1. bookVolume 50 (2016): Issue 1 (March 2016)
Journal Details
License
Format
Journal
eISSN
1581-3207
First Published
30 Apr 2007
Publication timeframe
4 times per year
Languages
English
Open Access

Effectiveness of electrochemotherapy after IFN-α adjuvant therapy of melanoma patients

Published Online: 16 Feb 2016
Volume & Issue: Volume 50 (2016) - Issue 1 (March 2016)
Page range: 21 - 27
Received: 20 Oct 2015
Accepted: 30 Nov 2015
Journal Details
License
Format
Journal
eISSN
1581-3207
First Published
30 Apr 2007
Publication timeframe
4 times per year
Languages
English
Introduction

Melanoma is, due to the high risk of metastases development and its resistance to different treatment strategies, still the most lethal skin cancer. The most effective treatment for primary melanoma of stage I and II is its removal by radical surgical excision with the associated safety margin, usually followed by a sentinel lymph node biopsy. Although this approach is curative in many cases, relapse with disseminated disease occurs in some patients. Therefore, in patients with an increased risk for recurrent disease adjuvant immunotherapy might be applied.1,2

The sole recognized postsurgical adjuvant therapy still is interferon alpha (IFN-α). In several clinical studies both interferon types, the high-dose interferon alpha-2b (IFN-α2b) and low-dose interferon alpha-2a (IFN-α2a) were shown to have significant effect on progression-free survival.35 Recent meta-analysis showed statistically significant improvement in disease free survival and overall survival in patients with high risk melanoma (stage IIb-IIIc according to The American Joint Committee on Cancer [AJCC] TNM Cancer Staging Manual 7th edition6) treated with adjuvant IFN-α after surgery.7,8

When melanoma recurs, other treatment modalities are needed for local or systemic control of the disease. Most commonly used are systemic chemotherapy with dacarbazine, irradiation, isolated limb perfusion or electrochemotherapy and in recent years also new targeted therapies with BRAF and/or MEK inhibitors and antibodies against CTLA-4.9,10

Electrochemotherapy is one of the treatment modalities for local treatment of malignant melanoma, which is using electroporation as a delivery system for the chemotherapeutic drugs bleomycin or cisplatin into the tumor.1114 Under the high external electric field the plasma membrane becomes permeable, thus facilitating drug delivery into the tumors. Numerous clinical studies have demonstrated the effectiveness of electrochemotherapy on a variety of cutaneous and also deep seated tumors, such as liver metastases of colorectal cancer.15 Among cutaneous tumors, electrochemo-therapy is very effective in treatment of melanoma, with a complete response rate after a single treatment of 74%.16 Some studies have recently reported on beneficial effect on melanoma treatment after combining electrochemotherapy with new targeted therapies such as dabrafenib or ipilimumab.17,18 Furthermore, electrogene therapy with plasmids coding for interleukin-12 (IL-12) or antiangiogenic molecules, is also in clinical testing for melanoma treatment.1922

In preclinical studies, it was shown that adjuvant therapy with TNF-α, IL-2, IL-12 and CpG oligonucleotides might boost electrochemotherapy response.2330 However, the role of adjuvant IFN-α has not been explored yet, neither on preclinical or clinical level. Therefore, the aim of the study was to evaluate the safety and effectiveness of electro-chemotherapy on recurrent melanoma after IFN-α adjuvant therapy of melanoma patients.

Patients and methods
Study design and patient selection

The study was conducted as a retrospective single-center analysis of patients with advanced malignant melanoma treated with electrochemotherapy, who previously received IFN-α adjuvant therapy, after surgery of primary melanoma. All the patient files where electrochemotherapy was performed in the last 6 years, between January 2008 and December 2014, were reviewed regardless of the time point of IFN-α adjuvant therapy. Among all the (50) patients treated with electrochemotherapy in that time period only 5 of them met the requirements and were further investigated. The trial was approved by an Institutional Review Board and National Medical Ethic Committee 97/06/02. The patients signed the informed consent before the treatment.

Investigated entities

First the patient’s general characteristics (gender, age), the site and TNM, pathological stage (AJCC TNM Cancer Staging Manual, 7th edition) and Breslow thickness of primary melanoma were recorded. Than therapeutic dose and duration of IFN-α adjuvant therapy were recorded for each patient. The treatment free-interval between the end of IFN-α adjuvant therapy and electrochemotherapy treatment was calculated. The site and number of melanoma nodules treated with electrochemo-therapy were further recorded and afterwards effectiveness of electrochemotherapy was evaluated.

IFN-α adjuvant therapy

All five patients received IFN-α as a post-surgical adjuvant therapy. Patient 1 and 2 received low-dose IFN-α since the IFN-α adjuvant therapy was administered before 2010, when new guidelines for melanoma treatment at the Institute of Oncology Ljubljana were accepted. Patient 1 and 2 received Roferon-A® (interferon Alfa-2a) (Roche, Basel, Switzerland) subcutaneously at a dose of 3 or 6 million IU three times a week (Table 2) for 33 and 7 months, respectively, according to the instructions of an oncologist. Patient 3, 4 and 5 received high dose interferon Intron® A (interferon a- alpha 2b) (Merck, Kenilworth, New Jersey, USA) according to the Kirkwood scheme.31 The exact schedule and the dose was adjusted for each patient by his oncologist (Table 2).

