Gynecologic Oncology 138 (2015) 8388

Contents lists available at ScienceDirect

Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno

Clinical outcome of recurrent locally advanced cervical cancer (LACC)

submitted to primary multimodality therapies
F. Legge a,, V. Chiantera b, G. Macchia c, A. Fagotti d, F. Fanfani e, A. Ercoli f, V. Gallotta e, A.G. Morganti c,
V. Valentini g, G. Scambia e, G. Ferrandina e
a

Gynecologic Oncology Unit, F. Miulli General Regional Hospital, Acquaviva delle Fonti, Bari, Italy
Gynecologic Oncology Unit, Giovanni Paolo II Foundation, Campobasso, Italy
Department of Radiation Therapy, Giovanni Paolo II Foundation, Campobasso, Italy
d
Gynecologic Surgery Unit, University of Perugia, Perugia, Italy
e
Gynecologic Oncology Unit, Catholic University, Rome, Italy
f
Gynecologic Oncology Unit, Policlinico Abano Terme, Abano Terme, Padua, Italy
g
Department of Radiation Therapy, Catholic University, Rome, Italy
b
c

H I G H L I G H T S
First analysis of recurrences patterns and their association with survival in 364 LACC submitted to surgery after CTRT.
75 recurrences (20.6%) and 54 deaths (14.8%): 89.3% of the recurrences occurred within 24 months, 57.3% were extrapelvic.
Secondary radical resection was the only parameter with independent prognostic role for post-relapse survival.

a r t i c l e

i n f o

Article history:
Received 5 February 2015
Accepted 27 April 2015
Available online 1 May 2015
Keywords:
Recurrent cervical cancer
Chemoradiation
Radical hysterectomy
Post-relapse survival
Prognosis

a b s t r a c t
Objectives. Recurrence of disease represents a clinical challenge in cervical cancer patients, especially when all
available treatment modalities have been used in the primary setting.
The aim of this study was to analyze the patterns of recurrence and their association with clinical outcome in
locally advanced cervical cancer (LACC) patients submitted to primary chemoradiation (CTRT) followed by
radical surgery (RS).
Methods. This study was conducted on 364 LACC patients treated with CTRT plus RS since January 1996 to
July 2012. For each relapse, information on date of clinical/pathological recurrence, and pattern of disease presentation were retrieved. Post-relapse survival (PRS) was recorded from the date of recurrence to the date of death
for disease or last seen. Survival probabilities were compared by the log rank test. Cox's regression model with
stepwise variable selection was used for multivariate prognostic analysis for PRS.
Results. Within a median follow-up of 42 months, 75 recurrences (20.6%) and 54 disease-associated deaths
(14.8%) were recorded. By analysing the pattern of relapse, most of the recurrences were outside the irradiated
eld (n = 43, 57.3%) and the most frequently observed site was visceral (n = 16, 21.3%). Among the parameters
of the recurrence associated with PRS including the pattern of recurrence, the size of recurrence, SCC-Ag serum
levels at recurrence, and secondary radical surgery, only the last one retained an independent predictive role in
reducing the risk of death (p = 0.037).
Conclusions. The feasibility of secondary radical resection positively impacts on PRS of LACC patients submitted
to multimodality primary treatments.
2015 Elsevier Inc. All rights reserved.

1. Introduction

Conict of interest/disclosure statement: The authors have no conicts of interest to

declare.
Corresponding author at: Gynecologic Oncology Unit, F. Miulli General Regional
Hospital, Strada Acquaviva-Santeramo, 70021, Acquaviva delle Fonti, Bari, Italy.
Tel./fax: + 39 3803975117/0803054979.
E-mail address: francescolegge@libero.it (F. Legge).

http://dx.doi.org/10.1016/j.ygyno.2015.04.035
0090-8258/ 2015 Elsevier Inc. All rights reserved.

