Med Oncol (2017) 34:38 DOI 10.1007/s12032-017-0887-4
ORIGINAL PAPER
Concurrent chemotherapy alone versus irreversible electroporation followed by chemotherapy on survival in patients with locally advanced pancreatic cancer Giuseppe Belfiore1 • Maria Paola Belfiore2 • Alfonso Reginelli2 • Raffaella Capasso3 Francesco Romano4 • Giovanni Pietro Ianniello5 • Salvatore Cappabianca2 • Luca Brunese3
•
Received: 13 December 2016 / Accepted: 11 January 2017 Ó Springer Science+Business Media New York 2017
Abstract Pancreatic adenocarcinoma is one of the most fatal cancers, characterized by aggressive tumor growth and a short patient survival time between diagnosis and death. Safe and effective treatment options are limited, especially in cases when surgical resection is not possible. Irreversible electroporation (IRE) is a non-thermal ablation technique recently introduced in the treatment of pancreatic cancer. From 2013 to 2016, 29 cases of locally advanced pancreatic cancer (LAPC) treated with IRE were retrospectively analyzed and the median overall survival (OS) rates were compared with patients with the same diagnosis who received standard chemotherapy as reported in the literature. Literature was selected according to a predetermined protocol. Secondarily, preoperative and postoperative Karnofsky scores of the 29 IRE-treated patients were compared to determine improvement in quality-of-life. Median OS of IRE-treated patients was 14 months (SE 11 months, 95% CI range 9.86–18.14). For IRE-treated patients, the Karnofsky score increased from Tzero to T3m
& Alfonso Reginelli
[email protected] 1
Department of Diagnostic Imaging, ‘‘S. Anna-S. Sebastiano’’ Hospital, Via F. Palasciano, 81100 Caserta, Italy
2
Department of Clinical and Experimental Medicine, ‘‘F. Magrassi - A. Lanzara’’ Second University of Naples, Piazza Miraglia 2, 80131 Naples, Italy
3
Department of Medicine and Health Sciences, University of Molise, Via Francesco de Sanctis, 1, 86100 Campobasso, Italy
4
Department of Informatics, Second University of Naples, Piazza Miraglia 2, 80131 Naples, Italy
5
Department of Oncology, ‘‘S. Anna-S. Sebastiano’’ Hospital, Via F. Palasciano, 81100 Caserta, Italy
by a mean of 28.28 (SE 2.11, 95% CI range 23.95–32.60). In 27 patients, 6-month imaging follow-up showed a mean lesion volumetric decrease percentage of 40.32% (SE 2.76, 95% CI 34.63–46.01%). Treatment with IRE followed by chemotherapy substantially increases median OS rate and quality-of-life of LAPC-diagnosed patients when compared to patients treated with traditional methods, including chemotherapy. Further investigation of this multi-modal treatment is warranted. Keywords Irreversible electroporation Locally advanced pancreatic adenocarcinoma Chemotherapy
Introduction Pancreatic adenocarcinoma is the seventh leading cause of cancer mortality worldwide, responsible for 331,000 deaths a year [1]. This form of cancer is characterized by aggressive tumor growth, which largely goes unnoticed by patients until the disease has advanced. Due to the presentation of the disease, only 10–15% of patients are eligible for surgical resection at the time of diagnosis [2–5] and despite advances in treatment, the 5-year survival rate remains approximately 20% for patients deemed resectable [6, 7]. Locally advanced pancreatic adenocarcinoma (LAPC) is characterized by cancer which has spread within the pancreas, but has not metastasized elsewhere, yet it carries a 5-year survival rate of approximately 22% [8]. Patients with LAPC may opt for chemotherapy in an attempt to downstage the tumor to resectability or for palliative benefit. This unmet need has prompted researchers and practitioners to examine novel treatments and to optimize common therapeutic approaches [9–16].
