Accepted Manuscript Title: Veterinary interventional oncology: from concept to clinic Author: Chick Weisse PII: DOI: Reference:
S1090-0233(15)00124-0 http://dx.doi.org/doi:10.1016/j.tvjl.2015.03.027 YTVJL 4465
To appear in:
The Veterinary Journal
Accepted date:
23-3-2015
Please cite this article as: Chick Weisse, Veterinary interventional oncology: from concept to clinic, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.03.027. 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.
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Review Veterinary interventional oncology: From concept to clinic Chick Weisse * Animal Medical Center, New York City, NY, USA * Corresponding author. Tel.: +1 646 5861798 E-mail address: [email protected] (Chick Weisse)
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13 14
Highlights
materials for therapeutic purposes.
15 16
21
IO provides alternative therapeutic solutions for cancers with no safe or effective traditional options
19 20
Interventional oncology (IO) is a growing subspecialty of IR in human medicine.
17 18
Interventional radiology (IR) combines imaging modalities and delivery of
With IO, dose escalations to tumors can be achieved without increasing systemic exposures.
22 23 24 25
Abstract
26
Interventional radiology (IR) involves the use of contemporary imaging
27
modalities to gain access to different structures in order to deliver materials for
28
therapeutic purposes. Veterinarians have been expanding the use of these
29
minimally invasive techniques in animals with a variety of conditions involving
30
all of the major body systems. Interventional oncology (IO) is a growing
31
subspecialty of IR in human medicine used (1) to restore patency to malignant
32
obstructions through endoluminal stenting, (2) to provide dose escalations to
33
tumors without increasing systemic chemotherapy toxicities via superselective
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34
transarterial chemotherapy delivery, (3) to stop hemorrhage or reduce blood flow
35
to tumors via transarterial embolization or chemoembolization, and (4) to provide
36
therapies for those cancers with no safe or effective alternative options.
37 38
This review provides a brief introduction to a few of the techniques currently
39
available to veterinarians for cancer treatment. For each technique, the concept for
40
improved palliation, patient quality of life, or tumor control is presented, followed
41
by the most current veterinary clinical information available. Although promising,
42
more studies will be necessary to determine if veterinary IO will provide the same
43
benefits as has already been demonstrated in oncology care in humans.
44 45
Keywords:
Oncology;
Veterinary;
Interventional;
Treatment;
Dog;
Cat.
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46
Introduction
47
Interventional radiology (IR) involves the combination of minimally
48
invasive approaches and contemporary imaging modalities to gain access to
49
specific organs in order to deliver a variety of devices or medications for
50
therapeutic purposes (Rösch et al., 2003). First developed over 50 years ago, IR
51
techniques have expanded considerably with both vascular and non-vascular
52
procedures being performed routinely in humans (Rösch et al., 2003).
53
Specifically, IR techniques are being increasingly utilized to help manage humans
54
with cancer (interventional oncology or IO) in which traditional therapies have
55
failed or have been shown to provide little benefit. IO has been previously
56
referred to as the ‘fourth pillar’ of oncological care along with medical, surgical,
57
and radiation therapies (Geschwind and Soulen, 2008). The techniques are
58
particularly useful in cases of regional disease in order to maximize local
59
effectiveness and minimize systemic toxicity or complications.
60 61
Non-resectable and metastatic tumors present a difficult challenge for
62
veterinarians and pet owners. Surgery is rarely indicated when resections have a
63
high likelihood of subsequent complications and low likelihood of improved
64
survival times. The relatively limited efficacy of intravenous (IV) chemotherapy
65
for macroscopic disease, and the cost, occasional morbidity, and tumor resistance
66
associated with radiation therapy have stimulated the search for additional
Page 4 of 22
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therapeutic options. Initial results have been promising and regional techniques,
68
such as palliative stenting for malignant obstructions, intra-arterial chemotherapy,
69
trans-catheter arterial embolization/chemoembolization, and percutaneous tumor
70
ablation, are becoming increasingly investigated.
71 72
In the veterinary oncology community we have been evaluating the use of
73
these therapies in pets with cancer, and this review provides a brief introduction to
74
the concepts behind the most commonly used regional tumor therapies, and the
75
current clinical applications and results obtained to date.
76 77
Palliative stenting for malignant obstructions
78
Concept
79
Animals are often euthanased due to the local effects of a tumor rather
80
than the systemic impact associated with a large cancer burden. While these
81
conditions can occur in any lumen, such as those of the respiratory,
82
gastrointestinal, and cardiovascular systems (Fig. 1), one of the more common
83
examples is malignant obstructions of the urinary tract associated with transitional
84
cell carcinomas (TCCs) or prostatic tumors. These may result in life-threatening
85
signs associated with complete urinary tract obstruction and often lead to owner-
86
elected euthanasia, even when the disease remains otherwise localized.
87
Page 5 of 22
88
Minimally invasive endoluminal urethral stenting and endoscopic or
89
percutaneous ureteral stenting have been performed in humans to relieve both
90
lower and upper tract obstructions (Chao et al, 2011; Chitale et al., 2002). It
91
should be noted that while endoscopic-guided laser ablation is a common therapy
92
for the typically superficial TCCs found in humans, this is not recommended for
93
the less common and more aggressive muscle-invasive TCCs (which are the most
94
common form of canine TCC). In considering the complications of TCCs in dogs,
95
namely, laser ablation (L'Eplattenier et al., 2006; Cerf et al., 2012), cost, extended
96
hospitalization times, need for repeat procedures (~47%), possible limitation to
97
females, and other similar outcomes, stenting appears to compare favorably.
98 99
Clinic
100
Veterinary IO techniques involving the placement of intra-luminal stents
101
to palliate malignant obstructions have now been described for the respiratory,
102
gastrointestinal and cardiovascular systems, as well as for the urinary tract, which
103
seems to be the most commonly affected body system in our clinic (Fig. 1) (Hume
104
et al., 2006; Weisse et al., 2006, 2011; Culp et al., 2007; Schlicksup et al., 2009;
105
Berent et al., 2011; Hansen et al., 2012; McMillan et al., 2012; Blackburn et al.,
106
2013; Brace et al., 2014). These procedures are performed through natural orifices
107
(or small percutaneous holes) under fluoroscopic guidance, and often as
108
outpatient procedures.
