Characteristics and pattern of recurrence after curative

1130-0108/2015/107/539-546Revista española de enfeRmedades digestivasCopyRight © 2015 aRán ediCiones, s. l.

Rev esp enfeRm dig (MadridVol. 107, N.º 9, pp. 539-546, 2015

ORIGINAL PAPERS

Characteristics and pattern of recurrence after curative surgery in oesophageal cancerElena Rodríguez-Camacho, Salvador Pita-Fernández, Sonia Pértega-Díaz, Beatriz López-Calviño and Teresa Seoane-Pillado

Clinical Epidemiology and Biostatistics Research Group. Instituto de Investigación Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña. A Coruña, Spain

ABSTRACT

Background and aim: Recurrence in oesophageal cancer continues to remain high after curative surgery. The aim of this study was to determine the presence of recurrence after curative surgery during follow-up, and the associated variables.

Methods: A retrospective and prospective follow-up study in patients with an anatomical-pathological diagnosis of oesophageal cancer who underwent curative surgery (n = 57) in the health district of A Coruña (Spain) during the period 2003-2008. The calculation of recurrence-free survival was made using a competing risks survival analysis.

Results: Out of the 57 patients included in the study, 87.7% were men with a mean age of 61.4 ± 10.3 years. The median follow-up period was 18.5 months, during which 28 recurrences were detected (50.9%). Patients with dysphagia on diagnosis of the disease, as well as patients in stages III-IV, have a higher probability of recurrence during the follow-up period. The median disease-free interval was 8.5 months. After one year of follow up, 57.1% of the recurrences were diagnosed and 82.1% after 2 years of follow-up. The median post-recurrence survival rate was 4.7 months. After adjusting for a multivariate regression model, the variable with an independent effect for predicting recurrence is the TNM classification (HR = 8.49).

Conclusions: The majority of the recurrences will be developed during the 2 years after surgery, with a very poor prognosis. The predictor variable for recurrence is the TMN classification.

Key words: Oesophageal neoplasms. Recurrence. Oesophagectomy. Survival. Follow-up studies.

INTRODUCTION

Oesophagus cancer is the eighth most common cancer at worldwide level, and is the sixth main cause of death from cancer (1). Surgery involving oesophagectomy is still the main therapeutic option (2,3), although even after receiving curative treatment the possibility of recurrence

in patients, either locoregional or distant, is still high, with percentages varying between 29% and 59% (4-16).

Different factors affect the risk of recurrence, mainly the location of the tumour, the local stage of the tumour, the degree of cellular differentiation and the presence of metastasis on diagnosis (5-9,11,12,14,16). It is important to understand the factors that favour the presence of tumour recurrence, as well as the different patterns of recurrence, in order to be able to design suitable therapeutic strategies for these patients.

The aim of this study was to demonstrate the charac-teristics and progress of patients with oesophageal can-cer who have undergone curative surgery, as well as to study the risk factors for developing a recurrence. Also, in patients with tumour recurrence, to analyse the different patterns of recurrence, their therapeutic management and their evolution.

MATERIALS AND METHODS

Study population

A total of 180 patients were diagnosed with anatomical-patho-logical confirmation of cancer of the oesophagus (CIE 9ª: 150) at the University Hospital Complex in A Coruña (Spain) from 1 Janu-ary 2003 to 31 December 2008. This study included all patients in the cohort (57 patients) who had undergone curative surgery, which enabled complete removal of the tumour along with the metastatic lymph nodes. A retrospective review of the patients’ clinical records was carried out together with a prospective follow-up until 31 Jan-uary 2012, in order to guarantee a minimum follow-up period of 3 years. The study excluded prevalent or recurring cases, multiple cancers, metastatic cancers, or those that had been treated and/or diagnosed at other hospitals.

Rodríguez-Camacho E, Pita-Fernández S, Pértega-Díaz S, López-Calviño B, Seoane-Pillado T. Characteristics and pattern of recurrence after curative surgery in oesophageal cancer. Rev Esp Enferm Dig 2015;107:539-546.