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Gemcitabine (GEM) is the standard first-line chemotherapy for patients with LAPC, offering a statistically significant prolonged survival compared to 5-fluorouracil (5-FU). A study conducted by Burris et al involving 126 patients found that patients treated with gemcitabine experienced a greater survival rate and median survival duration (18% and 5.65 months, respectively), compared to patients treated with 5-FU only (2% and 4.41 months) [17]. However, the prognosis for patients with LAPC remains poor. Many studies on GEM-based combination scheme have failed to demonstrate an improvement in overall survival (OS) [18–20]. In pancreatic cancer, locally advanced malignancy is found in about 40% of patients at the time of presentation and most commonly includes invasion of vascular structures such as the superior mesenteric vessels or the celiac trunk [21, 22]. Advanced stages with vascular invasion have a higher probability of tumor micrometastasis, which can provoke early recurrence even after radical resection [23]. Therefore, in these cases, systemic chemotherapy is thought to be important for prevention of early dissemination. The use of chemoradiation remains controversial globally [24]. Irreversible electroporation (IRE) is a non-thermal ablation technique recently introduced in the treatment of pancreatic cancer [25]. IRE is not affected by a blood flow heat-sink effect and is demonstrated to be safe for critical structures, likely because it does not damage supporting connective tissue matrix [26, 27]. These features make IRE suitable for the treatment of unresectable pancreatic cancers that produce encasement of surrounding vessels and/or common bile duct. The endpoints of this study were the intermediate median OS, quality-of-life, and decreased volume of lesions of 29 patients with Stage III LAPC (median age 68.5, 55% male) treated with IRE followed by chemotherapy protocol of the Saint Anna and Sebastiano Hospital of Caserta. Furthermore this article reviews the recent trends in the management of LAPC with a particular emphasis on outcomes data of neoadjuvant treatment chemotherapy compared to the recent results obtained with neoadjuvant IRE therapy.
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Chemotherapy was performed 24 h after IRE treatment. The same lines of chemotherapy were performed in all patients (GEMOX: gemcitabine and oxaliplatin).The exclusion criteria were moderate-to-severe cardio-pulmonary failure, coagulation disorders, contraindication to general anesthesia and/or chemotherapy. IRE was performed percutaneously under CT guidance by an interventional radiologist with 30 years of experience (G.B.), using the NanoKnife IRE device (AngioDynamics, Queensbury, NY). All procedures were performed under general anesthesia with deep paralysis, defined as zero twitches before IRE delivery as a standard anesthesia twitch monitor. The day after the procedure, patients underwent clinical, biochemical and contrast-enhanced CT evaluation to identify possible complications after treatment. If no complications or contraindications were reported, the same day patients started chemotherapy with a combination of gemcitabine (1000 mg/mq) and oxaliplatin (100 mg/mq) biweekly. Imaging follow-up was performed by a contrast-enhanced CT scan at 1, 3 and 6 months after the treatment, and then every 3 months thereafter. Literature analysis Results from our retrospective study were compared to the data culled from neoadjuvant treatment chemotherapy outcomes literature. Literature search strategy IRE ? chemotherapy A comprehensive search of the literature was performed, including PUBMED (http://www.ncbi.nlm.nih.gov/ pubmed), American Society of Clinical Oncology abstracts (http://www.asco.org), and the Cochrane Database http:// www.thecochranelibrary.com). The following key words were used in the search: chemotherapy for locally advanced pancreatic cancer, Gemcitabine chemotherapy, irreversible electroporation for LAPC, clinical trial, neoadjuvant protocol, Irreversible electroporation followed by chemotherapy alone (Gemcitabine) (Figs. 1, 2, 3). Inclusion and exclusion criteria: literature analysis
Methods From 2013 to 2016, 29 patients with LAPC (16 men and 8 women; mean age 68.5, range 55–81 years) were treated with percutaneously CT-guided IRE followed by chemotherapy. All patients had a single target lesion measured according to Response Evaluation Criteria In Solid Tumors (RECIST). Tumors were located in the pancreatic head for 15 patients, 5 in the isthmus, and 9 in the body-tail.