Page 6 of 22
109 110
IO techniques involving the urinary tract are generally rapid, safe,
111
minimally invasive, and effective, and complications (such as tumor ingrowth into
112
the stent or stent migration) are minor or uncommon. Stented malignant urethral
113
obstructions were reported to have been relieved immediately in 97% of patients,
114
with mild to absent stranguria in 75% of patients (Weisse et al., 2006; McMillan
115
et al., 2012; Blackburn et al., 2013). Animals receiving chemotherapy and non-
116
steroidal anti-inflammatory drugs (NSAIDs) in addition to stenting demonstrated
117
prolonged survival times (250 days) in partially to completely obstructed patients
118
with low morbidity (i.e., limited to 25% major incontinence rates) (Blackburn et
119
al., 2013). The technique is generally performed as an outpatient procedure at
120
many of the major oncology veterinary centers in the USA and appears to be one
121
of the favored techniques for minimally invasive management of acute malignant
122
urinary obstructions in dogs. Recently, similar positive outcomes, characterized
123
by low morbidity and similar incontinence rates, have been reported with urethral
124
stenting in cats with benign or malignant urethral obstructions (Brace et al.,
125
2014).
126 127
Similar techniques can also be used in upper urinary tract obstructions
128
through an 18 G renal puncture performed under ultrasound guidance, followed
129
by fluoroscopic guide wire, catheter, and stent manipulations. In a recent series of
Page 7 of 22
130
canine malignant ureteral obstructions treated with percutaneous ureteral stent
131
placement, the techniques were successful in 11/12 dogs with all azotemic dogs
132
demonstrating reduction in blood urea nitrogen (BUN) and serum creatinine
133
concentrations, and a reduction in the degree of hydronephrosis in the 10 dogs
134
that were evaluated post-operatively (Berent et al., 2011). This procedure is
135
typically outpatient and remains technically demanding; however, it can also be
136
performed via a small open surgical technique for those without prior
137
interventional training.
138 139
While euthanasia for local obstruction is often no longer necessary due to
140
the advent of intraluminal stenting, management of subsequent metastases is
141
becoming more critical to control. Local surgical resection is often incomplete
142
due to the common trigonal location, or is non-durable when apical tumors are
143
removed due to skip metastases or de novo TCC tumors elsewhere within the
144
lower urinary tract. Recently, a combination interventional/surgical procedure has
145
been described (in an abstract format) outlining how to facilitate en block
146
resection of the distal ureters, bladder, and proximal urethra; the objective was to
147
enable more aggressive tumor resections in the hope of improving tumor-free
148
margins in these often diffuse, complex surgical cases (Fig. 1F) (Weisse et al.,
149
2014). Alternatively, regional chemotherapy administration may provide
150
improved biological response rates as described below.
Page 8 of 22
151 152
Intra-arterial chemotherapy delivery
153
Concept
154
Current therapies for bulky tumors that are not amenable to complete
155
surgical resection commonly include chemotherapy, radiation therapy, and
156
surgical debulking, but none are consistently able to produce durable remissions
157
(Geschwind and Soulen, 2008). Specific tumor cell subtypes tend to be more
158
sensitive to certain chemotherapeutic agents, and increasing the concentration of
159
these drugs tends to increase both tumor cell death and systemic toxicity. This
160
dynamic creates a delicate balance of risk vs. benefit that must be considered by
161
the oncologist before choosing a chemotherapy plan and dose, or prescribing a
162
dose escalation.
163 164
IR techniques can deliver these drugs into the terminal arteries that are
165
feeding the tumors via minimally invasive approaches. The theoretical result is
166
elevated regional drug concentrations within the tumor without the systemic side
167
effects that would occur had similar levels been achieved through higher
168
concentrations administered IV. A local dose escalation is achieved without the
169
associated increased systemic toxicities. Several studies have confirmed both the
170
higher levels of chemotherapeutic agents within the targeted tissues and the
Page 9 of 22
171
improved tumor remissions in laboratory animals (von Scheel et al., 1984;
172
Sumiyoshi et al., 1991; Hoshi et al.,1997).
173 174
Clinic
175
These techniques are performed via a small surgical cut-down to the
176
carotid or femoral arteries performed under fluoroscopic guidance. These are now
177
routine outpatient procedures and have been described in clinical veterinary cases
178
(Weisse et al., 2009), and at the Animal Medical Center we have recently
179
completed a recent study that supports this theory (unpublished data). In this
180
retrospective work, two statistically similar populations of dogs with urothelial
181
carcinoma received either (1) IV carboplatin and oral NSAIDs, or (2) super-
182
selective intra-arterial carboplatin and meloxicam (Fig. 2). The intra-arterial
183
group demonstrated a statistically greater reduction in tumor length, and in
184
percent length, width and unidimensional measurements compared with the IV
185
group. The intra-arterial group was also statistically more likely to achieve a
186
positive tumor response as characterized by modified RECIST criteria1. In
187
addition, compared with the IV group the intra-arterial group was statistically less
188
likely to develop some adverse events, including anorexia and lethargy, following
189
chemotherapy. Complications were minor or uncommon, and consisted of
190
chemotherapy-associated adverse events (similar to what is observed with 1
See: http://www.eortc.org/investigators-area/recist (accessed 01 February 2015)
Page 10 of 22
191
systemically administered chemotherapeutic agents) or rarely surgical incision
192
discomfort/irritation.
193 194
Trans-arterial embolization (TAE)/chemoembolization (TACE)
195
Concept
196
Embolization refers to the delivery of a device or materials to interrupt
197
blood flow. This can occur naturally in a disease state such as with a
198
thromboembolism, or can be therapeutically achieved during an IO procedure in
199
which small particles (typically polyvinyl alcohol or hydrogel polymers in the 80
200
- 500 m diameter range) injected into a tumor capillary bed obstruct blood flow,
201
resulting in subsequent tissue ischemia. The more ‘distally’ (or closer to the
202
capillary bed) the embolization occurs, the more likely ischemia will be achieved
203
(which is why very small particles are chosen for these procedures).