Patients’ characteristics

Patient 1Patient 2Patient 3Patient 4Patient 5
GenderMaleMaleFemaleFemaleFemale
Birth year19581935193719531941
TNM

according to AJCC TNM Cancer Staging Manual 7th edition (2010)6; ECT = electrochemotherapy

T3aNOMOT2aNOMOT4bN1aMOT3aN1aMOT4bN1aMO
Patological stage

according to AJCC TNM Cancer Staging Manual 7th edition (2010)6; ECT = electrochemotherapy

Stage IIaStage IbStage IIIbStage IIIaStage IIIb
Breslow4 mm1.5 mm10 mm2.8 mm9.5 mm
Ulceration//10 mm/2.5 mm
Localisation of primary tumorRight lower legLeft footRight footRight lower legBack
Localisation of metastases treated with ECTRight lower legLeft foot (dorsum)Left lower legRight lower legBreast, left side

Treatment regime

Patient 1Patient 2Patient 3Patient 4Patient 5
INF-a dose6 million IU 3 × weekly (s.c.)3 million IU 3 × weekly (s.c.)35 milion IU 20 × (i.v.) in 8 weeks/15 million IU 3× weekly (s.c.) for 13 weeks/ 10 milion IU 3 × weekly (s.c.) for 13 weeks

prematurelly terminated treatment due to ineffective treatment;

30 milion IU 20 × (i.v.) in 4 weeks followed by 15 million IU 3× weekly (s.c.) for 35 weeks followd by 10 milion IU 3 × weekly (s.c.) for 12 weeks30 milion IU 9 × (i.v.) in 2 weeks followed by 20 milion IU 11× (i.v.) in 3 weeks followed by 15 million IU 3× weekly (s.c.) for 13 weeks

intravenous dose (i.v. dose) was decreased to 20 million IU due to pathological liver tests - prematurelly terminated treatment due to side effects

INF-α treatment period2 years 9 months7 months8 months12 months4 months
Last date of INF-α treatmentMarch 2004August 1998July 2012January 2012June 2011
Disease free interval4 months5 years 6 months6 months3 months2 months
Surgically excised metastases

details on localization and number of excised metastates in paragraph Pacients’ caracteristics.

YesYesNoYesYes
Interval between INF-α and ECT treatment4 years 8 months12 years 11 months7 months6 months7 months
ECT treatmentNovember 2008July 2011February 2013July 2013January 2012
ECT drugCisplatinCisplatinBleomycinBleomycinBleomycin
Number of lesions2180235
Size of the nodules1.0 × 1.5 cm 1.5 × 1.5 cm3 × 3 cm0.3–1 cm0.1–0.8 cm0.7–1.5 cm
Effect after 4 weeksCRCR> 85% CRAll CR100% PR
LRD

after last record date at the Institute of Oncology Ljubljana patients were given only paliative care at their regional centers

or date of death (D)
April 2010 (LRD)December 2014 (LRD)April 2014 (LRD)December 2013 (D)March 2013 (D)

CR = complete response; ECT = electrochemotherapy; i.v. = intravenous; PR = partial response; s.c. = subcutaneously; s.c = subcutaneous;

Electrochemotherapy

Patients were treated according to the Standard Operating Procedure (SOP) for electrochemotherapy.16 Briefly, electrochemotherapy of cutaneous melanoma nodules was performed using either intravenous bleomycin (Bleomedac, Medac, Wedel, Germany) in a dose of 15,000 IU/m2 or intratumoral cisplatin (Cisplatin, Medac) injection in a concentration of 2 mg/ml and dose is applied according to ESOPE protocol.16 Standard pulse parameters for electrochemotherapy (voltage to distance ratio 1300 V/cm, 8 pulses, 100 μs, 5000 Hz) were used.16 Electric pulses were generated by Cliniporator pulse generator (IGEA, s.r.l., Carpi, Italy) and delivered by parallel stainless steel plate electrodes with 6 or 8 mm distance in between. Electric pulses were applied to the tumors nodules in a way so as to cover the whole tumor area, including the safety margin.

Response assessment

Antitumor efficacy was evaluated 4 weeks after electrochemotherapy, patient were then monitored monthly. Treatment response was defined either as complete response (CR), when the tumor was not palpable, partial response (PR), when the tumor decreased more than 50% of the measurable lesions; no change (NC), when tumor decreased less than 50% or increased up to 25%, or progressive disease (PD), when tumor increased for more than 25%. Determination was based on criteria of WHO Handbook for Reporting Results of Cancer Treatment where for all response definitions minimum 4-week duration was required for qualifying the response.