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Inclusion criteria were: (1) randomized, prospective, controlled open or blinded trial (2) patients with radiological diagnosis of LAPC, and (3) assessment in the literature data of the gemcitabine combination therapy efficacy vs IRE followed by combination chemotherapy. Exclusion criteria were: (1) Non-randomized trials and quasi-randomized trials, (2) studies of curatively aimed resection, and (3) studies where patients had metastatic disease to avoid clinical heterogeneities different studies.
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Fig. 1 Literature analysis methodology
Fig. 2 Frequency of tumor percentage decreases
Overall survival and quality-of-life measure: IRE retrospective study The median OS was calculated using the Kaplan–Meier method as measured from the first day after IRE treatment to the time of the analysis (May 2016) or the date of the death. The quality-of-life was calculated using paired t test. Statistical analysis was performed with R (Version 2.15.2, Foundation for Statistical Computing, Vienna, Austria).
Fig. 3 Overall survival by treatment for 29 patients with Stage III LAPC undergoing IRE followed by chemotherapy
The Karnofsky scale was used to discern patient degrees of dependence and functional capacity after treatment, and calculated using paired t test (Table 2). The scale ranges from 100% (patients are utterly independent and present with no evidence of disease) to 0% (deceased). The scores were calculated and assessed before and after treatment and at three-month increments thereafter.
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Volume analysis The volume analysis was based on CT images by two radiologists with 25 and 30 years’ experience. They retrospectively evaluated the size (greatest diameter), density and enhancement of the tumor. A complete response to IRE treatment was defined as a local disappearance of the tumor mass. A partial response (PR) was defined as a reduction of less than of 30% of the sum of the diameters of target lesions according to RECIST. Complications were assessed based on the Society of Interventional Radiology classification System as major or minor [28].
Results A total of 29 patients (16 men and 13 women; with LAPC) were identified retrospectively; their characteristics by treatment group was shown in Table 1. Outcomes analysis After a median follow-up of 29 months, the median OS was 14 months (SE 11 months, 95% CI range 9.86–18.14). The recurrence rate, 3%, was low. The statistical volume analysis on the 27 lesions demonstrated partial response in all patients with mean percentage decrease volume after six months of 40.3% (SE 2.7, 95% CI 34.6–46). No major complications were observed after treatment. After a median 29 months follow-up, 22 patients died from disease progression (15 from metastatic disease and 7 from peritoneal carcinosis) and not from complications related to the procedure, 7 patients were still alive (3 at 12 months, 2 at 6 months, and 2 at 3 months). Three patients underwent surgery after 6 months after IRE treatment because of lesions downstaging and they died from the progression of the disease (Table 2). Immediately after IRE followed by chemotherapy treatment, patients scored 57.93 (SE 10.13) on the Karnofsky scale, pointing to a need for considerable medical assistance and attention. Patient quality-of-life empirically peaked 3 months after treatment, with an overall Karnofsky score of 86.2 (SE 18.4). The Karnofsky score increased from Tzero to T3m by a mean of 28.28 (SE 2.11, 95% CI range 23.95–32.60) (Table 3). At this time, patients were able to carry out normal activity, albeit with effort, and presented with some signs of recent treatment.
Discussion In this study, patients experienced low (3%) recurrence after a median follow-up of 29 months, demonstrating how IRE followed by chemotherapy can inhibit tumors
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regrowth even in advanced stage patients. Quality-of-life also markedly improved, rising from 57.93 (SE 10.13) on the Karnofsky scale immediately after percutaneously CTguided IRE followed by chemotherapy treatment, to an overall Karnofsky score of 86.2 (SE 18.4) 3 months after treatment. In a recent study published by Martin and colleagues, where 200 patients were Stage III LAPC were treated with IRE. In that study, 48% of patients underwent induction chemotherapy while 52% received chemoradiation for a median of 6 months prior to the main IRE treatment. Although 37% of patients sustained some form of complication, median OS stood at 24.9 months (range 12.4–85 months) [29]. The recurrence rate was 3% after a median follow-up of 29 months, which is comparable to the results obtained in our retrospective analysis. In comparison to the published literature, we observed an improvement in OS when compared with standard of care. This successful combination of IRE with a more commonly used palliative treatment has precedence in clinical study, although most cases see IRE as the succeeding, adjuvant treatment. In a study by Mansson et al. [30], 24 patients with LAPC were treated with IRE, with the aim of the study being an examination of the efficacy and safety of the treatment after chemotherapy and/or radio-chemotherapy. After the adjuvant IRE treatment, 11 (46%) of patients experienced related complications, with 3 (12.5%) patients experiencing serious complications. The first of the three had thrombosis of the superior mesenteric vein, requiring portography with a stent. The second patient had gastric retention requiring an endoscopy and subsequent surgery, while the third experienced ulcerous bleeding in the duodenum and also required endoscopy and angiographic embolization. Notably, one distinctive patient in the cohort underwent chemotherapy 2 weeks after IRE treatment, and subsequently died from pneumonia 34 days after. Mansson noted that 14% patients received additional chemotherapy after IRE, but this did not result in better survival compared to those who did not (mean 252 days vs. mean 254 days, respectively). In a case study by Trueba-Arguinarena et al., a 66-yearold male patient with LAPC was treated with two cycles of neoadjuvant chemotherapy (nab-paclitaxel and gemcitabine) prior to IRE ablation. The patient experience severe pain up to a week after ablation, and also presented with splenic and mesenteric vein thrombosis. After a transfusion treatment, these complications resolved, and the patient was discharged two weeks later after ablation without analgesic medication [31]. In comparison, the lack of complications seen in our patient group is encouraging and points to the value of IRE combined with chemotherapy as a safe treatment combination. However, the use of
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Table 1 Patient characteristics Patient
Sex
Age
Site
1
M
78
HEAD
2
F
77
3
F
63
4
M
5
Lesion volume
Residual volume 6 months
Decrease at 6 months
No. of IRE Probes IRE
Follow-up
Status
Months of survival
76
59
22.37
4
10
DEAD
33
HEAD
59
27
54.24
5
8
DEAD
24
HEAD
122
92
24.59
4
7
DEAD
12
79
HEAD
97
32
67.01
5
11
DEAD
24
M
60
ISTHMUS
170
56.3
N/A
5
3
DEAD
3
6
F
55
ISTHMUS
57
32
43.86
5
9
DEAD
13
7 8
M M
60 68
BODY-TAIL BODY-TAIL
42 61
5 38
88.10 37.70
2 3
14 12
DEAD DEAD
26 18
9
F
57
HEAD
39
23.4
N/A
3
4
DEAD
4
10
F
72
HEAD
49
36
26.53
4
7
DEAD
18
11
F
82
HEAD
69
38
44.93
3
6
DEAD
20
12
M
70
HEAD
98
54
44.90
4
10
DEAD
21
13
F
64
HEAD
120
87
27.50
4
9
DEAD
14
14
M
75
ISTHMUS-HEAD
153
76
50.33
4
8
DEAD
11
15
F
72
ISTHMUS
94
66
29.79
3
12
DEAD
18
16
M
80
BODY-TAIL
115
81
29.57
3
10
DEAD
14
17
M
59
BODY-TAIL
97
52
46.39
3
8
DEAD
12
18
F
70
HEAD
134
81
39.55
3
7
DEAD
13
19
F
65
BODY-TAIL
126
88
30.16
3
7
DEAD
12
20
M
77
BODY-TAIL
84
48
42.86
2
9
DEAD
11
21
M
64
HEAD
88
44
50.00
3
ALIVE
16
22 23
M F
58 61
HEAD ISTHMUS
98 94
55 51
43.88 45.74
4 3
ALIVE ALIVE
9 13
24
F
71
BODY-TAIL
25
M
81
HEAD
26
M
65
HEAD
27
F
68
BODY-TAIL
28
M
69
29
M
68
124
89
28.23
3
DEAD
11
97
55
43.30
4
DEAD
12
74
51
31.08
4
ALIVE
8
116
84
27.59
4
ALIVE
6
HEAD
84
62
26.19
3
ALIVE
5
BODY-TAIL
90
52
42.22
3
ALIVE
4
irreversible electroporation in oncological treatment is novel in of itself, and the need for more prospective studies is magnified in order to understand its role in combination with other palliative treatments. IRE has also been used as a clinical last resort, as some practitioners turn to it when patients are otherwise unresponsive to chemotherapy as demonstrated with either CT or MRI imaging. In a study involving 10 patients by Paiella et al., all patients presented with Stage III LAPC, but were all unresponsive to previous chemotherapy treatment. Paiella successfully evaluated the safety of IRE, as OS was noted to be 7.5 months (range 2.9–15.9) with only 1 (10%) patient presenting with complication [32]. IRE has been noted as a safer alternative to other ablative treatments, including radiofrequency (RF) ablations. A primary reason is the lack of thermal energy utilization to induce the formation of micropores in the
Table 2 Paired t test Karnofsky scores Mean
N
SD
Std. error mean
Tzero
57.9310
29
10.13456
1.88194
T3m
86.2069
29
18.40299
3.41735
T6m
82.0000
25
11.54701
2.30940
T9m
69.5652
23
16.09016
3.35503
T12m
55.2174
23
26.43509
5.51210
T15m
67.2727
11
23.70270
7.14663
T18m
53.7500
8
32.48626
11.48563
cellular membrane. IRE is based on a bioelectric phenomenon marked by the permeabilization of the cellular membrane in response to extremely short, microsecondlong electric pulses. The phospholipid bilayer, which is
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Table 3 Paired t test Karnofsky score differences Paired differences Mean
SD
Std. error mean
t
df
Sig. (2-tailed)
95% confidence interval of the difference Lower
Upper
Pair 1
Tzero–T3m
-28.27586
11.36064
2.10962
-32.59722
-23.95451
-13.403
28
.000
Pair 2
Tzero–T6m
-22.00000
9.12871
1.82574
-25.76815
-18.23185
-12.050
24
.000
Pair 3 Pair 4
Tzero–T9m Tzero–T12m
-10.00000 4.34783
12.06045 21.70590
2.51478 4.52599
-15.21533 -5.03851
-4.78467 13.73416
-3.976 .961
22 22
.001 .347
Pair 5
Tzero–T15m
-2.72727
21.48996
6.47947
-17.16442
11.70988
-.421
10
.683
Pair 6
Tzero–T18m
12.50000
30.11881
10.64861
-12.67996
37.67996
1.174
7
.279
woven into the structure of the cellular membrane, massively destabilizes and leads to apoptotic cell death. Within the range of electric field magnitude capable of inducing this destruction, there exists a subset capable of causing pore formation without joule heating [33]. As a result, there is an absence of the ‘‘heat sink’’ effect, particularly in nearby connective tissue and vascular structures. In this report, we record no major complications after IRE treatment as confirmed by CT imaging. These results are similar to those of a study conducted by Narayanan and colleagues, where 15 IRE procedures were conducted in 14 patients for the treatment of pancreatic adenocarcinoma [34]. One patient experienced spontaneous pneumothorax during anesthesia, and another experienced pancreatis. The two patients made full recoveries, and there were no mortalities directly related to the procedure. Both studies demonstrate the safety of IRE as a treatment method. This study demonstrates a low rate of complications likely attributable to the noninvasive percutaneous CTguidance IRE approach, which allows for quicker application of chemotherapy regimens (24 h after treatment) and improved absorption of drug in the lesion. This study was limited by the absence of a control group and by the relatively small number of patient cases to select for analysis. Results from the 29 individuals suggest efficacy of IRE ? chemotherapy, but longer studies involving larger patient sample sizes are needed to help confirm treatment effect. The data were analyzed retrospectively, which means that selection and treatment biases, along with confounding errors, may have played a role in data calculation.
Conclusion Treatment with IRE followed by chemotherapy substantially increases median OS rate and quality-of-life of LAPC-diagnosed patients when compared to patients treated with traditional methods, including chemotherapy.
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Further investigation of this multi-modal treatment is warranted. Compliance with ethical standards Conflict of interest The Authors declare that they have no conflict of interest. Ethical standards All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Patient consent Informed consent was obtained from all patients.
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