Annals of Oncology 15: 296–300, 2004

Original article DOI: 10.1093/annonc/mdh049

Use of totally implantable central venous access ports for high-dose

chemotherapy and peripheral blood stem cell transplantation:
results of a monocentre series of 376 patients
R. Biffi1*, S. Pozzi1, A. Agazzi2, U. Pace1, A. Floridi1, S. Cenciarelli1, V. Peveri1, A. Cocquio2,
B. Andreoni1 & G. Martinelli2
1
Division of General Surgery, European Institute of Oncology, Milan; 2Division of Clinical Hematoncology, European Institute of Oncology, Milan, Italy

Received 30 April 2003; revised 26 August 2003; accepted 5 September 2003

Background: The complication rate of central venous totally implantable access ports (TIAP), used for high-
dose chemotherapy with autologous stem cell transplantation support, has not been fully investigated to date,

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due to the almost exclusive use of externalised, tunnelled devices in this clinical setting.
Patients and methods: During a 66-month period (from 1 January 1997 to 30 June 2002), 376 patients
suffering from breast cancer, ovarian cancer, lymphoma or multiple myeloma were treated with high-dose
chemotherapy and autologous stem cell transplantation at the European Institute of Oncology (Milan, Italy).
A single type of port was used, constructed from titanium and silicone rubber, connected to a 7.8 F polyurethane
catheter (Port-A-Cath™; SIMS Deltec, Inc., St Paul, MN, USA) inserted into the subclavian vein. They were
followed prospectively for device-related complications until the device was removed, the patient died or the
study was closed (30 June 2002).
Results: No TIAP-related deaths were observed in this series. Seven pneumothoraxes (1.8%) occurred as a
complication of TIAP placement, one patient only (0.2%) requiring a tube thoracostomy. Port pocket infection
occurred twice in this series (0.53%, 0.01 episodes/1000 days of use), whereas three patients suffered from port-
related bacteraemia (0.8%, 0.016/1000 days of use). Infections were successfully treated with antibiotics; all
three cases had the ports removed at programme completion. Four cases of deep vein thrombosis were detected
(1.06%, 0.022/1000 days of use); low molecular weight heparin was given, followed by oral anticoagulants.
Finally, one case of extravasation occurred (0.26%, 0.005/1000 days of use), requiring port removal and local
medical therapy.
Conclusions: The use of TIAPs has resulted in a safe and effective option for high-dose chemotherapy deliver-
ance and stem cell transplantation, in spite of inducing severe neutropenia and increasing the risk of sepsis in
this category of oncology patient.
Key words: central venous catheters, high-dose chemotherapy, peripheral blood stem cells transplantation,
ports

Introduction totally implantable central venous access ports (TIAP) in patients

undergoing HDCT and autologous PBSCT or BMT [3]; a possible
A central venous access is always necessary for the management
explanation for this is that TIAP cannot be easily withdrawn,
of patients undergoing high-dose chemotherapy (HDCT), with
unlike cuffed or non-tunnelled catheters, when an infectious
concomitant bone marrow transplantation (BMT) or autologous
catheter-related complication occurs. In addition, their crude cost
peripheral blood stem cells transplantation (PBSCT), as it allows
is much higher than tunneled, cuffed external devices, although
for easy drawing of blood samples and administration of drugs,
comparative and comprehensive economic evaluations are scanty.
antibiotics, blood products, fluids and nutrition; all essential parts
The aim of this study was to investigate, in a prospective way, the
of the therapeutic programme. Tunnelled, cuffed silastic catheters
use of TIAP in this clinical setting, analysing the relevant number
(Hickman-Broviac, Bard Inc., Salt Lake City, UT, and similar
of consecutive patients treated at a single institution with a single
devices) provide trouble-free function for most patients and cur-
type of device.
rently represent the most frequently adopted intravenous line [1, 2].
There are very few studies and little data concerning the use of
Patients and methods
At the European Institute of Oncology (Milan, Italy), 376 cancer patients were
*Correspondence to: Dr R. Biffi, Division of General Surgery, European
Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy. Tel: +39- treated with HDCT and autologous PBSCT during a 66-month period from
02-57489672; Fax: +39-02-57489878; E-mail: roberto.biffi@ieo.it 1 January 1997 to 30 June 2002. Patient characteristics and the HDCT regimens