Results
Patients’ characteristics

Only 5 patients fulfilled all the requirements for inclusion into this retrospective study. Among them there were two male and three female patients with a median age of electrochemotherapy treatment 71 years (range from 50–76 years). TNM and pathological stage were recorded for all five patients, as well as Breslow thickness (Table 1). The localizations of primary tumors were on the upper leg, foot or the back (Table 1). All the patients were identified as patients with high risk of recurrence and were therefore assigned for IFN-α adjuvant therapy. The relapse of melanoma occurred in all five patients. Recurrence time was variable among patients; from a few months to a few years (Table 1). Other comorbidities were also recorded for all 5 patient; only patient 2 had arterial hypertension and no other comorbidities were recorded.

IFN-α adjuvant therapy and disease progression

Adjuvant therapy with IFN-α in our investigated patients can be divided into two subtypes; low-dose treatment for patients 1 and 2 and high dose treatment for another three patients (Table 2). After the completed adjuvant therapy with IFN-α, in all five patients disease had progressed to a meta-static disease. Disease free interval, progression of the disease and treatment procedures vary for each patient (Table 2). Based on the decision of an institutional committee for melanoma treatment, electrochemotherapy was offered to the patients as another treatment option after several surgical excisions and in patient 1 and 2 also irradiation.

In patient 1 inguinal lymph node metastasis occurred after a disease free interval and inguinal and retroperitoneal lymph node dissection was performed thereafter. The patient was irradiated as well. When progression of the disease occurred 3 years later, two metastases were excised within 2 months and the patient was irradiated again. In 2 months new metastases, which were treated with electrochemotherapy, occurred.

In patient 2 after a disease free interval a metastasis on the limb occurred and was immediately excised. Four years later, another excision with following inguinal dissection and irradiation was performed. In the following 2 years three in-transit metastases were excised from the dorsum of the left foot. A new metastasis occurred 1 year after the last in-transit metastasis excision, which was then treated with electrochemotherapy.

Disease free interval for the patient 3 was 6 months; thereafter multiple metastases occurred on the limb and were treated with electrochemo-therapy.

In patient 4 a metastasis occurred on the scar of a primary excised melanoma only 3 months after completing adjuvant therapy with IFN-α. It was immediately excised, although PET/CT scan and thin needle biopsy showed multiple metastases in the same area, which were then treated with electrochemotherapy.

In patient 5 the disease-free interval was 2 months, followed by two excisions of metastases and shortly afterwards electrochemotherapy of 5 metastases on the trunk. Due to partial response of all 5 metastases, these metastases and newly formed metastases on the trunk were again treated with electrochemotherapy 6 weeks after the first treatment.

Electrochemotherapy following IFN-α adjuvant therapy

At the time of electrochemotherapy patient 2 was presented with a single metastasis on the limb, whereas patients 1, 3, 4 and 5 were presented with multiple metastases on the limb (patient 1, 3 and 4) or trunk (patient 5). All metastases present at the time of electrochemotherapy were treated. Electrochemotherapy was effective in all five patients, with a variable response rate (Table 2).

In patient 1 and 2 cisplatin was given intratumoraly due to previous irradiation of the patients. In some studies, it was reported that previous irradiation can cause lower effectiveness of i.v. electro-chemotherapy.32 Fibrosis can be one of the causes for lower effectiveness. Less fluid in the tissue results in less lymphatic infiltration and also lower current in the nodule and can therefore contribute to the lower effectiveness of electrochemotherapy of pre-iradiated tissues. Intratumoral injection of chemotherapeutic drug can overcome those obstacles and can results in higher effectiveness.

Electrochemotherapy following IFN-α adjuvant therapy was effective treatment modality, regardless of drug used for electrochemotherapy, bleomycin or cisplatin. Single metastasis responded completely, while multiple metastases had a variable response rate. In patient 4 all 23 metastases responded completely, in patient 3 more than 85% of all together 80 metastases responded completely and in patient 5 all 5 metastases had partial response. Taking into account all metastases from all patients together there was an 85% complete response rate. After electrochemotherapy no side effects, such as local erythema, bleeding, infection on the site of electrochemotherapy, or muscle contractions, were reported. Nevertheless new metastases mostly occurred within 1 month (patients 1, 3 and 5) or 2 months (patient 4) after the treatment. In patient 2, with a single metastasis at the time of electrochemotherapy, new metastases occurred after 1 year and 10 months. In patient 1 additional electrochemotherapy of 14 new lesions was performed thereafter, which also resulted in 100% complete response. Nevertheless the disease progressed and although systemic chemotherapy with dacarbazine was administered, new distant metastases in the head and neck region occurred. Electrochemotherapy was then used for palliative care. In patient 2 disease also progressed and due to several metastases, isolated limb perfusion was performed 4 years after electrochemotherapy. No new metastasis occurred yet. Dacarbazine and later also ipilimumab were prescribed for patient 3 with progressive metastatic disease, with metastases present also in liver and lungs. In patient 4 new subcutaneous metastases were effectively irradiated and year after brain metastasis occurred. Electrochemotherapy response in all those patients (patient 1–4) remains the same during the whole observational period. Due to partial response of all 5 metastases in patient 5, these metastases and 12 newly formed metastases on the trunk were again treated with electrochemotherapy, 6 weeks after the first treatment. After the second electrochemotherapy treatment all 17 metastases (including 5 retreated metastases) responded completely. The patient was later treated with dacarbazine and vemurafenib due to soft tissue and lung metastases, but disease progressed with new metastases in lungs and brain.