Received: 26-02-2015Accepted: 03-05-2015

Correspondence: Elena Rodríguez-Camacho. Clinical Epidemiology and Biostatistics Unit. Complexo Hospitalario Universitario de A Coruña. Xer-encia de Xestión Integrada de A Coruña. C/ Xubias de Arriba, 84. 15006 A Coruña, Spaine-mail: [email protected]

540 E. RODRÍGUEZ-CAMACHO ET AL. Rev esp enfeRm Dig (maDRiD)

Rev esp enfeRm Dig 2015; 107 (9): 539-546

Measurements

A study was made of the socio-demographic variables of the patient, their personal backgrounds, comorbidity variables using Charlson’s comorbidity index, the symptoms present at diagnosis, location of the tumour, histopathological cell type and tumour stage (TNM, seventh edition) (17,18). As data on risk factors and symp-toms were collected retrospectively from clinical records, we regis-tered it if it was indicated in the clinical records, although we were unable to quantify the frequency and amount of cigarette or alcohol consumption, nor the number of kilograms lost.

An analysis was made of the treatment received, surgery, chemo-therapy and radiotherapy.

Tumour recurrence was considered as the detection during the post-surgical follow-up period of reappearance of the neoplastic dis-ease either locoregional, distant, or both. Locoregional recurrence was defined as a recurrence isolated to the area of the anastomosis (perianastomotic) or in lymph nodes in the mediastinum and upper abdomen (supraceliac). Distant recurrence was defined as any spread of disease beyond a locoregional recurrence. The recurrence-free interval was defined as the time from the curative surgery to the first recurrence (locoregional, distant or both).

For all dead patients, cause of death was obtained from the Gali-cian Mortality Registry (General Directory of Public Health, Xunta de Galicia, Spain), according to the 21 diagnostic categories of the 10th revision of the International Classification of Diseases (ICD-10).

Sample size justification

The study included a total of 57 patients. This sample size makes it possible to detect as significant a Hazard Ratio of 2.85 or more with a prevalence of exposure of 50% and a censored data percent-age of 50% (confidence: 95%; Statistical power: 80%).

Statistical analysis

A descriptive study was made of the variables that were obtained. The global survival rate was calculated using the Kaplan-Meier methodology and recurrence-free survival using competing risks survival analysis. Proportional hazard assump-tion was assessed graphically by visual judgement of the log-mi-nus-log survival plots, as well as checking the significance of a time-dependent variable added to the regression model (by means of an interaction of survival time and each individual covariate) for quantitative covariates. The accumulated occurrence of tumour recurrence during the follow-up period was estimated, considering non-recurrence mortality as a competitive event, using the method proposed by Kalbfleisch and Prentice (19). The accumulated occur-rence of tumour recurrence according to different characteristics was compared using the test proposed by Gray (20). Finally, in order to identify which characteristics were associated with the risk of tumour recurrence, a multivariate analysis was carried out using the model proposed by Fine and Gray (21). All of the tests were carried out bilaterally, considering values of p < 0.05 as significant. The analyses were carried out using the programmes Epidat 3.1, SPSS 19.0 and R 2.15.1.

Ethics

The study was carried out according to the principles laid down in the Declaration of Helsinki and ensuring compliance with Spanish Law 29/2009, which “Regulates the use of and access to electron-ic medical records. Confidentiality was maintained in accordance with the current Spanish Data Protection Law (15/1999). The study received written approval from the regional Ethics Committee for Clinical Research (code 2011/372 CEIC Galicia).

RESULTS

Characteristics of the patients studied

Out of the 57 patients included in the study, 87.7% were male. The mean age of the patients was 61.4 ± 10.3 years, and the mean Body Mass Index (BMI) was 25.2 ± 3.9 kg/m2. Twenty-two patients (38.6%) had a background of gastro-oesophageal reflux, 80.7% were smokers, 57.9% were alcohol drinkers, and 49.1% had both risk factors. The score on Charlson’s comorbidity index age-adjusted was 2.7 ± 1.7, with 50.9% of the patients in a high comor-bidity range (≥ 3 points).

