the non-pCR subgroup. Patient selection bias is may account for this given the discordance of older, poorer performance status patients not receiving adjuvant chemotherapy and the loss of any statistically significant OS benefit when adjusted for age in a multivariate analysis. Notably, however, there was no difference in the use of systemic therapy or resection after recurrence comparing the adjuvant therapy and surveillance alone populations. An increase in non-cancer related deaths was reported in the surveillance group that may also account for worse OS but not RFS. No discordance 12

ACCEPTED MANUSCRIPT between RFS and OS benefit was observed in the pCR subgroup, even when the same selection factors should apply. However, it should be noted that numbers in this population are much smaller.

Multiple randomised trials evaluating adjuvant chemotherapy in resected LARC have

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also failed to demonstrate survival benefits.14-18 The significance of these results continues to be debated and guidelines continue to recommend adjuvant therapy. Consistent with this, a high proportion of patients in routine care are still offered adjuvant chemotherapy despite the absence of a proven OS benefit in randomised

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studies.19

A number of hypotheses account for the improved OS survival trends seen in this

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analysis compared to previous trials. Firstly, within the limitations of a retrospective analysis; this study reports higher adherence and completion post-operative chemotherapy rates than those previously reported in larger randomised trials. The largest of these trials, the European Organisation for Research and Treatment of Cancer (EORTC) 22921 (Radiation Therapy, Surgery, and Chemotherapy in

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Treating Patients with Rectal Cancer That Can Be Surgically Removed) study reported that only 43% of patients randomised to post-operative chemotherapy received adequate dose frequency and intensity.15 In the current analysis, 71% of patients completed the full course of prescribed post-operative chemotherapy

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compared to the 22% completion rate reported in EORTC-22921.

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Choice of adjuvant chemotherapy regimen may also impact on survival. In this cohort, the majority of patients (93%) were offered post-operative 5-fluorouracil +/folinic acid typically administered over 6 months. Use of oxaliplatin was limited to 17/440 (4%) patients only. Adjuvant chemotherapy appeared well tolerated with only 13% ceasing treatment due to toxicity. The adjuvant chemotherapy regimen offered in the EORTC-22921 trial was limited to 4 cycles of 3-weekly 5-fluorouracil (350mg/m2)/folinic acid (20mg/m2), which may represent a suboptimal treatment regimen.. There is difficulty interpreting the lack of survival benefit demonstrated in the EORTC study when this trial used less intensive post-operative chemotherapy than typically prescribed in routine practice or in some current guidelines.20

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ACCEPTED MANUSCRIPT Furthermore, the true survival benefit of adjuvant chemotherapy may be underestimated in the published literature due to trial methodology. EORTC-22921 was designed to detect a greater than 10% survival advantage with adjuvant chemotherapy15,19 While all patients who received chemotherapy (pre- and postsurgery groups) experienced less local recurrence compared to radiotherapy alone

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(11.8% - 14.5% [three chemotherapy arms] vs 21.9% [radiotherapy alone]) there was no difference in OS. After 10.4 years follow up; there was no significant difference in OS with the use of adjuvant chemotherapy or with no chemotherapy (51.8% vs 48.4%). Likewise, there was no significant difference in disease free survival (DFS),

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47% vs 43.7% in the adjuvant chemotherapy and no chemotherapy groups, respectively. The CHRONICLE (Capecitabine and Oxaliplatin or Standard Follow-Up Care in Treating Patients Who Have Undergone Surgery for Locally Advanced

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Rectal Cancer) and PROTOR/SCRIPT have also evaluated use of postoperative chemotherapy. These trials closed due to poor accrual or have also been underpowered to assess if a true benefit from adjuvant chemotherapy exists.16,17

Without a convincing survival benefit demonstrated in randomised trials to support

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the use of adjuvant chemotherapy, potential overtreatment and toxicity remain a concern. One group where the benefit of adjuvant chemotherapy is particularly uncertain is in the approximately 20% of patients who achieve a pCR following preoperative CRT. In our analysis, in the 127/555 patients who achieved pCR, no

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significant difference in survival was demonstrated. (5-year OS HR 1.87; 95% CI: 0.42-8.21, p=0.409). Indeed, as pCR is already a predictor of improved outcome,

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further work is warranted to determine if adjuvant chemotherapy can be routinely omitted in this select group.