204 205
Chemoembolization involves super-selective intra-arterial chemotherapy
206
delivery in conjunction with subsequent particle embolization. Intra-arterial
207
chemotherapy has been shown to result in a 10- to 50-fold increase in intra-
208
tumoral drug concentrations when compared to systemic IV chemotherapy
209
administration (Dyet et al., 2000). Subsequent particle embolization results in
210
tumor cell necrosis and limits the release by tumor cells of chemotherapeutic
211
agents resulting in minimized systemic toxicity.
Page 11 of 22
212 213
This procedure is most commonly used in the treatment of diffuse
214
hepatocellular carcinoma (HCC) or metastatic liver disease in humans (Llovet et
215
al., 2002; Lammer et al., 2010; Lencioni et al., 2012). Most hepatic tumors
216
depend on hepatic arterial blood supply (up to 95%) for growth in contrast to the
217
normal liver parenchyma that receives the majority of its blood supply via the
218
portal vein (only ~20% from the hepatic artery) (Breedis et al., 1954). Hepatic
219
artery embolization should, at least theoretically, cause more ischemia to the liver
220
tumor, while the remaining normal hepatic parenchyma obtains sufficient
221
oxygenation from the portal venous system.
222 223
Reported complications in humans include hemorrhage at the vascular
224
access site, non-target embolization complications (skin necrosis for superficial
225
tumors,
226
infarction/abscessation, acute renal failure (for liver tumors), and post-
227
embolization syndrome (a collection of clinical signs characterized by malaise,
228
fever and pain) (Hemingway et al., 1988).
damage
to
normal
parenchyma
or
adjacent
organs),
hepatic
229 230
More recently, drug-eluting bead chemoembolization (DEB-TACE) has
231
been evaluated and has demonstrated improved results and fewer side effects for
232
larger liver tumors in humans. These techniques have demonstrated enhanced
Page 12 of 22
233
tumor responses and prolonged survival times when compared with the more
234
traditional therapies in humans with HCC (Llovet et al., 2002; Lammer et al.,
235
2010; Lencioni et al., 2012).
236 237
Clinic
238
The author has performed TAE, Lipiodol-based TACE, and DEB-TACE
239
in dogs with benign and malignant liver tumors in which surgery was
240
unsuccessful or declined. As with intra-arterial chemotherapy, these procedures
241
are performed through surgical cut-down arterial access, followed by fluoroscopic
242
vascular imaging using software (such as digital subtraction and road-mapping) to
243
guide the super-selective therapies. The techniques require an intricate knowledge
244
of local vascular anatomy to prevent non-target embolization, but can otherwise
245
be expected to result in fewer than 10-15% major complications. The procedure is
246
generally repeated at 6-week intervals and the tumor response is evaluated
247
following two treatments.
248 249
Our experience over the past 10 years suggests risks and complications in
250
veterinary patients are similar to those that have been described in humans, as
251
well as reduced systemic exposure to chemotherapy, minimal morbidity, and
252
improved tumor response rates compared to systemic chemotherapy (Weisse et
253
al., 2002, 2013; Marioni-Henry et al., 2007). A small number of patients develop
Page 13 of 22
254
post-treatment hemoabdomen, bile peritonitis, or hepatic abscessation following
255
hepatic tumor TACE, but in the experience of the author this is very uncommon.
256 257
A relatively small, prospective series of dogs with HCC receiving DEB-
258
TACE and subsequent IV chemotherapy has been performed (Weisse et al.,
259
2013). When receiving DEB-TACE, one dog had serum levels of the
260
chemotherapeutic agent measurable for only a median of 30-180 min (vs. 720 min
261
following IV administration) and one-fortieth of the total systemic exposure (area
262
under the curve or AUC) compared with the same dose administered IV (Weisse
263
et al., 2013). These data support the theory that TACE results in substantially
264
elevated levels of the chemotherapeutic agent within chemoembolized liver
265
tumors as well as reduced systemic chemotherapy exposure. Chemoembolization
266
has been performed in other tissues and its use will most likely expand (Fig. 3).
267 268
Percutaneous tumor ablation
269
Concept
270
Percutaneous tumor ablation techniques (radiofrequency as well as
271
microwave ablation, laser thermal ablation, cryoablation, and percutaneous
272
ethanol injection) tend to be most effective when there are a few, small lesions, as
273
the probes have relatively small ablation zones. These situations are fairly
274
uncommon in the author’s clinical experience; however, with the routine use of
Page 14 of 22
275
more advanced imaging techniques in veterinary medicine, lesions of this size and
276
number may become increasingly apparent during tumor re-staging procedures,
277
making tumor ablation techniques a reasonable option in the future.
278 279
The use of ablation devices to damage tissues is not a new one. The most
280
commonly used devices harness heat or cold (‘thermal ablation’) to damage
281
tissues. Percutaneous ethanol injection has been described in veterinary patients
282
for use in thyroid tumors (Wells et al., 2001).
283 284
Cryotherapy is a commonly used ablation therapy and many veterinarians
285
are familiar with its use in treating superficial tumors in horses and, occasionally,
286
in companion animals. Mammalian tissues receive lethal freezing when
287
temperatures reach -20 to -25 °C. Some tumors may be able to withstand lower
288
temperatures, but -40 °C is generally accepted to be lethal to all mammalian
289
tissues (Saldanha et al., 2010). Unlike other traditional therapies such as radiation
290
(some tumors are radiation sensitive and others are not), all tissues die at -40 °C.
291
The mechanisms of cell death following freezing temperatures are direct and
292
indirect, and include ischemia due to blood vessel freezing/thrombosis, and
293
cellular membrane breakdown due to intra- and extracellular ice crystal formation
294
with subsequent osmotic differences (Saldanha et al., 2010).
295
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296
Recent advances in cryotherapy include the ability to move from a liquid
297
to gas medium, allowing for much smaller probes (17 G) that can be placed into
298
organs within the body using ultrasonography, computed tomography (CT),
299
and/or magnetic resonance imaging (MRI) guidance (Saldanha et al., 2010).
300
Rapid argon freezing with fast helium thaws now permits small probes to be
301
placed within the body and rapid freeze-thaw cycles to be performed (Saldanha et
302
al., 2010).