Figure 1.

Melanoma lesions in patient 1 (A) and patient 5 (B) before and 6 weeks after electrochemotherapy (ECT). Both metastases in patient 1 responded completely, while in patient 5 although the crust is seen on the images there was nodule under it and response was evaluated as partial response.

Discussion

This is the first study to our knowledge which discusses the effectiveness of electrochemotherapy after IFN-α adjuvant therapy for treatment of melanoma metastases.

In recent years electrochemotherapy has been widely used in clinical studies for treatment of cutaneous and also deep seated tumors. Among skin cancers electrochemotherapy was very effective in the treatment of malignant melanoma, with a complete response rate after single treatment 74%, according to ESOPE study.16 Although the electrochemotherapy response rate is quite high, and effective on most of tumor histologies, recently there is some evidence that there is a variability in the response rates of different tumor histologies. The meta-analysis by Mali et al. has shown that melanoma tumors are less responsive than non-melanoma tumors. The effectiveness of electrochemotherapy was tumor type dependent, namely the complete response rate was 57% of melanoma tumors and 67% of other, non-melanoma tumors. Among carcinomas, basal cell carcinoma was the most responsive tumor type, with up to 89% complete responses.33

Furthermore, the importance of the immune response elicited by electrochemotherapy locally was explored.34,35 Immunogenic cell death of cancer cells was proposed to contribute to the curability of the treated metastases. The concept of immunogenic cell death, which is triggered by some cancer therapies, is initiated by damage-associated molecular patterns, which can further trigger an adaptive immune response against tumors.34 Some pre-clinical studies have explored the possibility of adjuvant electrogene therapy with plasmid encoding IL-12, which greatly increase the response rate of the electrochemotherapy treated tumors.30 The recent clinical study, investigating the combined treatment of ipilimumab and electrochemotherapy has shown a better response than ipilimumab alone.17

In this report we show that electrochemotherapy was safe and effective also after IFN-α therapy. IFN-α, although given to the patients in different periods before electrochemotherapy may also contribute to the response rate of the electrochemotherapy treated melanoma metastases. Namely, response rate in patients with electrochemotherapy after adjuvant IFN-α was 100% partial response (patient 5) or from 85% to 100% complete response (patient 1, 3 and 4) in patients with multiple metastases, which is an equal or even higher percentage than demonstrated in previous studies; 85% of metastases responded completely in the present study, while the results of meta-analysis showed that 57% of melanoma metastases responded completely.16,33

We might speculate that the effectiveness may be increased by the previous immunostimulatory IFN-α adjuvant therapy, which would be reflected in high response rate of the treated tumors. IFN-α is one of the type I interferons, an important interferon family, involved in immune-editing process. Their main importance is the effect on the hematopoietic cells; induction of bystander T cell proliferation, long-term survival and expression of anti-apoptotic genes.3637 Furthermore, interferons have also great impact on maturation and differentiation of dendritic cells, cells which are considered to be the most effective antigen presenting cells.34 Taking all this findings into account, IFN-α might have a significant role in a link between the innate and adaptive immune system. Similarly, new targeted therapy with ipilimumab acts on dendritic cells - cytotoxic T lymphocytes (CTLs) interaction. Dendritic cells are presenting tumor antigens to CTLs, which can then destroy cancer cells. But along with tumor antigens the dendritic cells present also an inhibitory signal, which can bind to a receptor on the CTLs; cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and thereby block the cytotoxicity of CTL. Ipilimumab binds to CTLA-4 and block the inhibitory signal.38,39

One of the possible reasons for the very good efficiacy of electrochemotherapy, following IFN-α adjuvant therapy is immune system activation by electrochemotherapy, which was previously modulated by IFN-α.40 Calvet et al. demonstrated in an in vivo preclinical study that electrochemotherapy not only has a cytotoxic effect towards cancer cells, but can also generate a systemic anticancer immune response, with imunogenic cell death.33,40 Dying cancer cells then behave as a therapeutic vaccine, leading to a cytotoxic immune response against remaining tumor cells.35,42 It was also demonstrated that electrochemotherapy is more effective in immunocompetent mice, causing complete tumor regression, whereas in immunodeficient mice the complete response was not obtained.35

The drawback of our study is that we have no data on the immune status of the patients and that this is an observational study. Nevertheless, although this group of patients is small it might indicate on the potential of combining immunostimulatory treatments with electrochemotherapy, which can be explored in different ways. One of the recent ideas is that electrochemotherapy can serve as a vaccination to adjuvant peritumoral immunostimulatory therapy that can boost the local effect as well it may have the systemic effect.42

Conclusions

The report demonstrates that combining electrochemotherapy with preceded IFN-α adjuvant therapy is a safe and effective treatment modality, which results in high complete response rate, not only in single metastasis, but also in multiple metastases. The high complete response rate might be due to IFN-α immune-editing effect, however further controlled studies on a larger number of patients are needed to support this presumption.