Overall, better clinical and/or pathological predictors are needed to determine patients who may best benefit from adjuvant chemotherapy and also to determine the optimal adjuvant regimen. One such predictor may be residual node positive disease following preoperative CRT. In this retrospective analysis, there was a higher rate of node positive disease at diagnosis in the adjuvant chemotherapy group compared to the surveillance-only group. Despite evidence of more advanced disease from the outset, administration of adjuvant chemotherapy resulted in a nonsignificant trend towards improved 5-year OS. The concept that persistently node14

ACCEPTED MANUSCRIPT positive rectal cancers benefit from the addition of post-operative chemotherapy is supported by the phase 2 ADORE (Adjuvant Oxaliplatin in Rectal Cancer) trial where patients with ypT3-4 or ypN+ disease following preoperative CRT were randomised to adjuvant 5-fluorouracil/leucovorin or FOLFOX for 4 months.21 Adjuvant FOLFOX resulted in improved 3-year DFS (71.6 vs 62.9%; p = 0.047) and 3-year OS (95% vs

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85.7%; p = 0.036) compared to 5-fluorouracil/leucovorin. In a subset analysis, use of adjuvant FOLFOX resulted in a significant DFS benefit in yp stage III disease (p = 0.04) but not in yp stage II disease (p = 0.47). A similar benefit was also demonstrated in the Phase 3 German AIO-04 study in which the addition of pre- and

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post- operative oxaliplatin significantly improved 3-year DFS (HR 0.79, p 0.03).22 From data available from our analysis, we were unable to determine if the use of

limited number of patients.

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FOLFOX in ypTxN+ disease translated to a significant DFS or OS benefit given the

In conclusion, this retrospective analysis demonstrated a significant OS benefit for patients

with

a

non-pCR

treated

with

adjuvant

fluoropyrimidine-containing

chemotherapy for resected LARC. No survival benefit was seen for pCR patients.

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Although based on retrospective data, these results reflect “real-life” practice and confirm that adjuvant chemotherapy can be delivered to a significant proportion of patients with LARC. Further efforts should be made to refine the subset of patients who will benefit most from adjuvant chemotherapy as well as develop treatment

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treatment.

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algorithms based on clinico-pathological and/or biomarker response to preoperative

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2. Benson AB, Venook AP, Bekaii-Saab T et al. Rectal Cacner, Version 2.2015 J

3. Glimelius B, Tiret E, Cervantes A et al. Rectal cancer: ESMO Clinial Practice

Suppl 6:vi81-8. doi: 10.1093/annonc/mdt240

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Guidelines for diagnosis treatment and follow-up. Ann Oncol. 2013 Oct;24

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8. Quah, H.M., Chou, J.F., Gonen, M. et al, Pathologic stage is most prognostic of disease-free survival in locally advanced rectal cancer patients after preoperative chemoradiation. Cancer. 2008;113:57–64.

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ACCEPTED MANUSCRIPT 9. Maas M, Nelemans PJ, Valentini V et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010;11:835–844.

10. Park IJ, You YN, Agarwal A et al. Neoadjuvant treatment response as an

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12. Maguire A, Sheahan K. Controversies in the pathological assessment of colorectal cancer. World J Gastroenterol. 2014 August 7; 20(29): 9850-9861

13. Kosmider S, Jones IT, Hibbert M, Johns J, McLaughlin S, Chapman M, Gibbs P. Establishing a national colorectal cancer database: lessons learnt from

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Bio21-MMIM. ANZJS. 78;803–809:2008

14. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative

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radiotherapy with rectal cancer. N Engl J Med 2006; 355: 1114–23

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chemotherapy after preoperative chemoradiotherapy in rectal cancer: longterm results of the EORTC 22921 randomised study. Lancet Oncol. 2014; 15:

184–190

16. Glynne-Jones R, Counsell N, Quirke P et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol. 2014 Jul;25(7):1356-62

17. Breugom AJ, van Gijn W, Muller EW et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total 17

ACCEPTED MANUSCRIPT mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015;26(4):696-701

18. Sainato A, Cernusco V, Valentini V et al. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally

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21. Hong YS, Nam BH, Kim KP et al. Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): an

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open-label, multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2014;15(11):1245-53

22. Rödel, Claus et al Oxaliplatin added to fluorouracil-based preoperative

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chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the

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multicentre, open-label, randomised, phase 3 trial. Lancet Oncology, 16(8):979 - 989

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ACCEPTED MANUSCRIPT TABLE AND FIGURE LEGEND

Table 1: Patient demographics

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Table 2: Post-operative chemotherapy regimen in pCR vs non-pCR group

Table 3: Univariate and multivariate analysis for overall survival associations in entire cohort

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Table 4: Univariate and multivariate analysis for overall survival associations in nonpCR cohort

Figure 1: Patient population

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Figure 2: Relapse-free survival

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Table 5: Subsequent lines of chemotherapy in relapsed patients

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Figure 3: Overall survival

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ACCEPTED MANUSCRIPT Table 1: Patient demographics Adjuvant chemotherapy

Surveillance group

n/%

n/%

452

103

n=555 Age ≤70

327 (72%)

51 (50%)

>70

125 (28%)

52 (50%)

Male

307 (68%)

55 (53%)

Female

145 (32%)

48 (47%)

0-1

426 (94%)

86 (84%)

≥2

17 (4%)

12 (12%)

9 (2%)

5 (4%)

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Gender

Unknown Stage at diagnosis T stage

29 (6%)

T3

367 (81%)

T4

55 (12%)

7

(7%)

85 (83%)

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T2

SC

Performance status

Unknown

11 (11%)

1 (<1%)

N stage N0

127 (28%)