303 304
In general, ablation therapies may be best suited for non-surgical patients
305
with a limited number of small tumors. There are currently no randomized
306
controlled clinical trials comparing different ablation modalities in humans, and
307
even fewer scientific reports in animals with naturally occurring diseases (Wells
308
et al., 2001; Murphy et al., 2011; Weisse et al., 2011). Ablations that cannot
309
achieve a clean margin around the tumor should not be employed with curative
310
intent; different modalities and different probes will change the lethal zone of
311
ablation. There are also technical modifications that can be used to reduce the
312
incidence of local tissue damage such as hydro-dissection and artificial
313
pneumothorax/ pneumoperitoneum. In addition, thermal ablation therapies can be
314
combined with vascular procedures (e.g. TACE) that reduce tumor blood flow
315
and the heat-sink effect associated with larger blood vessels.
316
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317
Clinic
318
The author has undertaken some preliminary investigations into the use of
319
cryotherapy for advanced tumors of the head (Weisse et al., 2011). Three cases
320
using a combination of TACE, TAE, and cryotherapy were all successfully
321
performed under CT guidance (Fig. 4) to place precisely the needle probes
322
percutaneously or via natural orifices (such as the nares) into the targeted tumor
323
resulting in measureable tumor responses (partial remissions). Concerns about the
324
use of these techniques in the head region include the risk of large resulting holes
325
where the tumor was located. Skin necrosis and oronasal fistulas should be
326
anticipated if the tumor extends across these areas, indicating that additional
327
surgical procedures may subsequently be necessary. Cryotherapy for canine
328
recurrent nasal adenocarcinoma has also been reported (Murphy et al., 2011).
329 330
Conclusions
331
IO techniques have the potential to provide veterinary patients with
332
benefits similar to those reported in humans. Initial veterinary clinical studies of
333
stenting for malignant obstructions, locoregional delivery of chemotherapy,
334
embolization or chemoembolization of non-resectable or metastatic tumors, and
335
percutaneous tumor ablations have all shown promising preliminary results.
336
While this subspecialty is in its infancy, IO will most likely play an increasingly
337
larger role in the management of veterinary cancer patients in the future.
Page 17 of 22
338 339
Conflict of interest statement
340
The author of this paper is a paid consultant to a number of medical device
341
companies (Infiniti Medical, Norfolk Vet, and Mila International but these played
342
no role in the manuscript writing or submission of this review for publication. The
343
author has no other financial or personal relationships that could inappropriately
344
influence or bias the content of the paper.
345 346
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von Scheel, J., Golde, G., 1984. Pharmacokinetics of intra-arterial tumour therapy: An experimental study. Archives in Otorhinolaryngology 239, 153-161. Weisse, C., Clifford, C., Nicholson, M., Salomon, J.A., 2002. Percutaneous bland arterial embolization and chemoembolization for the treatment of benign and malignant diseases. Journal of the American Veterinary Medical Association 221, 1430-1436. Weisse, C., Berent, A., Todd, K., Clifford, C., Solomon, J., 2006. Evaluation of palliative stenting for management of malignant urethral obstructions in dogs. Journal of the American Veterinary Medical Association 229, 226-234. Weisse, C., Berent, A., Sornemo, K., , 2009. Feasibility and safety associated with selective and superselective intra-arterial carboplatin and meloxicam delivery for urothelial tumors in dogs. Journal of Veterinary Internal Medicine 23, 712. Weisse, C., Berent, A.C., Leibman, N., Solomon, S., 2011. Case Report: Combined transarterial embolization, cyclophosphamide, and cryotherapy ablation for “Hi-Lo“ maxillary fibrosarcoma in a dog. Veterinary Endoscopy Society Proceedings https://docs.google.com/document/d/1h5qrUiDHwzpyDe9oS55Hmni0lhdu7oCIHzOz1EYAOs/edit?pli=1 Weisse, C., Berent, A., Scansen, B., Cober, R.E., 2012. Transatrial stenting (IVC to SVC) for long-term management of tumor obstruction of the right atrium in 3 dogs. Journal of Veterinary Internal Medicine 26, 1515. Weisse, C., Berent, A., Soulen, M., 2013. Comparison of serum doxorubicin levels following different DEB chemoembolization techniques as well as systemic administration in the same canine patients with naturally-occurring hepatocellular carcinoma. Journal Vascular Interventional Radiology 24, S413. Weisse, C., Berent. A., 2014. Radical cystectomy and bilateral subcutaneous ureterovesicular bypass (SUB) placement for advanced urinary bladder cancer in dogs. Journal of Veterinary Internal Medicine 28, 1346-1374. Wells, A.L., Long, C.D., Hornof, W.J., Goldstein, R.E., Nyland, T.G., Nelson, R.W., Feldman, E.C., 2001. Use of percutaneous ethanol injection for treatment of bilateral hyperplastic thyroid nodules in cats . Journal of the American Veterinary Medical Association 218, 1293-1297.
Page 21 of 22
493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531
Figure Legends Fig. 1. Serial radiographic images of stenting for malignant obstructions. (A) Ferret with oral placement of a pyloric stent for gastrointestinal carcinoma. (B) Cat with a colonic stent for colonic adenocarcinoma. (C) Dog with a trans-atrial stent spanning from the cranial vena cava to the caudal vena cava for a cardiac neuroendocrine tumor. (D) Dog with percutaneous placement of a pigtail stent for a ureteral obstruction secondary to a transitional cell carcinoma (TCC). Insert A: needle placement in renal pelvis (*) with contrast ureterogram (white arrows). Insert B: guide wire (white arrows) advanced down the ureter and out the urethra. Inserts C and D: pigtail stent advanced over the guide wire spanning obstruction. (E) Canine prostatic tumor with urethral obstruction (white arrows) before (insert A) and immediately following (insert B) stent placement. (F) Dog following total cystectomy and partial bilateral ureterectomy and urethrectomy due to a large TCC after subcutaneous ureterovesicular bypass (SUB) device placement. Fig. 2. Digital subtraction angiography in male (A) and female (B) dogs with urothelial carcinomas receiving intra-arterial chemotherapy administration. (A) Microcatheter (white arrows) positioned in the vaginal artery (Vag) during chemotherapy administration demonstrating diffuse urethral tumor and blush (white dashed line). (B) Microcatheter positioned in the prostatic artery (Pros) during with angiogram prior to chemotherapy administration demonstrating prostatic tumor and caudal vesical artery (CdVes) supplying urinary bladder. There is reflux into the internal pudendal (IP) artery. Fig. 3. Chemoembolization angiography in two dogs for nasal tumor (A-C) and multiple hepatocellular carcinomas (HCC) (D, E). Microcatheter positioned in the infra-orbital artery prior to (A), during (B), and following (C) nasal tumor chemoembolization demonstrating loss of tumor blush. (D and E) Digital subtraction angiography prior to (D) and following (E) chemoembolization of two HCCs (white dashed lines) demonstrating loss of tumor blush (Cha, Common hepatic artery; LHa, Left hepatic artery; RMHa, Right medial hepatic artery; RLHa, Right lateral hepatic artery; GDa, Gastroduodenal artery; RGEa, Right gastroepiploic artery). Fig. 4. Serial images prior to (A), during (B) and 6 weeks following (C) cryotherapy for nasal tumor demonstrating computed tomography (CT)-guided cryoprobe placement (B) and partial remission following treatment (C).
