Available online at www.sciencedirect.com

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EJSO 40 (2014) 234e239 www.ejso.com

Changing patterns of recurrent disease in colorectal cancer

I. Grossmann a,*, P.M. Doornbos b, J.M. Klaase a, G.H. de Bock b,T. Wiggers c

aDepartment of Surgery, Medical Spectrum Twente, Haaksbergerstraat 55, 7513 ER Enschede, The NetherlandsbDepartment of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1,

9713 GZ Groningen, The NetherlandscDepartment of Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1,

9713 GZ Groningen, The Netherlands

Accepted 30 October 2013

Available online 15 November 2013

Abstract

Background: Due to changes in staging, (neo)-adjuvant treatment and surgical techniques for colorectal cancer (CRC), it is expected that therecurrence pattern will change as well. This study aims to report the current incidence of, and time to recurrent disease (RD), further thelocalization(s) and the eligibility for successive curative treatment.Methods: A consecutive cohort of CRC patients, whom were routinely staged with CT and underwent curative treatment according to thenational guidelines, was analyzed (n ¼ 526).Results: After a mean and median FU of 39 months, 20% of all patients and 16% of all AJCC stage 0eIII patients had developed RD. Theannual incidences were the highest in the first two years but tend to retain in the succeeding years for stage 0eIII patients. The majority ofRD was confined to one organ (58%) and 28% of these patients were again treated with curative intent.Conclusions: In follow-up nowadays, less recurrences are found than reported in historical studies but these can more often be treated withcurative intent. A main cause for the decreased incidence of RD, next to improvements in treatment, is probably stage shift elicited by pre-operative staging. The outcomes support continuation of follow-up in colorectal cancer.� 2013 Elsevier Ltd. All rights reserved.

MeSH keywords: Colorectal neoplasms; Recurrence; Neoplasm staging; Follow-up studies

Introduction

In the last decades, several developments in the treat-ment of colorectal cancer (CRC) have led to a survivalimprovement.1,2 Optimal staging, routine use of total mes-ocolon and mesorectal excision, more extensive surgeryand combined treatment modalities are modern approachestowards CRC and its metastases and have resulted in ahigher chance on cure.2e9 These developments can benefitthe patient with recurrent disease (RD) as well; a

* Corresponding author. Current address: Department of Critical Care,

University of Groningen, University Medical Center Groningen, Hanze-

plein 1, 9713 GZ Groningen, The Netherlands.

E-mail addresses: irenegrossmann@me.com (I. Grossmann),

J.Klaase@mst.nl (J.M. Klaase), g.h.de.bock@umcg.nl (G.H. de Bock),

T.wiggers@umcg.nl (T. Wiggers).

0748-7983/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.ejso.2013.10.028

consideration that has contributed to a renewed effort tooptimize early detection of RD in follow-up (FU).10e13

Due to these changes in staging and treatment, it is ex-pected that the recurrence patterns will also change. Mod-ern staging routines lead to a better division betweencurable and incurable situations at the onset of diag-nosis,1,14 causing a change in the population that will bein oncological follow-up after treatment (stage shift).(Neo)-adjuvant treatment has led to a decrease in incidenceof RD, especially of local recurrences,7e9,15e17 and maydelay recurrences.18 On the other hand, also more patientswith locally advanced or metastatic CRC, whom are at highrisk of RD, are nowadays treated with curative intent andwill be amongst the FU population. Historical series fromthe last two decades report a range of RD incidences be-tween 26 and 55%.19e24 Given these changes it is likelythe recurrence patterns are changing as well, but it is

All surgicalpatientsn=720

Incurable patientsn=147

Curatively treated patients

235I. Grossmann et al. / EJSO 40 (2014) 234e239

unclear in what way. In the context of the development ofnew schedules in oncological follow-up it is important toknow what the present recurrence patterns look like.

This study aims to analyze the pattern of recurrence in aconsecutive cohort of patients with CRCwhomwere routinelystaged before treatment with abdominal CTand chest X-ray orCT, and treated according to the current standards in (neo)-adjuvant treatment.25 The analysis concerns the incidence ofand time to RD, additionally the type of recurrences includinglocalization(s) and the eligibility for curative treatment.