43 (42%)

N1

210 (46%)

39 (38%)

N2

102 (23%)

17 (17%)

13 (3%)

4 (4%)

Preoperative CRT completion rate Completed

TE D

x/unknown

423 (94%)

85 (82%)

19 (4%)

14 (14%)

16

9

3

2

10 (2%)

4 (4%)

97 (22%)

46 (45%)

308 (68%)

54 (52%)

Complete response (pCR)

97 (22%)

29 (28%)

No pCR

333 (74%)

71 (70%)

Unknown

22 (5%)

3 (3%)

Not completed - Toxicity

Unknown Surgical complication

No

AC C

Yes

EP

- Other

Operative histology

20

ACCEPTED MANUSCRIPT Table 2: Post-operative chemotherapy regimen Chemotherapy regimen n=452

n/%

5FU +/- folinic acid

419 (93%)

FOLFOX

19 (4%)

FOLFOX + Bevacizumab

1 (0.2%) 9 (2%)

RI PT

Capecitabine

5FU - 5-fluorouracil

AC C

EP

TE D

M AN U

SC

FOLFOX - 5-fluorouracil, folinic acid, oxaliplatin

21

ACCEPTED MANUSCRIPT Table 3: Univariate and multivariate analysis for overall survival associations in

AC C

EP

TE D

M AN U

SC

RI PT

entire cohort

22

ACCEPTED MANUSCRIPT Table 4: Univariate and multivariate analysis for overall survival associations in non-

AC C

EP

TE D

M AN U

SC

RI PT

pCR cohort

23

ACCEPTED MANUSCRIPT Table 5: Subsequent lines of chemotherapy in relapsed patients

Adjuvant chemotherapy group

Subsequent lines of therapy

Surveillance group

(n / 95 ) (n / 20) 13 (65%)

FOLFOX

33

8

FOXFOX + Bevacizumab

14

5FU/FA

6

Other

17

Second-line

24 (25%)

FOLFIRI

10

FOLFOX

2

Other

12

Third-line

13 (14%) 1

1

1

3

6 (30%) 2

M AN U

FOLFIRI

RI PT

70 (74%)

Cetuximab

3

SC

First-line

1

1 (5%) 1

4

Forth-line

5 (5%)

FOLFIRI

0 (0%)

2

FOLFIRI + Bevacizumab

1

FOLFIRI +Cetuximab

2

Fifth-line

1 (1%)

FOLFIRI

0 (0%)

1

AC C

EP

TE D

FOLFOX - 5-fluorouracil, folinic acid, oxaliplatin FOLFIRI - 5-fluorouracil, folinic acid irinotecan 5FU/FA - 5-fluorouracil, folinic acid

24

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1: Patient population

25

ACCEPTED MANUSCRIPT Figure 2: Relapse-free survival (RFS) for all cases (A), pCR subgroup (B) and non-

0.00

Surveillance only Adjuvant chemotherapy 24

36

48

60

72 84 96 Time (months)

108 120 132 144 156

TE D

Survival Probability (%) 0.40 0.60 0.80

1.00

M AN U

12

0.20

n=127 HR 01.37; 95% CI: 0.30-6.31; p=0.683

24

36

48

60

72 84 96 Time (months)

108 120 132 144 156

Survival Probability (%) 0.40 0.60 0.80

AC C

1.00

12

EP

0.00

Surveillance only Adjuvant chemotherapy 0

C

SC

0.20

n=555 HR 0.93; 95% CI: 0.53-1.62; p=0.780

0

B

RI PT

Survival Probability (%) 0.40 0.60 0.80

A

1.00

pCR subgroup (C)

0.20

n=405 HR 0.84; 95% CI: 0.50-1.40; p=0.502

0.00

Surveillance only Adjuvant chemotherapy 0

12

24

36

48

60

72 84 96 Time (months)

108 120 132 144 156

26

ACCEPTED MANUSCRIPT Figure 3: Overall survival (OS) for all cases (A), pCR subgroup (B) and non-pCR

0.20

n=555 HR 0.62; 95% CI: 0.37-1.05; p=0.074

36

48

60

72 84 96 Time (months)

108 120 132 144 156

TE D

1.00

Survival Probability (%) 0.40 0.60 0.80 0.20

n=127 HR 1.87; 95% CI: 0.42-8.21; p=0.409

0.00

Surveillance only Adjuvant chemotherapy 12

24

36

48

60

72 84 96 Time (months)

108 120 132 144 156

Survival Probability (%) 0.40 0.60 0.80

AC C

1.00

EP

0

C

24

M AN U

12

SC

0.00

Surveillance only Adjuvant chemotherapy 0

B

RI PT

Survival Probability (%) 0.40 0.60 0.80

A

1.00

subgroup (C)

0.20

n=405 HR 0.49; 95% CI: 0.28-0.86; p=0.014

0.00

Surveillance only Adjuvant chemotherapy 0

12

24

36

48

60

72 84 96 Time (months)

108 120 132 144 156

27