© 2004 European Society for Medical Oncology

 297

Table 1. Population characteristics, type of tumour and Table 2. Details of port use
chemotherapy programmes
No. of ports, n (%) 377 (100)
No. of ports 377 Days in situ
No. of patients 376 Mean 473
Age, years Range 1–1419
Mean 41.8 Days in situ (overall) 178.065
Range 22–62 Devices still in situ (30 June 2002), n (%) 232 (61.5)
Sex (male/female) 72/304 Devices removed for complications, n (%) 11 (2.9)
Sequential chemotherapy for lymphomaa, n (%) 79 (21) Devices removed after completion of treatment, n (%) 52 (13.7)
L-PAM chemotherapy for myelomab, n (%) 14 (3.7) Deceased patients, n (%) 82 (21.7)
High-dose EC chemotherapy for breast cancer 153 (40.7)
(± Taxotere®)c, n (%)
High-dose ICE chemotherapy for breast or 85 (22.6)
ovarian cancer (± Taxotere®)d, n (%) tazobactam was used for patients affected by solid tumours. An appropriate
Different HDC for breast cancer, n (%) 24 (6.3) systemic antibiotic therapy was subsequently started, based on the suscep-
tibilities of the isolate, if any. Criteria for the diagnosis of device-related

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Different HDC for other tumours, n (%) 21 (5.5)
bacteraemia were defined as follows: a, a >10-fold increase in colony-forming
a units (c.f.u.) of bacteria per ml of blood obtained through the device in
CTX 7 g/m2, MTX 8 g/m2 and VP-16 2 g/m2 (Idarubicin i.c. 15 mg/
comparison to peripheral blood cultures; b, >1000 c.f.u. of bacteria obtained
m2/day + L-PAM 180 mg/m2 + PBSC support).
b
through the device, in the absence of peripheral blood cultures; or c, positive
Alkeran 200 mg/m2 plus PBSC support in a single or double
catheter tip culture upon removal in the appropriate clinical setting. Device-
transplant.
c related bacteraemia was considered cured when culture results were negative
Iphosphamide 2500 mg/m2, carboplatin 300 mg/m2, etoposide 300
at the discontinuation of antimicrobial therapy and no evidence of clinical
mg/m2 and PBSC support repeated every 28 days for three cycles.
d infection occurred in the following 2 weeks.
Epirubicin 200 mg/m2, cyclophosphamide 4 g/m2 and PBSC support
Port pocket infection was defined as induration, erythema and tenderness
repeated every 28 days for three cycles.
around the port with culture-positive material aspirated from the port pocket.
CTX, cyclophosphamide; HDC, high-dose chemotherapy; MTX,
Cutaneous site infection was defined as induration, erythema, or tenderness
methotrexate; L-PAM, melphalan; PBSC, peripheral blood stem
and exudate at the port surface needle access site.
cells; VP-16, etoposide.
Thrombosis was detected with ultrasound and/or venography when clinic-
ally suggested by progressive arm or facial swelling. Prophylaxis for venous
thromboembolism (i.e. daily minidose oral warfarin or subcutaneous low
used are reported in Table 1. Each patient underwent the placement of a single
molecular weight heparin) was not applied in this study population.
type of TIAP, constructed from titanium and silicone rubber, connected to a
7.8 F polyurethane catheter (Port-A-Cath™; SIMS Deltec, Inc., St Paul, MN,
USA), inserted in the subclavian vein. All devices were placed under local Results
anaesthesia in the operating room and employing fluoroscopic control by three
experienced surgeons (R.B., S.P. and U.P.) using maximal sterile-barrier pre- Three hundred and seventy-seven devices were placed in 376 patients
cautions. A confirmatory chest X-ray was always obtained after placement and (304 female, 72 male), resulting in a total of 178.065 days in situ;
a central venous access form was filled in by the operator after the procedure. adequate follow-up was obtained in all cases (mean, 473 days;
A single dose of cefazoline sodium 2 g was given intravenously 15 min before range, 1–1419) and all patients except one received the planned
implantation. No breaks in operative technique or instrument sterility were chemotherapy and re-infusion of stem cells through the TIAP.
documented. Our institutional policy restricts the use and maintenance of ports Devices still in situ at the end of follow-up were 232 (61.5%);
to specialised nursing staff, who always perform the blood withdrawals for death occurred in 82 patients (21.7%), while 11 ports (2.9%)
laboratory testing. To prevent clot formation and catheter blockage, TIAPs
where prematurely removed as a consequence of complications
were flushed with 20 ml normal saline and then filled with sterile heparinised
and 52 devices (13.7%) were removed after the conclusion of the
saline after each infusion of medication or blood withdrawal (5 ml of a solution
containing 50 IU/ml heparin). Data from the follow-up of patients were
planned treatment (Table 2).
recorded at regular intervals and collected in a software registry, with specific
attention to device-related and overall complications. Follow-up was con- Early complications
tinued until the device was removed, the patient died or the study was closed
We did not observe any TIAP-related deaths in this series. A
(30 June 2002).
pneumothorax was observed as a complication of TIAP placement
Complications were classified into two main categories: (i) early (intra-
in seven patients (7/377, 1.8%); one patient only (0.2%) required a
operative and post-implantation period to first use) and (ii) late complications
(occurring after the first chemotherapy course given through the device).
tube thoracostomy to treat a large pneumothorax, with no addi-
Blood screening for bacteraemia was not performed at regular intervals
tional morbidity. One patient experienced an atrial fibrillation as a
since blood sampling for microbiology was obtained when clinically suggested consequence of the port implant; it was successfully treated with
(unexplained fever and/or signs of sepsis). Intravenous antimicrobial therapy, port removal and re-implantation on the opposite side. Finally,
