Abstract




Electrochemotherapy (ECT) is a well established treatment strategy for skin tumuors. The aim of this study was to evaluate the feasibil- ity and efficacy of electrochemotherapy in the palliative setting in patients with head and neck malignancies, in terms of improvement of quality of life and in control of pain and bleeding. Twenty-four patients with a loco-regional M0/M1 relapse not suitable for cure with radical intent by surgery or radiotherapy (RT) and not suitable for systemic therapy and/or already treated with it, were admitted to ECT protocol treatment. Clinical features, treatment response, and adverse effects were evaluated. An overall response of 100% was observed. Overall survival probability at 24 months was 46.5% (median OS: 9 months). The multiple application of ECT was associated with im- proved survival (p = 0.02). Pain, need for medical assistance or dressing and bleeding events was significantly reduced at 1 month after ECT (p < 0.001). ECT is effective as palliative treatment of non-resectable head and neck malignancies. Its main advantages are improved quality of life, local tumour control and limited side effects.




Introduction

Worldwide, carcinomas of the head and neck (HNC) account for more than 5% of all malignancies, which are squamous cell carcinomas in 90% of cases 1. Despite multimodal treatment, 50-60% of patients with stage III or IV disease relapse locoregionally. Of these, most are not suitable for salvage treatment and are eventually candidates for palliation 2.

In case of unresectable recurrent or persistent disease, Head and Neck 2015 NCCN guidelines recommend re-irradiation +/– systemic therapy, systemic therapy, clinical trial, or best supportive care 3. These treatment options should be evaluated considering the patient’s performance status (PS) and life expectancy.

Electrochemotherapy (ECT) is a well established treatment for cutaneous tumours consisting in the combination of electroporation and chemotherapy 6. Electroporation has been studied for approximately 20 years as a means of facilitating the transport of normally non-permeant molecules into cells. By applying an electric field to the cells, the membrane become permeable, allowing chemotherapeutic agents such as bleomycin to enter the cell7, increasing its toxicity 8 9.

There are four different possible clinical applications of ECT: palliative treatment in case of advanced stage of disease; neoadjuvant role in the form of cytoreductive therapy; organ and function sparing treatment in patients in which conventional therapies cannot be performed; treatment of highly vascularised nodules 10. The interest for ECT in treatment of the tumours in the H&N area has increased because specific clinical problems may arise due to failure or expected disfigurement of standard treatments. Many clinical reports described results of electrochemotherapy in treatment of H&N tumours 11-14.

The aim of this prospective study was to evaluate the feasibility and efficacy of ECT in the palliative setting in patients with recurrent inoperable head and neck malignancies not suitable for standard palliation by systemic chemotherapy.

Materials and methods

From April 2012 to April 2015 a total of 24 patients, observed at the Department of Otolaryngology Head and Neck Surgery of the National Cancer Institute Regina Elena, Rome, Italy (21 males, 3 females, age 37-88 years; mean: 69.9 years; median 70 years), with recurrent inoperable head and neck malignancies were submitted to ECT treatment. The clinical trial was approved by the institutional ethics committee and ECT indication was agreed by a multi- disciplinary tumour board for each patient (registration code RS 362/13). Each patient was asked to give written informed consent to participate to the study.

All patients had already been treated by multimodal therapy and, at the time of inclusion, presented with a loco-regional M0 or M1 relapse not suitable for a cure with radical intent by surgery or RT, and not suitable for systemic therapy and/or already treated with it. Patient demographics and staging characteristics are shown in Table I. The histological characteristics of tumour were assessed.

Twenty patients (84%) were affected by squamous cell carcinoma (SCC), 1 skin melanoma (4%), 1 synovial sarcoma (4%), 1 adenocarcinoma (4%) and 1 mucoepidermoid carcinoma (4%). In 14 cases (58%), ECT was delivered at the primary tumour site, in 7 cases (29%) at laterocervical lymph nodes and in 3 cases (13%) at the primary site and laterocervical lymph nodes (Table I). Only palpable lymph nodes were treated, as revealed by staging. Cervical nodes metastases were all voluminous and palpable. All patients affected by recurrent, metastatic, or primary HNC not suitable for surgery or chemo/radiotherapy on the basis of poor general condition, age, cardiac deficit not related to electrical malfunction, reduced lung performance, comorbidities, high risk of major intra-postoperative complications, risk of anaesthesia, previous treatments, and when the surgery would be too aggressive to be curative, were eligible.