Page 22 of 22
S1090-0233(15)00124-0 http://dx.doi.org/doi:10.1016/j.tvjl.2015.03.027 YTVJL 4465
To appear in:
The Veterinary Journal
Accepted date:
23-3-2015
Please cite this article as: Chick Weisse, Veterinary interventional oncology: from concept to clinic, The Veterinary Journal (2015), http://dx.doi.org/doi:10.1016/j.tvjl.2015.03.027. 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.
1 2 3 4 5 6 7 8 9 10 11
Review Veterinary interventional oncology: From concept to clinic Chick Weisse * Animal Medical Center, New York City, NY, USA * Corresponding author. Tel.: +1 646 5861798 E-mail address: [email protected] (Chick Weisse)
12
Page 1 of 22
13 14
Highlights
materials for therapeutic purposes.
15 16
21
IO provides alternative therapeutic solutions for cancers with no safe or effective traditional options
19 20
Interventional oncology (IO) is a growing subspecialty of IR in human medicine.
17 18
Interventional radiology (IR) combines imaging modalities and delivery of
With IO, dose escalations to tumors can be achieved without increasing systemic exposures.
22 23 24 25
Abstract
26
Interventional radiology (IR) involves the use of contemporary imaging
27
modalities to gain access to different structures in order to deliver materials for
28
therapeutic purposes. Veterinarians have been expanding the use of these
29
minimally invasive techniques in animals with a variety of conditions involving
30
all of the major body systems. Interventional oncology (IO) is a growing
31
subspecialty of IR in human medicine used (1) to restore patency to malignant
32
obstructions through endoluminal stenting, (2) to provide dose escalations to
33
tumors without increasing systemic chemotherapy toxicities via superselective
Page 2 of 22
34
transarterial chemotherapy delivery, (3) to stop hemorrhage or reduce blood flow
35
to tumors via transarterial embolization or chemoembolization, and (4) to provide
36
therapies for those cancers with no safe or effective alternative options.
37 38
This review provides a brief introduction to a few of the techniques currently
39
available to veterinarians for cancer treatment. For each technique, the concept for
40
improved palliation, patient quality of life, or tumor control is presented, followed
41
by the most current veterinary clinical information available. Although promising,
42
more studies will be necessary to determine if veterinary IO will provide the same
43
benefits as has already been demonstrated in oncology care in humans.
44 45
Keywords:
Oncology;
Veterinary;
Interventional;
Treatment;
Dog;
Cat.
Page 3 of 22
46
Introduction
47
Interventional radiology (IR) involves the combination of minimally
48
invasive approaches and contemporary imaging modalities to gain access to
49
specific organs in order to deliver a variety of devices or medications for
50
therapeutic purposes (Rösch et al., 2003). First developed over 50 years ago, IR
51
techniques have expanded considerably with both vascular and non-vascular
52
procedures being performed routinely in humans (Rösch et al., 2003).
53
Specifically, IR techniques are being increasingly utilized to help manage humans
54
with cancer (interventional oncology or IO) in which traditional therapies have
55
failed or have been shown to provide little benefit. IO has been previously
56
referred to as the ‘fourth pillar’ of oncological care along with medical, surgical,
57
and radiation therapies (Geschwind and Soulen, 2008). The techniques are
58
particularly useful in cases of regional disease in order to maximize local
59
effectiveness and minimize systemic toxicity or complications.
60 61
Non-resectable and metastatic tumors present a difficult challenge for
62
veterinarians and pet owners. Surgery is rarely indicated when resections have a
63
high likelihood of subsequent complications and low likelihood of improved
64
survival times. The relatively limited efficacy of intravenous (IV) chemotherapy
65
for macroscopic disease, and the cost, occasional morbidity, and tumor resistance
66
associated with radiation therapy have stimulated the search for additional
Page 4 of 22
67
therapeutic options. Initial results have been promising and regional techniques,
68
such as palliative stenting for malignant obstructions, intra-arterial chemotherapy,
69
trans-catheter arterial embolization/chemoembolization, and percutaneous tumor
70
ablation, are becoming increasingly investigated.
71 72
In the veterinary oncology community we have been evaluating the use of
73
these therapies in pets with cancer, and this review provides a brief introduction to
74
the concepts behind the most commonly used regional tumor therapies, and the
75
current clinical applications and results obtained to date.
76 77
Palliative stenting for malignant obstructions
78
Concept
79
Animals are often euthanased due to the local effects of a tumor rather
80
than the systemic impact associated with a large cancer burden. While these
81
conditions can occur in any lumen, such as those of the respiratory,
82
gastrointestinal, and cardiovascular systems (Fig. 1), one of the more common
83
examples is malignant obstructions of the urinary tract associated with transitional
84
cell carcinomas (TCCs) or prostatic tumors. These may result in life-threatening
85
signs associated with complete urinary tract obstruction and often lead to owner-
86
elected euthanasia, even when the disease remains otherwise localized.