including amikacine and ceftazidime, was initiated empirically in febrile one patient had an accidental arterial puncture during the implant
neutropenic patients suffering from lymphoma or myeloma, whereas piperacillin– procedure, which did not cause any significant complication.
298
Table 3. Late complications
Complication No. % /1000 days of port use
Deep vein thrombosis 4 1.06 0.022
Pocket infection 2 0.53 0.010
Port related bacteraemia 3 0.8 0.016
Extravasation 1 0.26 0.005
Total 10 2.65 0.053
Furthermore, no cases required an early revision of the implant
for malfunction of the catheter due to a narrowing of the lumen or
primary dislocation.
Late complications
Late complications observed in this study are listed in Table 3.
Port pocket infection occurred twice in this series (0.53%, 0.01
episodes/1000 days of use); the causative agent was not identified
in one case by laboratory tests, although a purulent discharge was
collected from the port’s subcutaneous pocket. The other case was
caused by Staphylococcus epidermidis. The devices were removed
and the infection successfully cured, with no additional morbidity.
Twenty-eight patients developed febrile neutropenia of unknown
origin (FUO), while only three suffered from port-related bacter-
aemia (0.8%, 0.016/1000 days of port use). Causative agents were
Streptococcus mitis and S.epidermidis (two cases). The infections
occurred 25–38 days after implantation, and were successfully
treated with the appropriate systemic antibiotics; the ports were
removed after completing the therapeutic programme.
Four cases of deep vein thrombosis have been detected (1.06%,
0.022/1000 days of port use), at varying intervals after port place-
ment (range 14–35 days). Low molecular weight heparin was given,
then to obtain a therapeutic INR (International Normalized Ratio),
oral anticoagulants were administered for 3 months. Ports were
always removed. Finally, one case of extravasation occurred
(0.26%, 0.005/1000 days of port use), requiring port removal and
local medical therapy. All patients received therapeutic support
through the port, such as antiemetics, fluids, platelets and red
blood cells transfusions, and antibiotics; blood samples were regu-
larly collected. No problems were reported during or following
these procedures. In only 12 of 376 cases has it been necessary to
apply 25 000 IU urokinase to remove fibrin from the catheter and
restore normal flow through the device.
After discharge of the patient, washing the TIAP just once every
3 months with normal saline maintained its complete functional-
ity.
Discussion
Tunnelled, cuffed silastic catheters (Hickman-Broviac and similar
devices) currently represent the most frequently adopted intra-
venous line for patients undergoing HDCT with concomitant
BMT or autologous PBSCT [1, 2], as multiple blood tests, trans-
Actions taken
Anticoagulation and port removal
Antibiotics and port removal
Antibiotics and port removal
Removal and local treatment
fusions and nutrition are more easily accomplished with a larger
bore catheter, allowing high flow and easy removal, with a cuff
and a subcutaneous tunnel limiting the possibility of catheter-
related infections. The innovative use of TIAP in this clinical
setting, based on a small series of patients, has been previously
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reported by our group [3]; the present paper is an update of that
initial experience and represents the largest published series of
TIAP used for HDCT deliverance with concomitant PBSCT. With
a lack of well designed and appropriately powered randomised
trials, it is difficult to compare different device-related morbidity;
data reported in the literature are sometimes conflicting [4–7]—
most series reflecting differences in the patient populations being
treated, rather than superiority of one device over another. Com-
pared to tunnelled catheters, port infections tend to be lower;
several retrospective studies have noted higher infection rates for
external devices compared with TIAP in selected patient popula-
tions [8, 9], but a prospective randomised study was unable to
demonstrate a statistically significant difference [10]. This study
showed that infection rates are much higher for both tunnelled
catheters and ports than reported by others, in part due to the fact
that the vast majority of the patient population had haematological
malignancies. The active, negative role of neutropenia in promot-
ing catheter-related infections was clearly demonstrated by a study
of nosocomial septic events in cancer patients: 61% of septic
episodes occurred when the patients were neutropenic [11].
In a randomised study of infectious morbidity in patients with
solid tumours, TIAP have been shown to be associated with fewer
infections than were catheters [12]. Most often, these septic events
respond to the appropriate antibiotics without the need for catheter
withdrawal [13, 14]; removal may be necessary for persistent
or recurrent bacteraemia or for fungal infections. In spite of an
accurate implant procedure and appropriate post-implantation
care, catheter-related infections are reported in 11–45% of
patients with Hickman catheters [10, 14, 15], 0–22% of patients
with TIAP [7, 10, 16–18] and 7–32% of patients with Groshong
catheters [Bard Inc., Salt Lake City, UT; 14, 16, 19–22]. BMT
recipients are particularly prone to developing catheter-related
infectious complications; usually they exceed 20% for subcutaneous
tunnelled devices [8, 23]. Non-tunnelled catheters have been
recently proposed for patients undergoing BMT [24] as they can be
easily inserted and withdrawn without surgery; conversely, they
exhibited a 15% catheter-related infection rate. Data from our
study, derived from a large, prospective, non-randomised study,
support the conclusions of most retrospective papers: the infec-