The technical procedure and patient selection were based on the ESOPE guidelines 15 16. Inclusion criteria were: life expectancy longer than 6 months; measurable cutaneous or mucosal tumour lesions. Exclusion criteria included: clinically manifested arrhythmia, interstitial lung fibrosis, epilepsy, active infection, known allergy to bleomycin, kidney failure, previous treatment with bleomycin at the maximum cumulative dosage and different anticancer therapies administered within 2 weeks of the ECT 16 17. Before treatment all patients underwent radiologic evaluation with CT and/or MRI to define the widest diameter of the lesion. RECIST criteria (Response Evaluation Criteria in Solid Tumors, version 1.1) were applied for evaluation of the results after ECT: complete response (disappearance of all target lesions; any pathological lymph nodes must have reduction in short axis to #x003C; 10 mm); partial response (at least a 30% decrease in the sum of diameters of target lesions); progressive disease (at least a 20% increase in the sum of diameters of target lesions; stable disease (neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease) 18.

All lesions were documented by photographs to evaluate aesthetic and functional results after treatment.

ECT protocol

The procedure was done under mild sedation. When feasible, local anaesthesia consisted of tissue infiltration with 2% lidocaine.

All patients received an intravenous bolus injection of 15,000 IU/m2 of bleomycin. Eight minutes after the infusion electric pulses were delivered by different types of needle electrodes (hexagonal, or finger) chosen according to the site, volume and shape of the lesions to be treated, and generated by a Cliniporator (IGEA srl, Carpi, Italy). We used hexagonal electrodes in 20 patients (83%) and finger electrode in 4 cases (17%). Needles were inserted into and around the tumour lesions including 1 cm of safe margin. ECTs were completed within 25 minutes after intravenous administration of bleomycin.

Post-operative evaluation

Patients were evaluated one month after the treatment and every 3 months until 24 months. Tumour response was evaluated according to RECIST criteria 13 (Table I). Pain was evaluated using a visual analogical scale (VAS) 19 varying from 0 (no pain) to 10 (extreme pain) before ECT and 1 months after ECT. At each visit, patients were submitted to the same examinations used during pre-operative evaluation (clinical and radiological, photographic). Furthermore, we evaluated hospitalisation time, number of dressings performed by medical staff and bleeding events 1 month before and after ECT. We delivered a single ECT treatment in 14 patients, 2 in 6 patients, 3 in 3 patients and 4 in 1 patient (Table I). In the poration column of Table I, the number of electrodes insertion for each treatment is also indicated. At each follow up visit, in case of evident and symptomatic persistence in terms of pain and/or bleeding, a new treatment with ECT was planned.

Statistical considerations

Endpoints included overall survival (OS), disease specific survival (DSS), safety, tolerability, pain control and post-operative care that impact on quality of life. DSS and OS were measured from the time of treatment until death and analysed using the Kaplan-Meier method. A Wilcoxon test was used where appropriate for continuous variables. A multivariate analysis was performed using the Cox proportional hazards model. Statistical significance was considered when p #x003C; 0.05. The SAS software was used for the statistical analyses (SAS for Windows, version 9.3, SAS Institute Inc., Cary, NC).

Results

ECT was completed successfully in all patients. All patients were discharged within 24 hours from admission. Post-operative bleeding events never occurred. No major complications were encountered. Post-operative fever was observed in 1 patient (patient 6) and was successfully managed using paracetamol. Post-operative pain was successfully managed at home using oral paracetamol in 23 patients (1 gm every 8 hours) for 5 days. Only in 1 patient were opioid medications required for pain control.

The mean follow-up time was 7.6 months (range 2-18 months). Main oncological results are summarised in Table I. OS probability at 12 months was 46.5%, while median OS was 9 months. DSS probability at 12 months was 63%. In 2 of 24 patients a complete response (CR) was observed, while a partial response (PR) was obtained in 22 patients. Twenty of 24 patients were histologically classified as SCC. Repeated treatment was planned at each follow-up visit in case of evident and symptomatic persistence and was necessary in 4 patients as pain and bleeding was still present.