Cervical cancer is the third most commonly diagnosed cancer and

the fourth leading cause of cancer death in females worldwide. Despite
improvements in screening programs, which have reduced the incidence of advanced stage cervical cancer [1] and the widespread of
chemoradiation (CTRT) as treatment for locally advanced cervical cancer
(LACC), about 3050% of patients diagnosed with LACC will recur and

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F. Legge et al. / Gynecologic Oncology 138 (2015) 8388

ultimately die for the disease [2]. In this context, investigational

approaches employing completion surgery after CTRT have been
explored in order to allow, with respect to brachytherapy, the evaluation
of pathologic response and the surgical removal of possible radiochemoresistant tumor foci thus improving local control and potentially survival. This trimodality approach indeed, resulted in disease-free and
overall survival rates at least comparable to exclusive chemoradiation, with a different long-term toxicity prole [35]: in particular,
chronic toxic effects (e.g. proctitis, cystitis, hydronephrosis) resulted
lower compared to exclusive CTRT probably because of replacement
of utero-vaginal brachytherapy with completion surgery [4]. Among
major criticisms raised against CTRT followed by radical surgery are
the potential higher risk of long-term complications together with the
potential depletion of all available treatment modalities for the recurrent disease [46]. Indeed, the treatment choice for recurrent disease
is primarily dependent on previous therapy and secondarily on the
site of the recurrent tumor together with the patient's performance
status [7,8]. The prognosis of recurrent, previously irradiated, cervical
cancer, with the exception of isolated centropelvic operable lesions, is
grim with reported 5-year survival rates of 313% [911]. As a consequence, the treatment of recurrent LACC remains a clinical challenge,
especially when all available treatment modalities have been used in
the primary setting.
The aim of this study was to analyze the clinico-pathological characteristics and the distribution of recurrences in the specic population of
LACC patients submitted to CTRT followed by completion surgery. The
prognostic impact of the characteristics of recurrence, including its
secondary treatment, has been also investigated.

2. Patients and methods

Since January 1996 to July 2012, 381 consecutive LACC (FIGO Stage
IB2IVA) patients were accrued at the Gynecologic Oncology Unit of
the Catholic University (Rome/Campobasso). Inclusion criteria were:
biopsy-proven carcinoma of the cervix (stage IB2IVA), no evidence of
distant disease, age b80 years, ECOG performance status b 2, adequate
bone marrow, renal and liver function, and no prior cancer other than
basal cell carcinoma. All patients signed a written informed consent
agreeing to be submitted to the neoadjuvant CTRT plus radical surgery
protocol and for their data to be collected, and underwent to whole
pelvic irradiation in 22 fractions (1.8 Gy/day, totalling 39.6 Gy) in combination with cisplatin (20 mg/m2, 2-h intravenous infusion) and
5-uorouracil (1000 mg/m2, 24-h continuous intravenous infusion)
(both on days 14 and 2730), as previously described [1215]; slightly
different schemes of platinum-based chemotherapy and radiotherapy
(total dose from 39.6 to 50.4 Gy) were also employed [1214]. Four
weeks after the end of CTRT, patients were evaluated for objective
response according to RECIST criteria [16], and triaged to laparotomic
radical hysterectomy with pelvic aortic lymphadenectomy (the last
procedure reserved to patients with enlarged aortic lymph node at
imaging/palpation or positive pelvic lymph nodes). After surgery,
patients underwent physical examination, complete blood count and
chemistry with serum tumor markers including Squamous Cell Carcinoma
Antigen (SCC-Ag) measurements, every 3 months for the rst 2 years
and twice per year thereafter; chest radiography and abdominopelvic
MRI (or alternatively chest-abdominopelvic CT scan) were performed
every 6 months for the rst 3 years and every 12 months thereafter;
additional diagnostic procedures were performed according to specic
clinical suspicion [3]. Relapsing patients were triaged to rescue therapies
and represent the object of this analysis. Secondary surgery was considered for patients with single/discrete number of recurrent lesions limited
to a single anatomical district or organ, amenable to complete surgical
eradication; pelvic exenteration was considered, in the absence of extrapelvic disease, for centro-pelvic recurrence non-xed to the pelvic side
wall.