87
Page 5 of 22
88
Minimally invasive endoluminal urethral stenting and endoscopic or
89
percutaneous ureteral stenting have been performed in humans to relieve both
90
lower and upper tract obstructions (Chao et al, 2011; Chitale et al., 2002). It
91
should be noted that while endoscopic-guided laser ablation is a common therapy
92
for the typically superficial TCCs found in humans, this is not recommended for
93
the less common and more aggressive muscle-invasive TCCs (which are the most
94
common form of canine TCC). In considering the complications of TCCs in dogs,
95
namely, laser ablation (L'Eplattenier et al., 2006; Cerf et al., 2012), cost, extended
96
hospitalization times, need for repeat procedures (~47%), possible limitation to
97
females, and other similar outcomes, stenting appears to compare favorably.
98 99
Clinic
100
Veterinary IO techniques involving the placement of intra-luminal stents
101
to palliate malignant obstructions have now been described for the respiratory,
102
gastrointestinal and cardiovascular systems, as well as for the urinary tract, which
103
seems to be the most commonly affected body system in our clinic (Fig. 1) (Hume
104
et al., 2006; Weisse et al., 2006, 2011; Culp et al., 2007; Schlicksup et al., 2009;
105
Berent et al., 2011; Hansen et al., 2012; McMillan et al., 2012; Blackburn et al.,
106
2013; Brace et al., 2014). These procedures are performed through natural orifices
107
(or small percutaneous holes) under fluoroscopic guidance, and often as
108
outpatient procedures.
Page 6 of 22
109 110
IO techniques involving the urinary tract are generally rapid, safe,
111
minimally invasive, and effective, and complications (such as tumor ingrowth into
112
the stent or stent migration) are minor or uncommon. Stented malignant urethral
113
obstructions were reported to have been relieved immediately in 97% of patients,
114
with mild to absent stranguria in 75% of patients (Weisse et al., 2006; McMillan
115
et al., 2012; Blackburn et al., 2013). Animals receiving chemotherapy and non-
116
steroidal anti-inflammatory drugs (NSAIDs) in addition to stenting demonstrated
117
prolonged survival times (250 days) in partially to completely obstructed patients
118
with low morbidity (i.e., limited to 25% major incontinence rates) (Blackburn et
119
al., 2013). The technique is generally performed as an outpatient procedure at
120
many of the major oncology veterinary centers in the USA and appears to be one
121
of the favored techniques for minimally invasive management of acute malignant
122
urinary obstructions in dogs. Recently, similar positive outcomes, characterized
123
by low morbidity and similar incontinence rates, have been reported with urethral
124
stenting in cats with benign or malignant urethral obstructions (Brace et al.,
125
2014).
126 127
Similar techniques can also be used in upper urinary tract obstructions
128
through an 18 G renal puncture performed under ultrasound guidance, followed
129
by fluoroscopic guide wire, catheter, and stent manipulations. In a recent series of
Page 7 of 22
130
canine malignant ureteral obstructions treated with percutaneous ureteral stent
131
placement, the techniques were successful in 11/12 dogs with all azotemic dogs
132
demonstrating reduction in blood urea nitrogen (BUN) and serum creatinine
133
concentrations, and a reduction in the degree of hydronephrosis in the 10 dogs
134
that were evaluated post-operatively (Berent et al., 2011). This procedure is
135
typically outpatient and remains technically demanding; however, it can also be
136
performed via a small open surgical technique for those without prior
137
interventional training.
138 139
While euthanasia for local obstruction is often no longer necessary due to
140
the advent of intraluminal stenting, management of subsequent metastases is
141
becoming more critical to control. Local surgical resection is often incomplete
142
due to the common trigonal location, or is non-durable when apical tumors are
143
removed due to skip metastases or de novo TCC tumors elsewhere within the
144
lower urinary tract. Recently, a combination interventional/surgical procedure has
145
been described (in an abstract format) outlining how to facilitate en block
146
resection of the distal ureters, bladder, and proximal urethra; the objective was to
147
enable more aggressive tumor resections in the hope of improving tumor-free
148
margins in these often diffuse, complex surgical cases (Fig. 1F) (Weisse et al.,
149
2014). Alternatively, regional chemotherapy administration may provide
150
improved biological response rates as described below.
Page 8 of 22
151 152
Intra-arterial chemotherapy delivery
153
Concept
154
Current therapies for bulky tumors that are not amenable to complete
155
surgical resection commonly include chemotherapy, radiation therapy, and
156
surgical debulking, but none are consistently able to produce durable remissions
157
(Geschwind and Soulen, 2008). Specific tumor cell subtypes tend to be more
158
sensitive to certain chemotherapeutic agents, and increasing the concentration of
159
these drugs tends to increase both tumor cell death and systemic toxicity. This
160
dynamic creates a delicate balance of risk vs. benefit that must be considered by
161
the oncologist before choosing a chemotherapy plan and dose, or prescribing a
162
dose escalation.
163 164
IR techniques can deliver these drugs into the terminal arteries that are
165
feeding the tumors via minimally invasive approaches. The theoretical result is
166
elevated regional drug concentrations within the tumor without the systemic side
167
effects that would occur had similar levels been achieved through higher
168
concentrations administered IV. A local dose escalation is achieved without the
169
associated increased systemic toxicities. Several studies have confirmed both the
170
higher levels of chemotherapeutic agents within the targeted tissues and the
Page 9 of 22
171
improved tumor remissions in laboratory animals (von Scheel et al., 1984;
172
Sumiyoshi et al., 1991; Hoshi et al.,1997).
173 174
Clinic
175
These techniques are performed via a small surgical cut-down to the
176
carotid or femoral arteries performed under fluoroscopic guidance. These are now
177
routine outpatient procedures and have been described in clinical veterinary cases
178
(Weisse et al., 2009), and at the Animal Medical Center we have recently
179
completed a recent study that supports this theory (unpublished data). In this
180
retrospective work, two statistically similar populations of dogs with urothelial
181
carcinoma received either (1) IV carboplatin and oral NSAIDs, or (2) super-
182
selective intra-arterial carboplatin and meloxicam (Fig. 2). The intra-arterial
183
group demonstrated a statistically greater reduction in tumor length, and in
184
percent length, width and unidimensional measurements compared with the IV
185
group. The intra-arterial group was also statistically more likely to achieve a
186
positive tumor response as characterized by modified RECIST criteria1. In
187
addition, compared with the IV group the intra-arterial group was statistically less
188
likely to develop some adverse events, including anorexia and lethargy, following
189
chemotherapy. Complications were minor or uncommon, and consisted of
190
chemotherapy-associated adverse events (similar to what is observed with 1
See: http://www.eortc.org/investigators-area/recist (accessed 01 February 2015)
Page 10 of 22
191
systemically administered chemotherapeutic agents) or rarely surgical incision
192
discomfort/irritation.