Univariate and multivariate analysis were performed considering as prognostic factors age, gender, ECOG performance status, histology, TNM, application site, number of treatments received per month and use of adjunctive treatment. The only factor significant at univariate and multivariate analysis was the total number of treatments received (HR:0.20, CI:0.05-0.83, p = 0.02; HR:0.05, CI:0.00-0.71, p = 0.02, respectively; Table II).

Pain evaluation using the VAS scale showed significant pain reduction after ECT. Mean VAS score before treatment was 6.65 vs 2.77 at 1 month after ECT (p #x003C; 0.001, Table III).

Before treatment, patients referred to our centre a mean of 6.8 times in the last month for the local management (dressings). After treatment, patients referred to our center for a mean of 1.29 times per month. The difference was statistically significant (p #x003C; 0.001, Table III). Before ECT, 11 patients (46%) experienced local bleeding at least once per week. One month after treatment, only 2 patients (2%) complained of occasional bleeding (p #x003C; 0.001).

Discussion

Even if the majority of patients presenting with an early HNC will remain disease-free after single modality treatment, many patients presenting with an advanced HNC, relapse either locoregionally only, at distant sites only or both.

A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation, while most patients with recurrent or metastatic disease only qualify for palliative treatment 20.

Goals of treatment in these circumstances are mainly symptom control, prevention of new cancer related symptoms, improvement in quality of life, disease stabilisation and possibly prolongation of OS. Often it is necessary to combine local and systemic treatments to achieve the objective of yielding higher cure rates and lower toxicities in head and neck cancers 21.

In this setting, systemic chemotherapy remains a palliative alternative to best supportive care. Only the cisplatin/5-fluorouracil regimen (PF) and more recently the EXTREME trial (cetuximab + PF regimen, then followed by cetuximab as maintenance therapy) have been demonstrated to improve the OS rate 5 22.

According to NCCN guidelines, systemic therapy can be used in association only in case of good PS (0-1) (e.g. EXTREME 5). The limitations of systemic therapy are in its toxicity.

The head and neck is a particularly complex anatomical region due to the presence of critical structures, such as carotid and cranial nerves, compacted in a small space. Thus, tumours in head and neck cancer patients are hard to manage 13 23-29. ECT results in a minimal or no functional impact and leads to healing of treated tumour lesions without damage to healthy tissues. For these reasons, ECT is described as an alternative to palliative chemo- or radiotherapy and partial and complete remission rates have been reported in various clinical trials with a low frequency of side effects 11 13 30-32.

Landstrom et al. carried out a phase II trial enrolling patients with early stage (T1-2) oral and base of tongue carcinomas treated with upfront ECT, followed by adjuvant radiation therapy. They observed no recurrence during the entire follow-up period and all patients were alive at 5 years and reported only mild local toxicity 33.

Bertino et al. in 2016 (actually the largest clinical trial focused on melanoma and non-melanoma skin cancers of the HN area treated with bleomycin electrochemotherapy) demonstrated that better responses are obtained with small lesions (≤ 3 cm), that primary tumours responded better than secondary (recurrent or metastatic) tumours and that treatment of naïve lesions responded better than pre-treated lesions. Interestingly, for recurrent tumour nodules, previous surgery least affected the outcome compared to (chemo) radiotherapy or multiple treatments 34.

Di Monta et al., in their retrospective, single-centre study, obtained a overall response after ECT treatment of stage III cSCC of 81% and CR of 22.7%. ECT is confirmed to display more effectiveness of other therapeutic options in locally advanced cSCC treatment 35.

In our study, a PR of 83.3% was observed, while only 2 patients (1.2%) presented a CR. Twenty patients (84%) were affected by SCC and in this group of patients we observed 10% CR and 100% PR. The low CR observed in comparison of literature data might be due to heterogeneity of our cohort including cutaneous or mucosal tumour localisation and for this reason not perfectly comparable to other studies. In our study, we performed univariate/multivariate analysis (Table II) considering as prognostic factors age, gender, ECOG performance status, histology, TNM, application site, number of treatments received per month and the use of adjunctive treatment. The only factor that resulted significant was the total number of treatments received. This result could be justified either as an ECT objective survival benefit or as a normal consequence derived from the prolonged survival by some patients. Hopefully, to better investigate the impact of the considered prognostic covariates, a more numerous sample is probably needed.