Figure 1.

Melanoma lesions in patient 1 (A) and patient 5 (B) before and 6 weeks after electrochemotherapy (ECT). Both metastases in patient 1 responded completely, while in patient 5 although the crust is seen on the images there was nodule under it and response was evaluated as partial response.
Melanoma lesions in patient 1 (A) and patient 5 (B) before and 6 weeks after electrochemotherapy (ECT). Both metastases in patient 1 responded completely, while in patient 5 although the crust is seen on the images there was nodule under it and response was evaluated as partial response.

Treatment regime

Patient 1Patient 2Patient 3Patient 4Patient 5
INF-a dose6 million IU 3 × weekly (s.c.)3 million IU 3 × weekly (s.c.)35 milion IU 20 × (i.v.) in 8 weeks/15 million IU 3× weekly (s.c.) for 13 weeks/ 10 milion IU 3 × weekly (s.c.) for 13 weeks

prematurelly terminated treatment due to ineffective treatment;

30 milion IU 20 × (i.v.) in 4 weeks followed by 15 million IU 3× weekly (s.c.) for 35 weeks followd by 10 milion IU 3 × weekly (s.c.) for 12 weeks30 milion IU 9 × (i.v.) in 2 weeks followed by 20 milion IU 11× (i.v.) in 3 weeks followed by 15 million IU 3× weekly (s.c.) for 13 weeks

intravenous dose (i.v. dose) was decreased to 20 million IU due to pathological liver tests - prematurelly terminated treatment due to side effects

INF-α treatment period2 years 9 months7 months8 months12 months4 months
Last date of INF-α treatmentMarch 2004August 1998July 2012January 2012June 2011
Disease free interval4 months5 years 6 months6 months3 months2 months
Surgically excised metastases

details on localization and number of excised metastates in paragraph Pacients’ caracteristics.

YesYesNoYesYes
Interval between INF-α and ECT treatment4 years 8 months12 years 11 months7 months6 months7 months
ECT treatmentNovember 2008July 2011February 2013July 2013January 2012
ECT drugCisplatinCisplatinBleomycinBleomycinBleomycin
Number of lesions2180235
Size of the nodules1.0 × 1.5 cm 1.5 × 1.5 cm3 × 3 cm0.3–1 cm0.1–0.8 cm0.7–1.5 cm
Effect after 4 weeksCRCR> 85% CRAll CR100% PR
LRD

after last record date at the Institute of Oncology Ljubljana patients were given only paliative care at their regional centers

or date of death (D)
April 2010 (LRD)December 2014 (LRD)April 2014 (LRD)December 2013 (D)March 2013 (D)

Patients’ characteristics

Patient 1Patient 2Patient 3Patient 4Patient 5
GenderMaleMaleFemaleFemaleFemale
Birth year19581935193719531941
TNM

according to AJCC TNM Cancer Staging Manual 7th edition (2010)6; ECT = electrochemotherapy

T3aNOMOT2aNOMOT4bN1aMOT3aN1aMOT4bN1aMO
Patological stage

according to AJCC TNM Cancer Staging Manual 7th edition (2010)6; ECT = electrochemotherapy

Stage IIaStage IbStage IIIbStage IIIaStage IIIb
Breslow4 mm1.5 mm10 mm2.8 mm9.5 mm
Ulceration//10 mm/2.5 mm
Localisation of primary tumorRight lower legLeft footRight footRight lower legBack
Localisation of metastases treated with ECTRight lower legLeft foot (dorsum)Left lower legRight lower legBreast, left side

Veronesi U, Adamus J, Aubert C, Bajetta E, Beretta G, Bonadonna G, et al. A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med 1982; 307: 913–6.VeronesiUAdamusJAubertCBajettaEBerettaGBonadonnaGA randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanomaN Engl J Med1982307913610.1056/NEJM198210073071503Search in Google Scholar

Pflugfelder A, Kochs C, Blum A, Capellaro M, Czeschik C, Dettenborn T, et al. Malignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”. J Dtsch Dermatol Ges 2013; 11 (Suppl 6): 1–116, 1-126.PflugfelderAKochsCBlumACapellaroMCzeschikCDettenbornTMalignant melanoma S3-guideline “diagnosis, therapy and follow-up of melanoma”J Dtsch Dermatol Ges201311(Suppl 6)11161-12610.1111/ddg.12113_supplSearch in Google Scholar

Hauschild A. Adjuvant interferon alfa for melanoma: new evidence-based treatment recommendations? Curr Oncol 2009; 16: 3–6.HauschildAAdjuvant interferon alfa for melanoma: new evidence-based treatment recommendations?Curr Oncol2009163610.3747/co.v16i3.447Search in Google Scholar

Cole BF, Gelber RD, Kirkwood JM, Goldhirsch A, Barylak E, Borden E. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1996; 14: 2666–73.ColeBFGelberRDKirkwoodJMGoldhirschABarylakEBordenEQuality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group studyJ Clin Oncol19961426667310.1200/JCO.1996.14.10.2666Search in Google Scholar

Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, et al. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 1998; 351: 1905–10.GrobJJDrenoBde la SalmonièrePDelaunayMCupissolDGuillotBRandomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on MelanomaLancet199835119051010.1016/S0140-6736(97)12445-XSearch in Google Scholar

Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17: 1471–4.EdgeSBComptonCCThe American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNMAnn Surg Oncol2010171471410.1245/s10434-010-0985-420180029Search in Google Scholar

Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010; 102: 493–501.MocellinSPasqualiSRossiCRNittiDInterferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysisJ Natl Cancer Inst201010249350110.1093/jnci/djq00920179267Search in Google Scholar

Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev 2013; 6: CD08955.MocellinSLensMBPasqualiSPilatiPChiarion SileniVInterferon alpha for the adjuvant treatment of cutaneous melanomaCochrane Database Syst Rev20136>CD00895510.1002/14651858.CD008955Search in Google Scholar

Kaufman HL, Kirkwood JM, Hodi FS, Agarwala S, Amatruda T, Bines SD, et al. The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Oncol 2013; 10: 588–98.KaufmanHLKirkwoodJMHodiFSAgarwalaSAmatrudaTBinesSDThe Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanomaNat Rev Clin Oncol2013105889810.1038/nrclinonc.2013.15323982524Search in Google Scholar

Karimkhani C, Gonzalez R, Dellavalle RP. A review of novel therapies for melanoma. Am J Clin Dermatol 2014; 15: 323–37.KarimkhaniCGonzalezRDellavalleRPA review of novel therapies for melanomaAm J Clin Dermatol2014153233710.1007/s40257-014-0083-724928310Search in Google Scholar

Sersa G, Miklavcic D, Cemazar M, Rudolf Z, Pucihar G, Snoj M. Electrochemotherapy in treatment of tumours. EJSO 2008; 34: 232–40.SersaGMiklavcicDCemazarMRudolfZPuciharGSnojMElectrochemotherapy in treatment of tumoursEJSO2008342324010.1016/j.ejso.2007.05.01617614247Search in Google Scholar

Testori A, Rossi CR, Tosti G. Utility of electrochemotherapy in melanoma treatment. Curr Opin Oncol 2012; 24: 155–61.TestoriARossiCRTostiGUtility of electrochemotherapy in melanoma treatmentCurr Opin Oncol2012241556110.1097/CCO.0b013e32834fcaa822249204Search in Google Scholar

Cadossi R, Ronchetti M, Cadossi M. Locally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of electrochemotherapy. Future Oncol 2014; 10: 877–90.CadossiRRonchettiMCadossiMLocally enhanced chemotherapy by electroporation: clinical experiences and perspective of use of electrochemotherapyFuture Oncol2014108779010.2217/fon.13.23524799067Search in Google Scholar

Testori A, Faries MB, Thompson JF, Pennacchioli E, Deroose JP, van Geel AN, et al. Local and intralesional therapy of in-transit melanoma metastases. J Surg Oncol 2011; 104: 391–6.TestoriAFariesMBThompsonJFPennacchioliEDerooseJPvan GeelANLocal and intralesional therapy of in-transit melanoma metastasesJ Surg Oncol2011104391610.1002/jso.2202921858834Search in Google Scholar

Edhemovic I, Brecelj E, Gasljevic G, Marolt Music M, Gorjup V, Mali B, et al. Intraoperative electrochemotherapy of colorectal liver metastases. J Surg Oncol 2014; 110: 320–7.EdhemovicIBreceljEGasljevicGMarolt MusicMGorjupVMaliBIntraoperative electrochemotherapy of colorectal liver metastasesJ Surg Oncol2014110320710.1002/jso.2362524782355Search in Google Scholar

Marty M, Sersa G, Garbay J, Gehl J, Collins C, Snoj M, et al. Electrochemotherapy–An easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. Eur J Cancer Suppl 2006; 4: 3–13.MartyMSersaGGarbayJGehlJCollinsCSnojMElectrochemotherapy– Aneasy highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) studyEur J Cancer Suppl2006431310.1016/j.ejcsup.2006.08.002Search in Google Scholar

Simeone E, Benedetto L, Gentilcore G, Capone M, Caraco C, Di Monta G, et al. Combination therapy with ipilimumab and electrochemotherapy; preliminary efficacy results and correlation with imunological parameters. J Transl Med 2014; 12 (Suppl 1): 05.SimeoneEBenedettoLGentilcoreGCaponeMCaracoCDi MontaGCombination therapy with ipilimumab and electrochemotherapy; preliminary efficacy results and correlation with imunological parametersJ Transl Med201412Suppl 10510.1186/1479-5876-12-S1-O5Search in Google Scholar

Valpone S, Campana L, Pigozzo J, Chiarion-Sileni V. Consolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenib. Radiol Oncol 2015; 49: 71–4.ValponeSCampanaLPigozzoJChiarion-SileniVConsolidation electrochemotherapy with bleomycin in metastatic melanoma during treatment with dabrafenibRadiol Oncol20154971410.2478/raon-2014-0035436260925810704Search in Google Scholar

Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12. Curr Gene Ther 2010; 10: 300–11.CemazarMJarmTSersaGCancer electrogene therapy with interleukin-12Curr Gene Ther2010103001110.2174/15665231079182342520560875Search in Google Scholar

Daud AI, DeConti RC, Andrews S, Urbas P, Riker AI, Sondak VK, et al. Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 2008; 26: 5896–903.DaudAIDeContiRCAndrewsSUrbasPRikerAISondakVKPhase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanomaJ Clin Oncol200826589690310.1200/JCO.2007.15.6794264511119029422Search in Google Scholar

Spanggaard I, Snoj M, Cavalcanti A, Bouquet C, Sersa G, Robert C, et al. Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase I first-in-man study. Hum Gene Ther Clin Dev 2013; 24: 99–107.SpanggaardISnojMCavalcantiABouquetCSersaGRobertCGene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase I first-in-man studyHum Gene Ther Clin Dev2013249910710.1089/humc.2012.240Search in Google Scholar

Heller LC, Heller R. Electroporation gene therapy preclinical and clinical trials for melanoma. Curr Gene Ther 2010; 10: 312–7.HellerLCHellerRElectroporation gene therapy preclinical and clinical trials for melanomaCurr Gene Ther201010312710.2174/156652310791823489Search in Google Scholar

Cemazar M, Todorovic V, Scancar J, Lampreht U, Stimac M, Kamensek U, et al. Adjuvant TNF-α therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectiveness. Radiol Oncol 2015; 49: 32–40.CemazarMTodorovicVScancarJLamprehtUStimacMKamensekUAdjuvant TNF-α therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectivenessRadiol Oncol201549324010.1515/raon-2015-0005Search in Google Scholar

Gerlini G, Di Gennaro P, Borgognoni L. Enhancing anti-melanoma immunity by electrochemotherapy and in vivo dendritic-cell activation. Oncoimmunology 2012; 1: 1655–7.GerliniGDi GennaroPBorgognoniLEnhancing anti-melanoma immunity by electrochemotherapy and in vivo dendritic-cell activationOncoimmunology201211655710.4161/onci.21991Search in Google Scholar

Sersa G, Cemazar M, Menart V, Gaberc-Porekar V, Miklavcic D. Anti-tumor effectiveness of electrochemotherapy with bleomycin is increased by TNF-alpha on SA-1 tumors in mice. Cancer Lett 1997; 116: 85–92.SersaGCemazarMMenartVGaberc-PorekarVMiklavcicDAnti-tumor effectiveness of electrochemotherapy with bleomycin is increased by TNF-alpha on SA-1 tumors in miceCancer Lett1997116859210.1016/S0304-3835(97)00170-5Search in Google Scholar

Heller L, Pottinger C, Jaroszeski MJ, Gilbert R, Heller R. In vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunity. Melanoma Res 2000; 10: 577–83.HellerLPottingerCJaroszeskiMJGilbertRHellerRIn vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunityMelanoma Res2000105778310.1097/00008390-200012000-0001011198480Search in Google Scholar

Mir LM, Roth C, Orlowski S, Belehradek J, Fradelizi D, Paoletti C, et al. Potentiation of the antitumoral effect of electrochemotherapy by immunotherapy with allogeneic cells producing interleukin 2. C R Acad Sci III 1992; 314: 539–44.MirLMRothCOrlowskiSBelehradekJFradeliziDPaolettiCPotentiation of the antitumoral effect of electrochemotherapy by immunotherapy with allogeneic cells producing interleukin 2C R Acad Sci III199231453944Search in Google Scholar

Mir LM, Orlowski S, Poddevin B, Belehradek J. Electrochemotherapy tumor treatment is improved by interleukin-2 stimulation of the host’s defenses. Eur Cytokine Netw 1992; 3: 331–4.MirLMOrlowskiSPoddevinBBelehradekJElectrochemotherapy tumor treatment is improved by interleukin-2 stimulation of the host’s defensesEur Cytokine Netw199233314Search in Google Scholar

Roux S, Bernat C, Al-Sakere B, Ghiringhelli F, Opolon P, Carpentier AF, et al. Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses. Cancer Immunol Immunother 2008; 57: 1291–300.RouxSBernatCAl-SakereBGhiringhelliFOpolonPCarpentierAFTumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responsesCancer Immunol Immunother200857129130010.1007/s00262-008-0462-018259749Search in Google Scholar

Sedlar A, Dolinsek T, Markelc B, Prosen L, Kranjc S, Bosnjak M, et al. Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity. Radiol Oncol 2012; 46: 302–11.SedlarADolinsekTMarkelcBProsenLKranjcSBosnjakMPotentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicityRadiol Oncol2012463021110.2478/v10019-012-0044-9357289323412658Search in Google Scholar