Patient and methods

n=573

Study design

Post-operative deathsn=24

Curatively treated living patients

n=549

This study is an observational cohort study analyzing therecurrence patterns in a consecutive cohort of patientswhom were curatively treated for colorectal cancer andeligible for FU. The study was done at the Medical Spec-trum Twente, a large community teaching hospital in theeastern part of the Netherlands. It is a regional referral cen-ter for liver and lung surgery, but has no facilities for thetreatment of peritoneal carcinomatosis (PC). If necessary,patients are transferred to one of the national referral cen-ters for metastases treatment.

No follow-upn=23 (4%)

Patient data collection and selection

Eligible for analysisn=526

Figure 1. Selection of patient cohort.

All patients who underwent surgical treatment for CRCin the period 2007e2010 were prospectively registered in adatabase designed for colorectal surgery, including patientcharacteristics, staging, neo-adjuvant treatment, surgicalprocedure, post-operative course, pTNM stage, adjuvanttreatment, treatment of metastases and FU. This baselinecohort was routinely staged with abdominal CT and chestX-ray or CT before treatment and treated according tothe current Dutch guidelines. Patients were consideredeligible for FU when they were treated with curative intentand alive after discharge (Fig. 1). Patients were consideredincurable in case of a macroscopically incomplete (R2)resection of the primary tumor, when the patient had noresection of the primary tumor, or when no intended cura-tive treatment of distant metastases was done. These pa-tients were excluded from the analysis. Data on eventsduring the FU period were retrospectively collected tillJanuary 2013 from both paper and digital patient files. Pa-tients that did not have any form of follow-up were alsoexcluded from further analysis (Fig. 1).

Patients’ staging, treatment and follow-up

Routine pre-operative staging with a CT of chest andabdomen was introduced as a regional guideline in 2007and preceded similar national guideline recommendations(2008). CT scanning was performed on a 16 and 64 slicescanner (Toshiba Aquillion 16 and 64) after intravenous

contrast injection (visipaque 320, 90 ml, 3 ml/s) in the por-tal venous phase, with a slice thickness of 1 mm and areconstruction of 0.8 mm. Patients with rectal cancer upto 12 cm from the anal verge were additionally stagedwith a pelvic MRI for determination of the local invasionand possible lymph node metastases and received neo-adjuvant (chemo)-radiation in case of a threatened circum-ferential resection margin and/or the strong suspicion ofpathological lymph nodes. Pathological staging was basedupon the TNM classification 2002 (6th edition) and classi-fied according to the American Joint Committee on Cancer(AJCC) stages (6th edition), which were the most recentversions at the time of data collection. The diagnosis ofsynchronous metastases was based upon radiological imag-ing (CT scan for liver and lung metastases), combined withper-operative findings (for liver and PC).14,26 For PC histo-logical confirmation was obtained in all cases. Patients withcolon cancer with lymph node metastases or unfavorabletumor characteristics such as a pT4 stage, were eligiblefor adjuvant treatment consisting of 5-FU/Oxaliplatin based

Table 1

Patient characteristics (n ¼ 526).a

Value %

Age

Mean 68 years

Median 69 years

Range 38e92 years

Gender

Male 303 58%

Female 223 42%

Localization primary tumor

Colon 215 41%

Rectosigmoidb 189 36%

Rectumc 122 35%

Staging procedure on distant metastases before

treatment

Abdominal CT with chest X-ray or chest CT 489 93%

Ultrasound of the liver with chest X-ray 12 2%

Additional staging with PET/CT due to

indifferent findings

17 3%

Neo-adjuvant treatment

Neo-adjuvant long course radiotherapy

(25 � 2�Gy) with capecitabine

77

236 I. Grossmann et al. / EJSO 40 (2014) 234e239

regimes.25 Follow-up after curative treatment of non-metastatic CRCconsisted of serumCEAmeasurements every3months combined with bi-annual ultrasound of the liver andyearly chest X-ray. Patients that underwent curative treatmentformetastaticCRChad amore intensive FU, consisting of im-aging every 3months in the first two years and bi-annually af-ter year two, combined with regular CEA measurementsevery3months. These schemeswere according to thenationalguidelines and did not differ in patients with either colon orrectal cancer. Diagnosis of RDwas made on additional radio-logical imaging (CT, PET/CTandMRI) combined with CEAvalues. Local recurrences were defined as recurrences situ-ated on the anatomical site of the primary tumor.