There are many potential benefits with the use of ECT, the most important of which is its reliability and versatility. The treatment can be performed in virtually every patient independently of the performance status. In fact, it does not require general anaesthesia: we performed all procedures in mild sedation, in an office-based setting, without performing a tracheostomy, even in patients with PS 4. The avoidance of intubation allowed us to better manage patients suffering from microstomia, oral cavity oedema, pain and trismus.

ECT is very simple to be performed, does not require a long learning curve and is repeatable every 30 days 13. Probably the best indicator that electrochemotherapy is not too demanding or painful procedure is that among the interviewed patients, 20 of 24 (83.3%) would be willing to accept the treatment again if it indicated. From the first case, we were able to efficaciously complete every treatment without delays or complications. While systemic chemotherapy requires multiple administrations, each ECT treatment is completed in less than 25 minutes because after a single dose of intravenous bleomycin administration, the maximal plasmatic concentration is reached in 8 minutes, is maintained for about 20 minutes and then is gradually reduced. Additionally, any systemic chemotherapy using single or multiple agents imply a certain degree of toxicity that can result in a general impairment (e.g.: anaemia, leukopenia).

In our study, we did not experience any major complications or prolonged hospitalisations. This means that ECT can be performed safely even in PS 3-4 without deterioration of quality of life. The main ECT contraindication is represented by lung fibrosis which could be exacerbated by bleomycin. In order to prevent this possibility, all patients performed arterial blood gas analysis the day before the application.

Even in case of partial response, ECT resulted in improvement, especially in terms of pain and bleeding reduction, and need for medical/paramedical care.

ECT by itself is responsible for a certain degree of post-operative pain which was successfully managed using oral paracetamol at home. Only in 1 patient were opioid medications required for pain control. Pain evaluation through the VAS scale resulted in a significant pain reduction after ECT (p #x003C; 0.001, Table III). This resulted in reduction in the administration of pain medications, which are considerably used and often abused by advanced stage HNC patients. A recent study showed that pre-operative pain, previous irradiation, large tumour size and high current values are predictors of post-operative pain. Knowing the risk factors, pain treatment can be better planned in advance 36.

The utility of ECT was also evident from the significant reduction of medical assistance (dressings, Table III). Patients were able to take care by themselves of the treated area by simple disinfection and dressings. They requested medical assistance only 1.29 times per month. These results depend partially on the significant reduction of bleeding events after ECT. In fact, bleeding was one the main reasons for medical assistance. One month after treatment, only 2 patients (8%) complained of occasional bleeding.

Reducing the need for the medical support results undoubtedly in an improvement in quality of life both from a psychological point of view (able to self-care) and from a practical point of view (fewer trips to the hospital, costs reduction).

ECT cicatrisation and pain/bleeding reduction is probably due to the ‘vascular lock phenomenon’. In fact, blood flow changes occur after the delivery of electric pulses in vivo 37. In the case of normal tissues, these effects appear as a transient hypoperfusion. In the case of tumour tissues, the vascular lock is much longer than in normal tissues and restoration of the initial blood flow levels may take hours. The mid-term and long-term antivascular effects of ECT could thus result from the killing of tumour endothelial cells, which could prevent the rapid reorganisation of tumour vasculature. Consequently, an almost permanent, extremely hypoxic situation is created after ECT 38.

A limitation of our study is the relatively small sample size and patient heterogeneity in terms of clinical features and treatment. Our study includes both primary and lymph node recurrences and patients who received concomitant palliative systemic chemotherapy. Our investigation on ECT is still ongoing and we aim to publish more data in the future with more representative samples, stratified by histology, recurrence site and concomitant treatments.

Conclusions

ECT was shown to be effective in the palliative treatment of non-resectable HNC. The advantages of ECT include improved quality of life and local tumour control, no damage to healthy tissue and limited side effects. We advocate its use in the palliative treatment of HNC, especially in patients with unfavourable PS.

Figures and tables

Table I..