193 194
Trans-arterial embolization (TAE)/chemoembolization (TACE)
195
Concept
196
Embolization refers to the delivery of a device or materials to interrupt
197
blood flow. This can occur naturally in a disease state such as with a
198
thromboembolism, or can be therapeutically achieved during an IO procedure in
199
which small particles (typically polyvinyl alcohol or hydrogel polymers in the 80
200
- 500 m diameter range) injected into a tumor capillary bed obstruct blood flow,
201
resulting in subsequent tissue ischemia. The more ‘distally’ (or closer to the
202
capillary bed) the embolization occurs, the more likely ischemia will be achieved
203
(which is why very small particles are chosen for these procedures).
204 205
Chemoembolization involves super-selective intra-arterial chemotherapy
206
delivery in conjunction with subsequent particle embolization. Intra-arterial
207
chemotherapy has been shown to result in a 10- to 50-fold increase in intra-
208
tumoral drug concentrations when compared to systemic IV chemotherapy
209
administration (Dyet et al., 2000). Subsequent particle embolization results in
210
tumor cell necrosis and limits the release by tumor cells of chemotherapeutic
211
agents resulting in minimized systemic toxicity.
Page 11 of 22
212 213
This procedure is most commonly used in the treatment of diffuse
214
hepatocellular carcinoma (HCC) or metastatic liver disease in humans (Llovet et
215
al., 2002; Lammer et al., 2010; Lencioni et al., 2012). Most hepatic tumors
216
depend on hepatic arterial blood supply (up to 95%) for growth in contrast to the
217
normal liver parenchyma that receives the majority of its blood supply via the
218
portal vein (only ~20% from the hepatic artery) (Breedis et al., 1954). Hepatic
219
artery embolization should, at least theoretically, cause more ischemia to the liver
220
tumor, while the remaining normal hepatic parenchyma obtains sufficient
221
oxygenation from the portal venous system.
222 223
Reported complications in humans include hemorrhage at the vascular
224
access site, non-target embolization complications (skin necrosis for superficial
225
tumors,
226
infarction/abscessation, acute renal failure (for liver tumors), and post-
227
embolization syndrome (a collection of clinical signs characterized by malaise,
228
fever and pain) (Hemingway et al., 1988).
damage
to
normal
parenchyma
or
adjacent
organs),
hepatic
229 230
More recently, drug-eluting bead chemoembolization (DEB-TACE) has
231
been evaluated and has demonstrated improved results and fewer side effects for
232
larger liver tumors in humans. These techniques have demonstrated enhanced
Page 12 of 22
233
tumor responses and prolonged survival times when compared with the more
234
traditional therapies in humans with HCC (Llovet et al., 2002; Lammer et al.,
235
2010; Lencioni et al., 2012).
236 237
Clinic
238
The author has performed TAE, Lipiodol-based TACE, and DEB-TACE
239
in dogs with benign and malignant liver tumors in which surgery was
240
unsuccessful or declined. As with intra-arterial chemotherapy, these procedures
241
are performed through surgical cut-down arterial access, followed by fluoroscopic
242
vascular imaging using software (such as digital subtraction and road-mapping) to
243
guide the super-selective therapies. The techniques require an intricate knowledge
244
of local vascular anatomy to prevent non-target embolization, but can otherwise
245
be expected to result in fewer than 10-15% major complications. The procedure is
246
generally repeated at 6-week intervals and the tumor response is evaluated
247
following two treatments.
248 249
Our experience over the past 10 years suggests risks and complications in
250
veterinary patients are similar to those that have been described in humans, as
251
well as reduced systemic exposure to chemotherapy, minimal morbidity, and
252
improved tumor response rates compared to systemic chemotherapy (Weisse et
253
al., 2002, 2013; Marioni-Henry et al., 2007). A small number of patients develop
Page 13 of 22
254
post-treatment hemoabdomen, bile peritonitis, or hepatic abscessation following
255
hepatic tumor TACE, but in the experience of the author this is very uncommon.
256 257
A relatively small, prospective series of dogs with HCC receiving DEB-
258
TACE and subsequent IV chemotherapy has been performed (Weisse et al.,
259
2013). When receiving DEB-TACE, one dog had serum levels of the
260
chemotherapeutic agent measurable for only a median of 30-180 min (vs. 720 min
261
following IV administration) and one-fortieth of the total systemic exposure (area
262
under the curve or AUC) compared with the same dose administered IV (Weisse
263
et al., 2013). These data support the theory that TACE results in substantially
264
elevated levels of the chemotherapeutic agent within chemoembolized liver
265
tumors as well as reduced systemic chemotherapy exposure. Chemoembolization
266
has been performed in other tissues and its use will most likely expand (Fig. 3).
267 268
Percutaneous tumor ablation
269
Concept
270
Percutaneous tumor ablation techniques (radiofrequency as well as
271
microwave ablation, laser thermal ablation, cryoablation, and percutaneous
272
ethanol injection) tend to be most effective when there are a few, small lesions, as
273
the probes have relatively small ablation zones. These situations are fairly
274
uncommon in the author’s clinical experience; however, with the routine use of
Page 14 of 22
275
more advanced imaging techniques in veterinary medicine, lesions of this size and
276
number may become increasingly apparent during tumor re-staging procedures,
277
making tumor ablation techniques a reasonable option in the future.
278 279
The use of ablation devices to damage tissues is not a new one. The most
280
commonly used devices harness heat or cold (‘thermal ablation’) to damage
281
tissues. Percutaneous ethanol injection has been described in veterinary patients
282
for use in thyroid tumors (Wells et al., 2001).