In case of uncertainty, repeat CEA measurements andimaging were done. Histological confirmation was obtainedwhen relevant for further treatment. Recurrent disease wastreated with curative intent when a radical resection of alltumor localization(s), sometimes after neo-adjuvant radio-or chemotherapeutic treatment, was possible and the indi-vidual patient was both motivated and fit for the necessarymetastases treatment.

Chemotherapy 4

Neo-adjuvant short course radiotherapy 34

Statistical analysis (5 � 5 Gy)

AJCC stage based on pTNM 6 (2002)

Stage 0 14 3%

Stage I 102 19%

Stage II 196 37%

Stage III 173 33%

Stage IV 41 8%

Adjuvant chemotherapy in colon/rectosigmoid

cancer (n ¼ 404)

165 41%

Stage I (n ¼ 66) 0 e

Stage II (n ¼ 161) 27 17%

Stage III (n ¼ 143) 102 71%

Stage IV (n ¼ 34) 27 29%

Follow-up time d

Mean 38,6 months

Median 39 months

Range (all patients) 1e72 months

a All patients that went into active FU (analyzed cohort).b All tumors in the intra-peritoneal rectum (at 10e15 cm from the anal

verge) and sigmoid colon.c All tumors in the extra-peritoneal rectum, clinically located from 0 to

w10 cm above the anal verge.d Time in FU ¼ time from primary surgery to date of diagnosis recurrent

disease, death or date of the last data collection (03-01-2013). The mini-

mum time between the last treated patient and data collection was 24

months.

Statistical analysis was carried out using SPSS 20. Theperiod a patient spent in follow-up was calculated by sub-tracting the date of surgery from the date an endpoint wasreached (diagnosis of RD, death or end of follow-up time).The AJCC stages were converted into two groups; stage0eIII disease and stage IV disease. By using the Ka-planeMeier analysis a survival plot was constructed basedon the finding of recurrent disease during the time infollow-up, stratified for AJCC stages. To allow comparingthis data to other reports in literature as is done in the discus-sion, the number of patients at baseline that developed an RDduring follow-up were calculated as well as the annual inci-dences of RD. The latter takes the drop-out and censoringduring follow-up into account andwas calculated by dividingthe number of metastases by the number of person years inthe follow-up for each year in follow-up.

Results

A total of 720 patients underwent surgery for CRC in thestudied time period. Initial incurable disease was diagnosedin 147 patients and additionally 24 patients whom weretreated with curative intent died following surgery for theprimary tumor. From the remaining 549 patients, 23 pa-tients (4%) were excluded because they did not have anoncological FU; for 16 patients this was a deliberate choicebased on the patients’ and physicians’ preference, mostlybecause of co-morbidity and age, and in 7 patients it re-mained unknown. The mean age of this group was 81 years,versus 68 years in the group of patients that went into FU.A consecutive cohort of 526 patients in FU was thuseligible for analysis (Fig. 1). Patient characteristics of this

group concerning age and sex, staging procedures, down-staging, stage distribution and adjuvant therapy aredescribed in Table 1.

Incidences of recurrent disease

After a mean and median follow-up time of 39 monthsand a minimum time lapse 2 years between the last treatedpatient and last data collection, 20%of all patients at baseline

Table 2

Recurrence pattern per initial disease stage.

Patients in FU (n ¼ 526)

Total RD %a

All patients in FU

Stage 0 þ I 116 6 5%

Stage II 196 28 14%

Stage III 173 45 26%

Stage IV 40 27 68%

All patients 526 106 20%

Patients with stage 0eIII 486 79 16%

Patient cohort without downstaging

Stage I 83 3 4%

Stage II 171 21 12%

Stage III 157 38 24%

Stage IV 34 23 67%

All patients 445 85 19%

Patients with stage 0eIII 411 62 15%

Patient cohort with downstagingb

Stage 0 þ I 33 3 9%

Stage II 25 7 29%

Stage III 16 7 44%

Stage IV 7 5 83%

All patients 81 22 27%

Patients with stage 0eIII 74 17 23%

a These percentages reflect the proportion of patients that was diagnosed

with RD after a mean and median FU of 39 months.b Downstaging implies neo-adjuvant treatment affecting the initial T and

N stage, which in this cohort included neo-adjuvant chemotherapy in colon

cancer (n ¼ 4) and long course chemo-radiotherapy in rectal cancer

(n ¼ 77).