2.1. Statistical analysis

The 2 test or Fisher's exact test for proportion were used to analyze
the distribution of clinico-pathological variables according to different
subgroups. Wilcoxon rank sum nonparametric test was used to analyze
the distribution of continuous values. Disease-free survival (DFS)
was calculated from the date of surgery to the date of relapse or the
date of the last follow-up; post-relapse survival (PRS) was calculated
from the date of relapse diagnosis to the date of death for disease or
the date of the last follow-up. Medians and life tables were computed
using the product limit estimate by KaplanMeier method [17], and
the log-rank test was used to assess the statistical signicance [18].
Cox's regression model was used to perform multivariate analysis of
prognostic factors [19].
Statistical analysis was carried out using SOLO (BMDP Statistical
Software, Los Angeles, CA, USA).
3. Results
Of 381 patients enrolled in our preoperative CTRT protocol, 3 patients
died from intercurrent disease, 4 refused surgery, 1 was lost at follow-up
and 9 progressed during treatment: as a consequence 364 patients were
successfully submitted to completion radical surgery. Clinico-pathological
characteristics of these LACC patients are reported in Table 1.
Among these, within a median follow-up time of 42 months (range
6199), 75 recurrences (20.6%) and 54 disease-associated deaths
(14.8%) were recorded; in addition 8 patients died from intercurrent
causes (5 treatment-related toxicities, one amyotrophic lateral sclerosis,
one breast cancer, one biliary tract cancer), totalling 62 (17%) deaths
for any cause.
The diagnosis of recurrence was histologically proven in 57 (76%)
cases, including 29 patients submitted to a major surgical procedure
(diagnostic/palliative or therapeutic laparoscopy/laparotomy) and 28

Table 1
Clinico-pathological characteristics of the primary tumors (n = 364).
Primary tumors' clinico-pathological characteristics
Age
40 years
N40 years
Histotype
Squamous
Adenoca/adenosquamous
Grade
12
3
F.I.G.O. stage
IB2IIB
IIIAIVA
Tumor size
4 cm
N4 cm
Radiation dose
40 Gy
4050 Gy
Radical surgery (QuerleuMorrow classication)
Class BC
Class D
Lymphadenectomy
Pelvic
Pelvic and paraortic
Pathological response
Complete/microscopic
Partial/no change
Lymph node metastasis
No
Yes
Adjuvant therapy
No
Yes

No. (%)
52 (14.3)
312 (85.7)
327 (89.8)
37 (10.2)
173 (47.5)
191 (52.5)
301 (82.7)
63 (7.3)
58 (15.9)
306 (84.1)
122 (33.5)
242 (66.5)
330 (90.7)
34 (9.3)
247 (67.8)
117 (32.2)
263 (72.3)
101 (27.7)
317 (87.1)
47 (12.9)
316 (86.8)
48 (13.2)

F. Legge et al. / Gynecologic Oncology 138 (2015) 8388

patients submitted to a diagnostic biopsy; in the remaining 18 patients

a biopsy was not safely feasible, and the diagnosis of recurrence was
based on CT/MRI with US scan or PET scan, combined to SCC marker
elevation. The clinico-pathological characteristics of the recurrences,
as well as the secondary treatment performed are reported in Table 2.
The pattern of recurrence was dened by surgical exploration in 29
(38.7%) cases, derived from PET plus standard imaging (CT scan and/
or MRI with or without specic US examination) in 32 (42.7%) cases,
and derived only from standard imaging in 14 (18.7%) cases. The median
interval time from completion surgery to the diagnosis of relapse was
8 months (range 1100) and 89.3% of the recurrences were recorded
within 24 months. Most of the recurrences presented as multiple lesions
(64.7%), larger than 3 cm in size (53.3%) and with a median SCC-Ag
value of >3 ng/ml. The pattern of recurrence most frequently observed
was extrapelvic (n = 43, 57.3%), and among single site recurrences, the
most frequently observed was visceral (n = 16, 21.3%) followed by central pelvic (n = 13, 17.3%) and lymph nodal (n = 11, 14.7%). The analysis of the distribution of the clinico-pathological characteristics of the
primary tumor according to the pattern of recurrence showed
no signicant association (data not shown). By analysing the sites of
relapse for each patient, the most frequently observed site was visceral
(n = 30), followed by central pelvic (n = 22), aortic lymph nodes
(n = 18), lateral pelvic (n = 16), peritoneal (n = 12), and extraabdominal lymph nodes (n = 9) (Fig. 1). Most of the relapsing patients
were treated with chemotherapy alone (n = 48, 64.0%), while radical

Table 2
Clinico-pathological characteristics of the recurrent tumors and secondary treatments (n = 75).
Recurrent tumors' clinico-pathological characteristics
Diagnostic tool
Standard imaging
Standard imaging plus PET
Surgery
DFS from primary treatment
b6 months
612 months
1324 months
N24 months
Number of lesions
Single
Multiple
Size of the largest lesion
3 cm
N3 cm
SCC-Ag levels
3 ng/ml
N3 ng/ml
Pattern of recurrence
Pelvic
Central
Lateral
Mixed
Extrapelvic
Lymph nodes
Visceral
Peritoneal
Mixed
Mixed (pelvic + extrapelvic)
Treatment
Radical surgery
Radical surgery plus chemo.
Radical surgery plus radio.
Radiotherapy
Chemotherapy
Nihil
Type of radical surgery (n = 18)
Pelvic exenteration
Pelvic nodule resection
Aortic lymph node resection
Cranial lesion resection
Lung resection
a

No. (%)
14 (18.7)
32 (42.7)
29 (38.7)
19 (25.3)
27 (36.0)
21 (28.0)
8 (10.7)

85

3
Brain

3
Laterocervical N

6
Bone

3
Mediastinic N
1
Axillary N

16
Lung

3
Liver

1
Stomach 1
Spleen

18
Aortic N
12
Peritoneal
2
16
Groin N
Latero-pelvic 22
Centro-pelvic

34 (45.3)
41 (64.7)
35 (46.7)
40 (53.3)
37 (49.3)
38 (50.7)
24 (32.0)
13 (17.3)
8 (10.7)
3 (4.0)
43 (57.3)
11 (14.7)a
16 (21.3)
8 (10.7)
8 (10.7)
8 (10.7)
3 (4.0)
13 (17.3)
2 (2.7)
3 (4.0)
48 (64.0)
6 (8.0)
6 (33.3)
1 (5.5)
6 (33.3)
3 (16.7)
2 (11.1)

7 aortic, 1 suvraclavear, 2 aortic + inguinocrural, 1 aortic + suvraclavear.

Fig. 1. Graphic representation of the sites of relapse reported for individual patients.

surgery with or without chemotherapy or radiotherapy was performed

in 18 patients (24.0%). In particular, patients who underwent to a
secondary radical surgery presented pelvic (n = 7, 38.9%) or lymph
nodal/visceral recurrent lesions (n = 11, 61.1%), whereas those submitted to medical treatments presented disseminated disease (peritoneal/
mixed pattern of recurrence) in 24 cases (42.1%) with pelvic and
lymph nodal/visceral recurrent lesions observed in 17 (29.8%) and 16
(28.1%) cases, respectively (p = 0.002): among the different clinicopathological parameters of the primary and recurrent tumors, only the
number of recurrent lesions (i.e. single lesions) and the pattern of recurrence (i.e. disease conned to a specic district such as the pelvic region,
the aortic lymph nodes, the brain or the lungs) were associated with the
feasibility of secondary radical surgery (p = 0.0001 and p = 0.002,
respectively).

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F. Legge et al. / Gynecologic Oncology 138 (2015) 8388

Within a median follow-up of 10 months (range 181 months) from

recurrence, 47% of relapsing patients died from the disease (5-years
PRS = 14%; median PRS = 11 months).
Univariate and multivariate analyses for PRS according to the
clinico-pathological features of the recurrent tumor and the type of
secondary treatment are reported in Table 3. Among the parameters
found associated with PRS, i.e. pattern of recurrence (p = 0.0012;
Fig. 2), size of recurrence (p = 0.03), SCC-Ag levels at the time of diagnosis of recurrence (p = 0.0068), and radical surgical resection of
the recurrence (p = 0.00001; Fig. 2), only the last one retained an independent predictive role in reducing the risk of death after recurrence
(p = 0.037). Moreover, the survival advantage of secondary radical
surgery was conrmed in patients with recurrences conned in single
anatomical districts/organs (i.e. pelvic region or lymph nodes or viscera;
p = 0.00001) and in both subgroups of women with recurrences conned in the irradiated pelvic elds (p = 0.002) and in non-irradiated
visceral/lymph nodal elds (p = 0.003).
No signicant differences were found in the rate, pattern and treatment of recurrences as well as in the PRS between the time frames
19962005 and 20062012 (data not shown).