283 284
Cryotherapy is a commonly used ablation therapy and many veterinarians
285
are familiar with its use in treating superficial tumors in horses and, occasionally,
286
in companion animals. Mammalian tissues receive lethal freezing when
287
temperatures reach -20 to -25 °C. Some tumors may be able to withstand lower
288
temperatures, but -40 °C is generally accepted to be lethal to all mammalian
289
tissues (Saldanha et al., 2010). Unlike other traditional therapies such as radiation
290
(some tumors are radiation sensitive and others are not), all tissues die at -40 °C.
291
The mechanisms of cell death following freezing temperatures are direct and
292
indirect, and include ischemia due to blood vessel freezing/thrombosis, and
293
cellular membrane breakdown due to intra- and extracellular ice crystal formation
294
with subsequent osmotic differences (Saldanha et al., 2010).
295
Page 15 of 22
296
Recent advances in cryotherapy include the ability to move from a liquid
297
to gas medium, allowing for much smaller probes (17 G) that can be placed into
298
organs within the body using ultrasonography, computed tomography (CT),
299
and/or magnetic resonance imaging (MRI) guidance (Saldanha et al., 2010).
300
Rapid argon freezing with fast helium thaws now permits small probes to be
301
placed within the body and rapid freeze-thaw cycles to be performed (Saldanha et
302
al., 2010).
303 304
In general, ablation therapies may be best suited for non-surgical patients
305
with a limited number of small tumors. There are currently no randomized
306
controlled clinical trials comparing different ablation modalities in humans, and
307
even fewer scientific reports in animals with naturally occurring diseases (Wells
308
et al., 2001; Murphy et al., 2011; Weisse et al., 2011). Ablations that cannot
309
achieve a clean margin around the tumor should not be employed with curative
310
intent; different modalities and different probes will change the lethal zone of
311
ablation. There are also technical modifications that can be used to reduce the
312
incidence of local tissue damage such as hydro-dissection and artificial
313
pneumothorax/ pneumoperitoneum. In addition, thermal ablation therapies can be
314
combined with vascular procedures (e.g. TACE) that reduce tumor blood flow
315
and the heat-sink effect associated with larger blood vessels.
316
Page 16 of 22
317
Clinic
318
The author has undertaken some preliminary investigations into the use of
319
cryotherapy for advanced tumors of the head (Weisse et al., 2011). Three cases
320
using a combination of TACE, TAE, and cryotherapy were all successfully
321
performed under CT guidance (Fig. 4) to place precisely the needle probes
322
percutaneously or via natural orifices (such as the nares) into the targeted tumor
323
resulting in measureable tumor responses (partial remissions). Concerns about the
324
use of these techniques in the head region include the risk of large resulting holes
325
where the tumor was located. Skin necrosis and oronasal fistulas should be
326
anticipated if the tumor extends across these areas, indicating that additional
327
surgical procedures may subsequently be necessary. Cryotherapy for canine
328
recurrent nasal adenocarcinoma has also been reported (Murphy et al., 2011).
329 330
Conclusions
331
IO techniques have the potential to provide veterinary patients with
332
benefits similar to those reported in humans. Initial veterinary clinical studies of
333
stenting for malignant obstructions, locoregional delivery of chemotherapy,
334
embolization or chemoembolization of non-resectable or metastatic tumors, and
335
percutaneous tumor ablations have all shown promising preliminary results.
336
While this subspecialty is in its infancy, IO will most likely play an increasingly
337
larger role in the management of veterinary cancer patients in the future.
Page 17 of 22
338 339
Conflict of interest statement
340
The author of this paper is a paid consultant to a number of medical device
341
companies (Infiniti Medical, Norfolk Vet, and Mila International but these played
342
no role in the manuscript writing or submission of this review for publication. The
343
author has no other financial or personal relationships that could inappropriately
344
influence or bias the content of the paper.
345 346
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Figure Legends Fig. 1. Serial radiographic images of stenting for malignant obstructions. (A) Ferret with oral placement of a pyloric stent for gastrointestinal carcinoma. (B) Cat with a colonic stent for colonic adenocarcinoma. (C) Dog with a trans-atrial stent spanning from the cranial vena cava to the caudal vena cava for a cardiac neuroendocrine tumor. (D) Dog with percutaneous placement of a pigtail stent for a ureteral obstruction secondary to a transitional cell carcinoma (TCC). Insert A: needle placement in renal pelvis (*) with contrast ureterogram (white arrows). Insert B: guide wire (white arrows) advanced down the ureter and out the urethra. Inserts C and D: pigtail stent advanced over the guide wire spanning obstruction. (E) Canine prostatic tumor with urethral obstruction (white arrows) before (insert A) and immediately following (insert B) stent placement. (F) Dog following total cystectomy and partial bilateral ureterectomy and urethrectomy due to a large TCC after subcutaneous ureterovesicular bypass (SUB) device placement. Fig. 2. Digital subtraction angiography in male (A) and female (B) dogs with urothelial carcinomas receiving intra-arterial chemotherapy administration. (A) Microcatheter (white arrows) positioned in the vaginal artery (Vag) during chemotherapy administration demonstrating diffuse urethral tumor and blush (white dashed line). (B) Microcatheter positioned in the prostatic artery (Pros) during with angiogram prior to chemotherapy administration demonstrating prostatic tumor and caudal vesical artery (CdVes) supplying urinary bladder. There is reflux into the internal pudendal (IP) artery. Fig. 3. Chemoembolization angiography in two dogs for nasal tumor (A-C) and multiple hepatocellular carcinomas (HCC) (D, E). Microcatheter positioned in the infra-orbital artery prior to (A), during (B), and following (C) nasal tumor chemoembolization demonstrating loss of tumor blush. (D and E) Digital subtraction angiography prior to (D) and following (E) chemoembolization of two HCCs (white dashed lines) demonstrating loss of tumor blush (Cha, Common hepatic artery; LHa, Left hepatic artery; RMHa, Right medial hepatic artery; RLHa, Right lateral hepatic artery; GDa, Gastroduodenal artery; RGEa, Right gastroepiploic artery). Fig. 4. Serial images prior to (A), during (B) and 6 weeks following (C) cryotherapy for nasal tumor demonstrating computed tomography (CT)-guided cryoprobe placement (B) and partial remission following treatment (C).
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