Forty-six patients (82.1%) presented with dysphagia at the time of diagnosis. A lower thoracic localisation (> 30-40 cm from the incisors) was the most frequent, in 49.1% of the cases. In the case of the tumours, 40 (70.2%) corresponded to squamous cell carcinomas, and 17 (29.8%) to adenocarcinomas. Thirty-seven patients (72.6%) were at stage II-III at the time of diagnosis, and five patients (9.8%) had metastatic lymph nodes (stage IV). Thirty-four patients (59.6%) received only surgical treatment, while 40.4% received surgical and oncological treatment (chemothera-py and/or radiotherapy). In those cases, chemotherapy and radiotherapy were mainly applied for neoadjuvant purposes (76.5% and 69.6% respectively) (Table I).

Progress of patients and likelihood of recurrence

The median follow-up period for the 57 patients who under-went curative surgery was 18.5 months (range: 0.3-92.4), with an overall chance of survival of 82.5% after six months, 59.2% after one year, and 23.1% after 5 years of follow-up.

During the follow-up, 28 (50.9%) patients were detect-ed with recurrence. Figure 1 shows the different progress options following curative surgery, together with the prob-ability of each of them in the different follow-up periods. In those patients who underwent curative surgery, the probability of being diagnosed with a tumour recurrence (locoregional tumour recurrence, distant recurrence or both) during the first year after surgery was 29.1%, while 25.5% of the patients died without presenting any recur-rence. Therefore, 45.4% of the patients who underwent curative surgery were alive and remained disease-free

Vol. 107, N.º 9, 2015 CHARACTERISTICS AND PATTERN OF RECURRENCE AFTER CURATIVE SURGERY IN OESOPHAGEAL CANCER 541


Table I. Baseline characteristics of the patients studied

na Mean SDb Median IQRc 95% CId (mean)

Age (years) 57 61.4 10.3 61.0 30.0-79.0 58.7-64.1

BMIe 41 25.2 3.9 24.8 18.2-32.8 23.9-26.4

Charlson’s comorbidity index 57 1.0 1.3 1.0 0.0-6.0 0.7-1.3

Charlson’s comorbidity index age adjusted 57 2.7 1.7 3.0 0.0-8.0 2.3-3.2

na % 95% CId (Mean)

Gender

Male

Female

50

7

87.7

12.3

78.3-97.1

2.9-21.7

Charlson’s comorbidity index age adjusted

No comorbidity (0-1 points)

Low comorbidity (2 points)

High comorbidity (≥ 3 points)

13

15

29

22.8

26.3

50.9

11.0-34.6

14.0-38.6

37.0-64.7

Gastro-oesophageal reflux*

Yes

No

22

35

38.6

61.4

25.1-52.1

47.9-74.9

Smoking

Yes

No

46

11

80.7

19.3

69.6-91.8

8.2-30.4

Alcohol consumption

Yes

No

33

24

57.9

42.1

44.2-71.6

28.4-55.8

Smoking and alcohol consumption

Yes

No

28

29

49.1

50.9

35.3-63.0

37.0-64.7

Dysphagia*

Yes

No

46

10

82.1

17.9

71.2-93.1

6.9-28.8

Tumour location

Cervical

Upper thoracic

Middle thoracic

Lower thoracic

Distal oesophagus

1

5

16

28

7

1.8

8.8

28.1

49.1

12.3

0.0-9.4

2.9-19.3

15.5-40.6

35.3-63.0

2.9-21.7

Histopathologic cell type

Squamous-cell carcinoma

Adenocarcinoma

40

17

70.2

29.8

57.4-82.9

17.1-42.6

TNM classification

Stage 0

Stage I

Stage II

Stage III

Stage IV

3

6

18

19

5

5.9

11.8

35.3

37.3

9.8

1.2-16.2

1.9-21.6

21.2-49.4

23.0-51.5

3.3-21.4

Treatment

Surgery

Surgery and chemotherapy and/or radiotherapy

34

23

59.6

40.4

46.0-73.3

26.7-54.0

na: Number of patients; SDb: Standard deviation; IQRc: Inter-quartile range; CId: Confidence interval; BMIe: Body mass index; *Symptoms/signs before oesophageal cancer diagnosis.



Fig. 1. Recurrence probability for patients with oesophageal cancer after curative surgery.

one year after the surgery. Similarly, the probability of tumour recurrence five years after the surgery is 52.4%, while 29.6% of the patients have died without presenting any recurrence. Therefore, only 18% of the patients will be alive and disease-free five years after curative surgery.

Risk factors for recurrence

The risk factors for recurrence analysed are shown in table I. In the univariate analysis, the histopathologic cell type was not significantly associated with the probability of recurrence during the follow-up, nor any other variable studied, although it may be seen that patients with dyspha-gia on diagnosis, as well as patients in stages III-IV, had a higher probability of recurrence during the follow-up peri-od, as shown in figure 2. After carrying out a multivariate regression analysis, adjusting for gender, age, BMI, Crude Charlson’s comorbidity index, smoking and alcohol con-sumption, histophathologic cell type, TNM classification and treatment, it was found that the TNM classification

is associated with the presence of recurrence during fol-low-up in a statistically significant way (Table II). In order to adjust for age as a clinically relevant and confounding variable and avoid over-adjustment, we included in the model the Crude Charlson’s comorbidity index.

Disease-free survival and recurrence pattern

In patients with recurrence (n = 28), the median for the disease-free interval was 8.5 months (range: 2.0-56.0). After one year of follow-up, 57.1% of the recurrences were diagnosed and 82.1% after 2 years of follow-up, detecting the last recurrence in our series after 56 months of fol-low-up. On evaluating the recurrence pattern we found 10 cases (35.7%) at locoregional level, 11 distant cases (39.3%), and 7 cases (25%) of mixed recurrences. The median for the disease-free interval was 3.5 months (range: 2.0-56.0) for locoregional recurrences, 8 months (range: 4.0-31.0) for distant recurrences, and 17 months (range: 8.0-41.0) for mixed recurrences.



Tab

le II

. Un

ivar

iate

an

d m

ult

ivar

iate

an

alys

is: P

rog

no

stic

fac

tors

fo

r re

curr

ence

of

the

dis

ease

aft

er c

ura

tive

su

rger

y

Oes

opha

geal

can

cer

recu

rren

ce

No

Yes

pC

rude

H

Rd

Adj

uste

d H

Rd†

95%

CIe

(Adj

uste

d H

Rd†)

naM

ean

SDb

Med

ian

IQRc

naM

ean

SDb

Med

ian

IQRc

Age

(yea

rs)

2762

.49.

061

.054

.0-5

9.0

2860

.011

.757

.053

.0-7

1.0

0.54

0.99

0.98

0.94

-1.0

2

BMIf

2026

.23.

926

.323

.0-2

9.6

1924

.33.

523

.920

.4-2

7.0

0.05

0.87

0.91

0.79

-1.0

6

Cru

de C

harls

on’s

com

orbi

dity

inde

x27

1.2

1.7

0.0

0.0-

2.0

280.

80.

91.

00.

0-1.

00.

180.

880.

690.

45-1

.06

Oes

opha

geal

can

cer

recu

rren

ce p

roba

bilit

y (%

)p

Cru

de

HRd

Adj

uste

d H

Rd†

95%

CIe

(Adj

uste

d H

Rd†)

6 m

onth

s1

year

3 ye

ars

5 ye

ars

Gen

der

Mal

e18

.827

.143

.851

.6-

11

Fem

ale

14.3

42.9

42.9

27.6

0.73

1.20

0.45

0.11

-1.8

0

Gas

tro-

oeso

phag

eal r

eflux

*

No

20.6

29.4

44.1

54.7

-1

Yes

14.3

28.6

42.9

47.6

0.62

0.83

--

Smok

ing

and

alco

hol c

onsu

mpt

ion

No

7.1

25.0

32.1

43.9

-1

1

Yes

29.6

33.3

51.9

63.0

0.17

1.67

1.20

0.44

-3.2

3

Dys

phag

ia*

No

0.0

10.0

20.0

30.0

-1

Yes

22.7

34.1

50.0

58.1

0.07

2.67

--

Wei

ght

loss

*

No

8.3

22.2

36.1

49.3

-1

Yes

38.9

44.4

61.1

61.1

0.12

1.86

--

His

topa

thol

ogic

cel

l typ

e

Squa

mou

s-ce

ll ca

rcin

oma

20.5

28.2

43.6

53.2

-1

1

Ade

noca

rcin

oma

12.5

31.3

43.8

50.0

0.92

0.96

2.50

0.82

-7.6

1

TNM

cla

ssifi

catio

n

Stag

es 0

-II8.