A
PRS (%)
100
Visceral/Lymph nodal

80

p=0.033

Pelvic

p=0.084

Peritoneal/Mixed

60

p=0.0004

40
20
0
0

12

24

36

48

60

72

84

96

months

B
PRS (%)
100
80
60

4. Discussion
40

This is the rst study presenting a comprehensive analysis of the

patterns of recurrence and their association with clinical outcome in a
large single-institutional series of LACC patients submitted to completion surgery after CTRT. Among 364 women submitted to this primary
trimodal treatment we observed a failure in 20.6% of the patients, which
compare favorably with the recurrence rate (28.3%) reported for similar
series of LACC patients treated with exclusive primary CTRT including
brachytherapy [20]. We also conrmed that most of recurrences, i.e.
89.3% in our population, were recorded within 2 years from the primary
treatment, suggesting the key role of frequent clinical and imaging
examinations during the early follow-up.
Interestingly enough, our trimodal strategy focused on completion
surgery after low dose (i.e. 4050 Gy) radiotherapy with concomitant
cisplatinuorouracil chemotherapy seems to warrant an optimal
Table 3
Univariate and multivariate analyses for post-relapse survival according to the
clinico-pathological features of the recurrence and the type of secondary treatment.
Recurrent tumors'
clinico-pathological
characteristics
Pattern of recurrence
Pelvic
Visceral/lymph
nodal metastasis
Peritoneal/mixed
DFS from primary
treatment
b6 months
6 months
Number of lesions
Single
Multiple
Size of the largest lesion
3 cm
N3 cm
SCC-Ag levels
3 ng/ml
N3 ng/ml
Radical surgery
No
Yes

Recurrences Deaths
No.
No. (%)

1-year
PRS (%)

pa

p
(2)

0.0012

0.12
(2.4)

33
50

0.32

22 (64.7)
32 (78.0)

54
39

0.063

0.81
(0.04)

24
27

13 (54.2)
24 (88.9)

64
37

0.030

0.11
(2.6)

33
34

20 (60.6)
27 (79.4)

66
26

0.0068

0.57
(0.3)

57
18

48 (84.2)
29
6 (33.3) 100

24
27

19 (79.2)
14 (51.8)

42
65

24

21 (87.5)

26

19
56

14 (73.7)
40 (71.4)

34
41

0.00001 0.037
(4.35)

Pelvic vs visceral/lymph nodal p = 0.033; pelvic vs peritoneal/mixed p = 0.084; visceral/

lymph nodal vs peritoneal/mixed p = 0.0004.
a
Log-rank test.
Logistic regression for 5 parameters of the recurrent tumor with p 0.10 in univariate
(2 of the model = 39.0 with p = 0.00001).

Radical Surgery

20

No Radical Surgery

p=0.00001

0
0

12

24

36

48

60

72

84

96

months
Fig. 2. Post-relapse survival (PRS) curves according to the pattern of recurrence (A) and
the achievement of complete surgical resection (B).

locoregional control: indeed we observed pelvic recurrences in only

6.6% of patients with respect to the 10.3% of locoregional failure reported
for the largest series of exclusive CTRT [20], a result enforced also by
considering the low rate of mixed pelvic plus distant recurrences (i.e.
3%) found in our series with respect to the 6.7% reported in the Eifel's
exclusive CTRT series. These data suggest that completion surgery is
effective for locoregional control at least as brachytherapy; however,
the low dose radiotherapy regimen used in our protocol may warrant
a better long term tolerability in terms of permanent therapy-related
toxicity and secondary tumors [4].
Moreover, among the 43 patients with extrapelvic relapse, 13
(30.2%) experienced early diagnosis (i.e. within 6 months from completion surgery) of recurrent/persistent disease, including 6 visceral, 3 peritoneal, 2 aortic lymph nodal and 2 mixed extra-abdominal lesions. Since
pre- and post-chemoradiation standard imaging (TAC and MRI) was
silent for extrapelvic disease and completion laparotomic surgery
missed the diagnosis of metastatic disease, the inclusion of PET/CT scan
and/or laparoscopic staging with paraaortic lymphadenectomy in the
pre-treatment work-up up may be useful in early identifying patients
with extrapelvic disease to be addressed to tailored treatments (e.g.
systemic chemotherapy and/or aortic extended-elds chemoradiation)
[21,22].
In addition, by analysing the site of recurrence for each patient, the
paraortic lymph nodes and the lungs were the extrapelvic areas more
frequently involved, thus highlighting the need of a particular consideration of these areas by including CT scan or PET/CT scan in the follow-up
of LACC patients [23].
The median survival after recurrence was 11 months in our series, a
result that compares favorably with the survival after recurrence reported for patients treated with primary denitive radiotherapy [7,24]
or chemoradiation [7]. Interestingly enough, patients with visceral
(e.g. lungs, bones, liver, brain) or lymph nodal metastatic relapse showed
a median survival doubled (23 months) with respect to those with pelvic
recurrence (10 months) and tripled with respect to those with peritoneal