Figure 2. Disease-free survival.

Table 3

Localization and treatment of recurrent disease.

n % of RD

(n ¼ 106)

% of all

(n ¼ 526)

Localization recurrent disease

Liver metastases 43 41% 8%

Lung metastases 41 39% 8%

Peritoneal carcinomatosis 26 25% 5%

Local recurrencea 25 24% 5%

Lymph node metastases 19 18% 4%

Other localizationsb 12 11% 2%

Recurrent disease confined to

one organ at diagnosis

61 58% 12%

Liver metastases 21 20%

Lung metastases 13 12%

Peritoneal carcinomatosis 12 11%

Local recurrence 11 10%

Lymph node metastases 2 2%

Other localizations 2 2%

Curative treatment of recurrent

disease

30c 28% 6%

Liver metastases 14 33% (14/43)

Lung metastases 8 20% (8/41)

Peritoneal carcinomatosis 3 11% (3/26)

Local recurrence 7 28% (7/25)

Lymph node metastases 2 10% (2/19)

Other localizations 1 8% (1/12)

237I. Grossmann et al. / EJSO 40 (2014) 234e239

developed recurrent disease (106/526). In the group of pa-tients with stage 0eIII disease this was 16% (79/486). Therecurrence rate per AJCC stage is given in Table 2. A greaterproportion of patients that received neo-adjuvant treatmentfor locally advanced disease (n ¼ 81, of whom 77 patientswith rectal cancer) had RD than those who did not receiveneo-adjuvant treatment (27% versus 19%).

Forty patients (8%) died of non-cancer related causes andfive patients (1%) died of unknown cause, but without docu-mented RD, during the follow-up period. The annual inci-dences of RD for patients with initial stage 0eIII diseasewere for year one 7.4% (34 out of 460 person-years (py)),year two 5.6% (23 out of 415 py), year three 3.9% (13 outof 334 py), year four 3.1% (7 out of 227 py) and year five1.6% (2 out of 126 py). The annual incidences of RD for pa-tientswith curatively treated synchronousmetastaseswere foryear one 37,3% (13 out of 35 py), year two 64,7% (13 out of20 py), year three 8.0% (1 out of 13 py) and year four 11.8% (1out of 9 py). Fig. 2 represents the disease-free survival of thegroups with respectively stage 0eIII and stage IV disease.

a Local recurrences: from rectal cancer up to 10 cm from the anal verge

(n ¼ 10), rectosigmoid (n ¼ 7) and colon cancer (n ¼ 8).b

Localization and treatment of recurrent disease

Including brain, skeleton, adrenal gland and incisional metastases.

c From 30 patients whom were treated with curative intent for RD, 25

patients had RD confined to one organ and five patients had RD on two

localizations (2 liver and lung, 1 LR and lymph nodes, 2 LR and liver);

the total number of curatively treated metastases therefore totals 35.

The localization and treatment for RD are described inTable 3. In the majority of patients, RD was confined toone organ at the time of diagnosis (58%). It was most often

localized in the liver (41%) and lung (39%), followed byPC (25%), local recurrence (24%) and lymph node metas-tases (18%). Curative treatment was eligible and performedin 28% of patients (30 out of 106). The proportion of pa-tients that underwent curative treatment per localizationof RD was: 33% for liver metastases (14 out of 43), 28%for local recurrence (7 out of 25), 20% for lung metastases

Table 4

Type of recurrence per localization of the primary tumor.

Local recurrence

(n ¼ 24)aDistant metastasis

(n ¼ 92)a

n (%) n (%)

Colon cancer (n ¼ 215) 9 (4%) 38 (18%)

Rectosigmoid cancer

(n ¼ 189)

4 (2%) 25 (13%)

Rectal cancer (n ¼ 122) 11 (9%) 29 (24%)

a The total of local recurrence and distant metastases is more than 106;

this is because 10 patients had both a LR and DM.