tious morbidity related to TIAP is very low, even in patients
undergoing HDCT. Compared with externalised catheters, TIAP
are irrigated less frequently, require no home care and are less
prone to environmental or cutaneous contamination when not
accessed. All these factors may contribute to the reduced inci-
dence of infections associated with TIAP. It should be underlined
that ∼75% of the patients we have treated suffered from solid
tumours (Table 1), with relatively short durations of neutropenia.
As the majority of studies using Hickman catheters (i.e. tunnelled
central venous externalised catheters) refer to haematology/oncol-
ogy patients with longer neutropenia, this may in part explain the
good results obtained here.
The incidence of catheter-related symptomatic venous throm-
bosis has been quite low in this study (Table 3); no useful data are
available from retrospective analyses of clinical and autopsy
reports in the medical literature, where the incidence varied from
0 to 50% [25, 26]. In a controlled randomised trial, prospective
venography was performed as part of a study of prophylactic low-
dose warfarin treatment, with a symptomatic thrombosis rate in
untreated patients of 12.5% and an overall rate (symptomatic plus
silent) of 38% (15 of 40) [27]. Another prospective study in cancer
patients using the same device (Port-a-Cath™ subclavian venous
catheter) reported a rate of upper extremity deep vein thrombosis
of 62% in the control group, and 6% in patients taking 2500 IU
subcutaneous Fragmin™ once daily for 90 days (relative risk,
6.75; P = 0.002, Fisher’s exact test [28]). Clinical data derived
from our study are not fully comparable, due to differences in the
patient populations and absence of regular ultrasound scans or
phlebografic monitoring, thus limiting the diagnosis of venous
thrombosis to clinically relevant cases; however, they do not
support the routine use of low dose anticoagulants in patients
bearing a TIAP [29], at least in this clinical setting (high-dose
chemotherapy and PBSCT).
The possibility of reinfusing PBSC and transfusing platelets
and blood from the TIAP without any significant complications
has been confirmed by this study, thus demonstrating a new use
for this kind of device. However, it should be noted that single-
lumen TIAPs can not be used for apheresis; it was performed in
our series through peripheral veins whenever feasible, and a double-
line, 14 F polyurethane catheter was inserted in the internal
jugular vein as a bedside procedure when peripheral veins were
not suitable for apheresis.
In conclusion, the use of totally implantable ports has resulted
in a good option for long-term access to central veins and delivery
of high-dose chemotherapeutic regimens with concomitant auto-
transplantation of stem cells, in spite of severe neutropenia and
increased risk of sepsis in this category of oncology patients.
Although multicentre randomised clinical trials are needed to
define the optimal device in this clinical setting, the results of this
prospective, non-randomised study support the wider use of TIAP
in oncology patients undergoing HDCT and autologous stem cells
transplantation.
Acknowledgements
This study has been supported by a research grant from Associ-
azione Italiana per la Ricerca sul Cancro (AIRC).
299
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