F. Legge et al. / Gynecologic Oncology 138 (2015) 8388

or mixed recurrences (7 months). Although, a less aggressive biological

behavior can be hypothesized for tumors relapsing in a single, previously
non-irradiated area, as previously shown in other tumors such as ovarian
cancer [25], we have to consider the potentially favorable impact of
secondary surgery. Indeed in our series, radical surgery was performed
in 40.7% of the patients with visceral or lymph nodal recurrences, in
29.2% of those with pelvic disease and in none with peritoneal disease
or mixed sites of recurrence. Moreover, among the different clinicopathological parameters of the primary and recurrent tumor, the pattern
of recurrence was the only one associated with feasibility of secondary
radical surgery.
We have to acknowledge that the study was not designed to compare radical resection of recurrent disease with respect to non-surgical
options and, being retrospective it may suffer from a selection bias
since patients who underwent a secondary radical surgery have recurrent disease conned in a single district/organ whereas those addressed
to other salvage treatments presented disseminated disease in 42.1% of
the cases. However, most clinically important we have to consider that:
i) the survival benet of secondary radical surgery was conrmed in
patients with disease conned in single anatomical districts/organs
(i.e. pelvic region or lymph nodes or viscera); and ii), among the parameters associated with recurrence's prognosis in univariate analysis,
secondary radical surgery was the only one factor that retained an independent prognostic role for survival, with a median PRS of 46 months
for patients submitted to complete resection of the relapsed lesions.
The prognostic impact of radical surgery has been previously reported
in patients with recurrent cervical cancer, with most of the papers
focusing on the role of pelvic exenteration. Pelvic exenteration indeed,
represents a valid therapeutic option for patients with previously irradiated central pelvic recurrence, with 5-years survival rates reported
between 30% and 40% [26,27]. In addition, possible indications for pelvic
exenteration have widened over the years, by including in the last
decade, patients with specic features (e.g. no tumor inltration at the
site of the sciatic foramen, no leg oedema) of lateral pelvic recurrences,
who can equally benet from pelvic exenteration with laterally extended
endopelvic resection (LEER) with curative intent [2729]. On the contrary exclusion criteria for secondary pelvic exenteration still vary
considerably: whereas the majority of surgeons consider intraperitoneal
tumor spread and multiple distant metastases as absolute contraindications to pelvic exenteration, lymph node involvement, large tumor size,
or disease free survival b6 months, despite having both a negative impact
on survival, are not unanimously regarded as absolute exclusion criteria
for this ultraradical procedure [26,27]. In this context, we conrmed,
as discussed above, the detrimental role of peritoneal recurrence as
carcinosis, whereas tumor size of the recurrence and the interval time
from the completion of primary treatment (i.e. DFS) was not found associated with survival. In particular, the lack of a clear prognostic role for
DFS in recurrent cervical cancer may indicate that a short DFS, differently
from ovarian cancer, does not represent only a marker of chemoresistance, given also the lower chance of response to platinum-based
chemotherapy of this disease, but may be mainly related to the persistence of microscopic disease from primary treatment [30]. As a consequence, a short DFS should not be considered as an absolute criterion
for excluding recurrent LACC patients from secondary radical surgery.
In addition to pelvic secondary radical surgery, we showed a survival
benet of surgical resection of metastatic lesions conned in single
anatomical districts outside the irradiated elds, mostly involving the
aortic lymph nodes, but also visceral metastasis in the brain or in the
lungs: this nding has been rarely investigated in the literature
with only a few case series reported mostly focusing on lung metastases
[31].
In conclusions, the feasibility of secondary radical resection positively
impacts on survival of recurrent LACC patients submitted to multimodality primary treatments, thus prompting practitioners treating
patients with recurrence from cervical cancer to consider secondary
surgery in the armamentarium of potential therapies.

87

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