238 I. Grossmann et al. / EJSO 40 (2014) 234e239

(8 out of 41), 11% for PC (3 out of 26) and 10% forregional lymph node metastases (2 out of 19).

The localization in terms of local recurrence versusdistant metastases depending the localization of the primarytumor is described in Table 4.

Discussion

This prospective observational cohort study concerns therecurrence pattern in a consecutive cohort of 526 CRC pa-tients whom were routinely staged before treatment andreceived (neo)-adjuvant treatment and follow-up accordingto the present national guidelines. After a median FU of 39months and a minimum time lapse of 24 months betweenthe last treated patient and date of last data collection,20% of all patients and 16% of AJCC stage 0eIII patientshad developed a recurrence. The highest annual recurrencerates were seen in the first two years after treatment of theprimary tumor but tend to retain in succeeding years for thegroup with initial stage 0eIII disease. From all patientswith RD, 28% could again be treated with curative intent.

Patterns of recurrence

The pattern of recurrence in time reveals that the highestannual incidences of RD are expected in the first two years.The incidences in year three to five however show only amoderate decrease in the group of patients with stage 0eIIIdisease when the annual incidences are corrected for drop-out. This same prolonged period was observed in theMOSAIC trial, where RD was diagnosed in an additional8e9% of patients in year four to six.15,16 Already one otherreport suggested that changes in neo-adjuvant treatment forrectal cancer can lead to an increase in disease-free intervaland late recurrences.18 The higher incidence of recurrencesper AJCC stage in the group that underwent neo-adjuvanttreatment resulting in locoregional downstaging reflects thepersistent prognostic significance of the initial tumor stage.

Changing patterns: outcomes in comparison tohistorical series

The reported number of patients that developed RD ismarkedly lower than the recurrence rates reported in

comparable mixed colon and rectal cancer populationsin historical series (26e55%).19e24 This ‘decrease’ isprobably for the larger part caused by the introductionof routine pre-operative staging with abdominal CT. Thestaging abdominal CT can detect otherwise unnoticedsynchronous metastases before surgery of the primary tu-mor, thus causing a stage shift in the baseline cohort. Thatthis effect takes place is supported by the observation thatthe reported incidence of synchronous metastases hasincreased over time from 10 to 15% up to 30% in currentseries.1,14 A probable contributing cause to the decrease ofrecurrences is the change in treatment for rectal cancerthat has significantly reduced the incidence of LR.27

This improvement is visible in the proportion of LRamong the population with RD in this study; 24% of allRD concerns an LR, whereas previous studies that alsoconsidered mixed populations with colon and rectum can-cer, reported LR proportions between 39% and54%.20,22,23 Further, the more effective adjuvant therapiesare likely to have contributed to the decreased incidenceof RD in colon cancer.15e17 Next to incidence the locali-zation of RD seems to have undergone some changes ascompared to historical reports.20,22,23,28,29 Local recur-rences have become less common, as mentioned, butlung metastases are found more often (39% versus4e14%). The last is probably an effect of the improve-ments in imaging techniques such as chest CT. For PC acomparison proved faulty; the main problem is the lackof comparable definitions amongst studies, that is re-flected in a wide range of reported incidences of ‘intra-abdominal extra-hepatic’, ‘loco-regional’ or ‘peritoneal’recurrences (3e27%).

Treatment of recurrences and follow-up

The eligibility for curative treatment seems to haveincreased, with 28% in this observational cohort as comparedto approximately 20% in older follow-up trials.21,30,31 Treat-ing metastatic disease with curative intent has long beendebated and sometimes still is, considering the fact thatmost patients will have a re-recurrence and die from it. None-theless several studies show that survival improves whencolorectal cancer metastases are treated with curativeintent.5,31,32 Thus although in follow-up nowadays less recur-rences may be found, when detected, treatment with curativeintent is often feasible. This outcome supports continuationof follow-up in colorectal cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Sources of funding

none.

239I. Grossmann et al. / EJSO 40 (2014) 234e239

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