012

.016

.030

.0-

11

Stag

es II

I-IV

20.8

25.0

33.3

-0.

072.

008.

492.

75-2

6.22

Trea

tmen

t

Surg

ery

24.2

33.3

39.4

50.5

-1

1

Surg

ery

and

chem

othe

rapy

and

/or

radi

othe

rapy

9.1

22.7

50.0

54.5

0.84

1.08

1.17

0.40

-3.3

8

na : N

umbe

r of

pat

ient

s; S

Db :

Sta

ndar

d de

viat

ion;

IQRc :

Inte

r-qu

artil

e ra

nge;

HRd :

Haz

ard

Ratio

; C

Ie : C

onfid

ence

inte

rval

; BM

If : Bo

dy m

ass

inde

x; *

Sym

ptom

s/si

gns

befo

re o

esop

hage

al c

ance

r di

agno

sis;

†:

Mul

tivar

iate

re

gres

sion

ana

lysi

s ad

just

ing

for:

Gen

der,

age,

BM

I, C

rude

Cha

rlson

’s co

mor

bidi

ty in

dex,

sm

okin

g an

d al

coho

l con

sum

ptio

n, h

isto

phat

holo

gic

cell

type

, TN

M c

lass

ifica

tion

and

trea

tmen

t.



Management of patients with recurrence, and post-recurrence survival

Once recurrence had been detected, treatment with chemo-therapy was given to 4 patients (14.3%), with radiotherapy to 8 patients (28.6%), and a combination of both in 1 patient (3.6%). A self-expanding oesophageal stent was fitted to 1 patient (3.6%), and the remaining 14 patients (50.0%) were given palliative management. The median post-recurrence sur-vival rate was 4.7 months. In the case of patients who received palliative care or an oesophageal stent, the median post-re-currence survival rate was 2.9 months, however in the case of the patients who received chemotherapy, radiotherapy or a combination of both, the post-recurrence survival rate reached 6.5 months (p = 0.074). The global post-recurrence survival curve and the curve for each treatment are shown in figure 3.

DISCUSSION

The recurrence of oesophageal cancer after curative sur-gery continues to be high. In this study, out of the total of

57 patients who underwent curative surgery, 50.9% had some kind of recurrence (locoregional recurrence and/or distant metastasis). This percentage concurs with those from other series published in Europe, in countries such as Great Britain, the Netherlands, France or Spain (7-10,13,16), or in Asia, in countries such as Japan or China (5,6,11,12).

After one year of follow-up, 53.6% of all of the recur-rences were detected; 82.1% after two years, and 85.7% after three years. The last recurrence documented in our series was after 56 months (4 years and 8 months) of fol-low-up. These results concur with those obtained by Abate et al. (14) in 2010, where 56% of the recurrences were detected in the first year of follow-up, 82% in the sec-ond year and 93% in the third year. Lou et al. (15) in a recently published study found that 54% of recurrences were detected in the first year of follow-up and 75% in the second year. Other series published at international level (4,10,16) concur in concluding that the majority of recur-rences are detected during the first 2 years of follow-up.

The majority of the studies analysed (5,6,8-14,16) have found that the degree of tumour invasion, as well as the presence of metastatic lymph, are variables that are asso-

Fig. 2. Recurrence probability for patients with oesophageal cancer after curative surgery according to tumour stage at diagnosis.



ciated with the recurrence of the disease, and similarly, in our study the patients with higher stages had a higher probability of recurrence.

The median for the disease-free interval in our study was 8.5 months (range: 2.0-56.0). Generally, the value for this interval is closer to one year of follow-up, as seen in the studies of Hulscher et al. (7) in the Netherlands, Dresner et al. (8) in the United Kingdom, Nakagawa et al. (11) in Japan, and Abate et al. (14) in California, with disease-free intervals with a median of 11 months, or in the studies of Mariette et al. (9) in France, Sánchez-Pernaute et al. (10) in Madrid or Chen et al. (12) in China, with a median disease-free interval of 12 months. However, in a study from Japan in 2012, Sugiyama et al. (4) found a

median of 8.6 months (range: 1.1-48.0), a figure that was very close to that of our population (Table III).

The prognosis for patients with recurrence is general-ly poor, with post-recurrence survival data of less than 12 months (6,9,12,14), varying between the median of 2.7 months from the study by Dresner et al. (8) in the UK, to the median of 11 months from the study of Lou et al. (15) in New York. In our study, the median for the post-recurrence survival rate was 4.7 months. Despite not finding any statistically significant differences, the post-re-currence survival rate in the patients who underwent more intensive treatment was significantly higher. Similar results were found by Abate et al. (14) in their study from 2010, where the median for the post-recurrence survival rate was 9 months in treated patients, compared to 3 months for patients who did not receive any treatment.

We believe that the limitations of this study are the fact that we do not have tumour markers that could play an important role in the prognosis of oesophageal cancer, and which would help to identify and predict the prognosis of this tumour, as well as to adapt the treatment individually to each patient.

In turn, we have verified that our results concur with those from more extensive series published at international level (8,9,13,14).

It is important to note that in our study we used the competitive risk methodology, which is appropriate for analysing the behaviour of a person who may experience different events during the follow-up of the disease, and that we also provide data on oesophageal cancer, an illness that has a high incidence and mortality rate, and for which there is little data at population level in our region.

CONCLUSIONS

This study shows that the recurrence of oesophageal cancer is very frequent, despite undergoing curative sur-gery. Most recurrences will occur during the 2 years after surgery, meaning that strict follow-up is essential during this period. After diagnosis of a recurrence the prognosis is poor, which means that subsequent studies are necessary to evaluate the different treatments, as well as the different tumour and genetic markers, in order to individually adapt the treatment to these patients.

ACKNOWLEDGMENTS

This study was partially supported by the Post-Special-ization Scholarship of the Professor Novoa Santos Foun-dation (A Coruña, Spain).

Fig. 3. Overall survival and treatment-specific Kaplan-Meier survival curves after recurrence in patients with oesophageal cancer who underwent curative surgery.

Surv

ival

pro

babi

lity

Surv

ival

pro

babi

lity

Time from diagnosis of recurrence (months)

Time from diagnosis of recurrence (months)

Chemotherapy and/or radiotherapy

Palliative treatment

p = 0,074



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Table III. Summary of the literature review on the recurrence of oesophageal cancer

Author Year Country na %Prognostic

factors

Time from surgery to recurrence

Median (months)

Recurrence

1 year 2 years 3 years

2014 Coruña (Spain) 57 50.9 TNM 11 (range: 1.8-56.0) 57.1% 82.1% 85.7%

Morita (5) 1994 Japan 187 50.8% N, TNM 4.7-27.6

Bhansali (6) 1997 Japan 90 43.0% T, NMean = 11 (range:

1.0-59.0)

Hulscher (7) 2000 The Netherlands 149 52.6% TNM 11 (1.4-62.5)

Dresner (8) 2000 United Kingdom 176 48.0% T, N 11.7 (range: 1.5-67) 50%

Mariette (9) 2003 France 439 52.4% TNM 12 (range: 6-96) 45.7% 90%

Sánchez-Pernaute (10) 2003 Madrid (Spain) 92 44.7% T, N, 12 75% 100%

Nakagawa (11) 2004 Japan 174 43.3% T, N 11

Chen (12) 2007 China 196 48.9% T, N 12.2 (range: 2.4-35.6) 100%

Smit (13) 2010 The Netherlands 202 58.9% N 28% 44%

Abate (14) 2010 California (EEUU) 590 40.0% TNM 11 (range: 3.0-72.0) 56% 82% 93%

Sugiyama (4) 2012 Japan 208 29.3% 8.6 (range: 1.1-48.0) 71% 84%

Lou (15) 2013 New York (EEUU) 1147 38.0% Treatment 54% 75%

López-Sebastián (16) 2013 Valencia (Spain) 61 49.2% TNM 10.5 (range: 7.0-68.0) 90%

na: Number of patients.

Documents

Characteristics and pattern of recurrence after curative