Patient Gender Age ECOG PS Histology and T site TNM (ryc) Application site Response Porations Electrode Treatment No. Adjunctive treatment
1 M 52 4 Larynx SCC T4aN2cM0 Tongue + LN PR 20 Hexagonal 1 None
2 M 79 3 Ear melanoma T4bN0M1 Retroauricular skin PR 40 Hexagonal 1 None
3 M 59 2 Oral cavity SCC T0N2cM0 LN PR 31-50 - 57-90 Hexagonal 4 None
4 M 83 3 Oral cavity SCC T0N2bM0 LN PR 14 Hexagonal 1 None
5 M 71 2 Oral cavity SCC T0N2bM0 LN PR 20-20 Hexagonal 2 Cetuximab
6 M 75 2 Preauricular skin SCC T1N2M1 LN + preauricular area PR 48-59 - 50 Hexagonal 3 None
7 F 83 3 Oral cavity SCC T4aN0M0 Buccal mucosa PR 35 Hexagonal 1 None
8 M 69 2 Oral cavity SCC T0N2cM0 LN PR 36 Hexagonal 1 None
9 F 62 3 Oral cavity SCC T4aN0M0 1/3 posterior tongue PR 13 Finger 1 None
10 M 64 2 Parotid adenocarcinoma T4aN0M1 Preauricular area PR 13 Hexagonal 1 None
11 M 74 3 Oral cavity SCC T4aN0M0 Chin skin/oral cavity PR 22 Hexagonal 1 None
12 M 88 4 External ear SCC T0aN3M0 External ear PR 52 Hexagonal 1 None
13 M 67 2 Larynx SCC T4aN0M0 Peristomal recurrence PR 67-50 Hexagonal 2 None
14 M 69 2 Oral cavity SCC T4aN2bM0 Oral cavity + LN CR 45 Finger 3 Methotrexate
15 F 37 1 Maxillary sinovial sarcoma T4aN0M1 Maxillary area PR 74-55 - 10 Hexagonal 3 None
16 M 79 2 Parotid mucoepidermoid carcinoma T4aN0M0 Preauricular area PR 65-82 Hexagonal 2 None
17 M 62 1 Frontal area skin SCC T0N3M0 LN PR 53 Hexagonal 1 Extreme
18 M 75 3 Oropharynx SCC T0N2bM0 LN PR 30-32 Hexagonal 2 None
19 M 87 3 Oral cavity SCC T0N3M0 LN PR 21 Hexagonal 1 None
20 M 85 2 Frontal area skin SCC T0N2M0 Preauricular area PR 25 Hexagonal 2 None
21 M 62 4 Chin skin SCC T4aN0M0 Chin skin PR 96 Hexagonal 1 None
22 M 68 3 Oral cavity SCC T4aN0M0 Floor of the mouth + lips PR 52 Finger 2 PDT
23 M 75 3 Oral cavity SCC T4aN0M0 Oral cavity mucosa PR 35 Finger 1 None
24 M 53 2 Oral cavity SCC T4aN0M0 Buccal mucosa CR 16 Hexagonal 1 None
Demographics and staging.

Table II..

Covariate Univariate analysis Multivariate analysis
HR 95% CI P HR 95% CI P
Age 0.87 0.23-3.28 0.84 1.13 0.12-10.43 0.90
Gender 2.16 0.42-11.07 0.35 0.66 0.05-7.95 0.74
ECOG PS 1.97 0.68-5.69 0.20 0.24 0.02-2.88 0.26
Histology 0.50 0.06-3.99 0.51 0.11 0,00-7148.48 0.69
T 1.02 0.73-1.44 0.87 1.24 0.26-5.89 0.78
N 0.85 0.50-1.45 0.56 1,07 0.195.94 0.93
M 0.36 0.04-2.92 0.34 0.63 0.00-31421.06 0.93
Application site 0.55 0.18-1.63 0.28 0.91 0.01-42.14 0.96
Treatment No. 0.20 0.05-0.83 0.02 0.05 0.00-0.71 0.02
Adjunctive treatment 0.45 0.05-3.64 0.46 0.95 0.07-12.54 0.97
Univariate and multivariate analysis of prognostic covariates.

Table III..

Pain (VAS) Mean Mean difference SD SD difference p
Time 0 6.65 1.16
PostT 1 month 2.77 3.87 1.01 1.21 #x003C; 0.001
Dressings
PreT/month 6.83 1.16
PostT/month 1.29 5.54 0.55 1.17 #x003C; 0.001
Pain and post-treatment management.