Moreno Nogueira JA, 1 Valero Arbizu M, Pérez Temprano R. Adjuvant treatment of melanoma. ISRN Dermatol. 2013; 2013: 545631.Moreno NogueiraJAValero ArbizuMPérez TempranoRAdjuvant treatment of melanomaISRN Dermatol.2013201354563110.5772/19242Search in Google Scholar

Groselj A, Kos B, Cemazar M, Urbancic J, Kragelj G, Bosnjak M, Veberic B, Strojan P, Miklavcic D, Sersa G. Coupling treatment planning with navigation system: a new technological approach in treatment of head and neck tumors by electrochemotherapy. Biomed Eng Online. 2015; 14 Suppl 3: S2.GroseljAKosBCemazarMUrbancicJKrageljGBosnjakMVebericBStrojanPMiklavcicDSersaGCoupling treatment planning with navigation system: a new technological approach in treatment of head and neck tumors by electrochemotherapyBiomed Eng Online.201514Suppl 3S210.1186/1475-925X-14-S3-S2456557526355773Search in Google Scholar

Mali B, Jarm T, Snoj M, Sersa G, Miklavcic D. Antitumor effectiveness of electrochemotherapy: a systematic review and meta-analysis. EJSO 2013; 39: 4–16.MaliBJarmTSnojMSersaGMiklavcicDAntitumor effectiveness of electrochemotherapy: a systematic review and meta-analysisEJSO20133941610.1016/j.ejso.2012.08.016Search in Google Scholar

Calvet CY, Famin D, André FM, Mir LM. Electrochemotherapy with bleomycin induces hallmarks of immunogenic cell death in murine colon cancer cells. Oncoimmunology 2014; 3: e28131.CalvetCYFaminDAndréFMMirLMElectrochemotherapy with bleomycin induces hallmarks of immunogenic cell death in murine colon cancer cellsOncoimmunology20143e2813110.4161/onci.28131Search in Google Scholar

Sersa G, Miklavcic D, Cemazar M, Belehradek J, Jarm T, LM. Mir. Electrochemotherapy with CDDP on LPB sarcoma: comparison of the anti-tumor effectiveness in immunocompetent and immunodeficient mice. Bioelectrochem Bioenerg 1997; 43: 279–83.SersaGMiklavcicDCemazarMBelehradekJJarmT LMMirElectrochemotherapy with CDDP on LPB sarcoma: comparison of the anti-tumor effectiveness in immunocompetent and immunodeficient miceBioelectrochem Bioenerg1997432798310.1016/S0302-4598(96)05194-XSearch in Google Scholar

Tough DF, Borrow P, Sprent J. Induction of bystander T cell proliferation by viruses and type I interferon in vivo. Science 1996; 272: 1947–50.ToughDFBorrowPSprentJInduction of bystander T cell proliferation by viruses and type I interferon in vivoScience199627219475010.1126/science.272.5270.19478658169Search in Google Scholar

Paquette RL, Hsu NC, Kiertscher SM, Park AN, Tran L, Roth MD, et al. Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol 1998; 64: 358–67.PaquetteRLHsuNCKiertscherSMParkANTranLRothMDInterferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cellsJ Leukoc Biol1998643586710.1002/jlb.64.3.3589738663Search in Google Scholar

Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 2007; 7: 95–106.MeleroIHervas-StubbsSGlennieMPardollDMChenLImmunostimulatory monoclonal antibodies for cancer therapyNat Rev Cancer200779510610.1038/nrc205117251916Search in Google Scholar

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23.HodiFSO’DaySJMcDermottDFWeberRWSosmanJAHaanenJBImproved survival with ipilimumab in patients with metastatic melanomaN Engl J Med20103637112310.1056/NEJMoa1003466354929720525992Search in Google Scholar

O’Brien MA, Power DG, Clover AJ, Bird B, Soden DM, Forde PF. Local tumour ablative therapies: opportunities for maximising immune engagement and activation. Biochim Biophys Acta 2014; 1846: 510–23.O’BrienMAPowerDGCloverAJBirdBSodenDMFordePFLocal tumour ablative therapies: opportunities for maximising immune engagement and activationBiochim Biophys Acta201418465102310.1016/j.bbcan.2014.09.00525286319Search in Google Scholar

Sersa G, Kotnik V, Cemazar M, Miklavcic D, Kotnik A. Electrochemotherapy with bleomycin in SA-1 tumor-bearing mice--natural resistance and immune responsiveness. Anticancer Drugs 1996; 7: 785–91.SersaGKotnikVCemazarMMiklavcicDKotnikAElectrochemotherapy with bleomycin in SA-1 tumor-bearing mice--natural resistance and immune responsivenessAnticancer Drugs199677859110.1097/00001813-199609000-000118949991Search in Google Scholar

Sersa G, Teissie J, Signori E, Kamensek U, Marshall G, Cemazar M, et al. Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. Cancer Immunol Immunother 2015; 64: 1315–27.SersaGTeissieJSignoriEKamensekUMarshallGCemazarMElectrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransferCancer Immunol Immunother20156413152710.1007/s00262-015-1724-2455473526067277Search in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo