Long term response of electrochemotherapy with reduced dose of bleomycin in elderly patients with head and neck non-melanoma skin cancer

Electrochemotherapy (ECT) is a local cancer treatment modality with proven antitumor efficacy in various histological types of malignant tumors.1 During an ECT procedure, electroporation is used to transiently increase cell permeability to a hydrophilic chemotherapeutic agent such as bleomycin (BLM) and cisplatin.2 Currently, intravenous administration of BLM is the most common way of drug administration utilized in ECT treatment.3, 4

ECT acts through at least three different mechanisms. The first mechanism is a direct cytotoxic effect driven by the transition of a chemotherapeutic agent into the tumor cells, which is enhanced by electroporation. ECT also has an impact on tumor blood vessels through sympathetic nerve stimulation and subsequent vasoconstriction lasting several hours. Consequently, drug washout from the tumor is delayed. Additionally, the cytotoxic effect on endothelial cells of tumor blood vessels results in the late destruction of tumor vasculature by vascular disrupting effect. The third mechanism involves immune response provoked by immunogenic cell death and enhanced tumor antigen expression.5

In the ECT treatment of non-melanoma skin cancer (NMSC) compelling results were achieved when using standard dose (15,000 IU/m²) of intravenously administrated BLM.6 According to published BLM pharmacokinetics study, an equally good antitumor response might be obtained with a reduced dose of BLM in the elderly population due to the slow elimination rate of BLM.7 Hence the updated SOP for ECT proposes de-escalation of standard dose due to high age and/or compromised creatinine clearance.3 Till today only two clinical studies have been focused on ECT effects with a reduced dose of BLM. Both compared treatment response two months after ECT and showed similar efficacy to the standard dose of BLM.8, 9 Even more, in one study authors observed faster healing time and favorable cosmetic outcomes when using the reduced dose.9

The aim of the present study was to evaluate the long-term ECT response in the group of elderly patients with NMSC treated with a reduced dose of BLM in comparison to the outcome in the patients treated with the standard dose of BLM.

Twenty-eight patients, 65 years or older, with histologically proven NMSC in the region of the head and neck, were included in the study. All the patients were treated by ECT, using intravenous bolus injection of BLM in standard (15,000 IU/m² body surface area) or reduced (10,000 IU/m² body surface area) dose. There were no statistically significant differences between both groups concerning the patients (age and sex) and tumors (diameter, histology type, and recurrent lesions) characteristics (P > 0.05). Details of patients and tumors treated with reduced and standard BLM doses are presented in Tables 1 and 2.

The experimental group consisted of 12 patients (10 men and 2 women; median age 81 years; range 67-92 years) with 24 lesions (17 BCCs, 7 SCCs), 18 (75%) tumors were treatment naïve. The largest tumor diameter ranged from 6 mm to 80 mm (median 21 mm). In control group 16 patients (8 men and 8 women; median age 78 years; range 65-89 years) had 28 lesions (25 BCCs; 3 SCCs), 24 (86%) tumors were treatment naïve. The largest tumor diameter ranged from 4 mm to 50 mm (median 17 mm).

The complete response rates two months after ECT were observed in control and experimental in 96% and 100%, respectively.9 All patients were further followed up at regular visits. In the experimental group, two patients died before six months follow up. One died due to the systemic dissemination of previously treated melanoma. The cause of death in another patient was an underlying disease, not related to skin cancer or ECT treatment. These two patients were excluded from the study. Out of 12 patients in the experimental group, 10 (83.0%) were evaluable at 6 months or longer. Median longterm follow up was 28 months in the experimental group (average 24.9 ± 7.4 months). Tumor recurred in 6/10 (60.0%) patients and in 7/18 (39.0%) tumors in median recurrence time 18.5 months (average 26.9 ± 9.0 months).

In the control group, 2/16 patients were excluded from the study. One died 4 months after the treatment due to other causes than cancer. The other patient did not come to a follow-up visit at 6 months and was lost to further follow-up. Fourteen patients (88%) were evaluable at 6 months or longer. Median long-term follow up was 40 months (average 36.0 ± 14.5 months). The recurrence was observed in 3/14 patients (21.4%) and in 4/26 nodules (15.4%) in a median time of 7.0 months (average 9.4 ± 5.6 months).

Overall, 6/28 (21%) patients included in the study died during follow-up due to other comorbidities. In neither of them the cause of death was related to NMSC or ECT treatment. After statistical analysis no significant difference in recurrence rate was observed between groups (Logrank test P=0,104).

No statistically significantly elevated levels of creatinine was detected neither in control (85.0 ± 28.6 μmol/L) nor in experimental group (86.4 ± 25.6 μmol/L, p > 0.1).

Until now, only a few studies evaluated the longterm efficacy of ECT treatment in NMSC in the head and neck region. Kristiansson et al. reported on 71% control rate in a case series of 7 patients with NMSC treated with ECT after a median follow up of 119 months.11 In the most comprehensive study regarding long–term follow up after ECT treatment of BCCs, 5-year recurrence rate of local and locally advanced BCC was 20% and 38%, respectively.12 It should be emphasized that ECT in these studies was performed according to the first version of SOP, thus standard dose (15,000 IU/m²) of intravenous administrated BLM was used.13 To the best of our knowledge, our clinical study is the only one where long-term effectiveness of ECT in NMSC in the head and neck region after the intravenous administration of a reduced dose of BLM was evaluated and was found to be equal to the effectiveness of ECT with standard dose.

The efficacy of a reduced BLM dose in elderly patients was confirmed in clinical studies after the identification of the main parameters of BLM pharmacokinetics.7, 8, 9 Ageing is related to the impairment of body functions, e.g., impaired renal function, and to a reduction in lean body mass. Both changes lead to reduced clearance of water-soluble drugs (such as BLM) and reduced volume of their distribution. Hence, the plasma concentration of BLM is higher than in younger adults. Thus, the use of the standard dose of BLM in elderly patients could lead to prolonged healing time and a more prominent inflammatory response, as a result of exceeded optimal concentrations of BLM. The rationale for dose de-escalation in elderly patients lays in diminishing possible systemic side effects (e.g., lung fibrosis), improving local healing and keeping total BLM dose as low as possible, especially in circumstances when multiple sessions of ECT are expected.8, 9 According to our previous study complete response rate two months after ECT was almost 100% when using both standard (15,000 IU/m²) or reduced (10,000 IU/m²) BLM dose in elderly patients with NMSC.9 One of the major drawbacks of that study was too short observation time for adequate assessment of clinical response. This is especially important in BCCs because they are slow-growing tumors and it often takes months to years for a tumor to relapse after initial treatment.14

After statistical analysis no significant differences were observed between control and experimental groups regarding clinical or tumor parameters. In the control group, 4 of 26 tumors recurred in the median follow up time of 7.0 months. In the experimental group of patients, 7 out of 18 tumors recurred in the median follow up time of 18.5 months. After statistical analysis, no significant differences in long term tumor control between groups were observed (p=0.104). This confirms our hypothesis that long-term tumor control could be achieved with a lowered BLM dose. Our finding is in concordance with results of previous clinical trials on the elderly population, that suggest equal efficacy of reduced dose two months after the treatment even though the concentration of BLM around the tumor immediately after electroporation is lower compared to the standard dose.8, 9 These findings can be explained with the pharmacokinetics of BLM in elderly patients, where higher concentrations are achieved due to reduced BLM clearance by the kidney and by the reduced volume of distribution.7

Although differences in the long-term tumor control between both groups were not statistically significant, we observe a trend towards a recurrence of BCCs in the experimental group. We might speculate that further studies with a larger cohort of patients could show a lower tumor control of BCCs treated with reduced dose, as a result of reduced local inflammatory response. One of the antitumor mechanisms of ECT involves immune response, provoked by immunogenic cell death and enhanced tumor antigen expression.5 This might be especially important in the treatment of BCCs since these tumors have the greatest mutational burden among all human cancers.15 Consequently, numerous tumor antigens provoke immune system, which is the most probable reason for the less aggressive nature of BCCs.15 Taking these facts into consideration, less prominent local immune response after reduced dose ECT might lead to a lower tumor control of BCCs.

The overall long-term tumor control rate at the end of the study was 79%. Deaths were correlated with underlying disease and not with NMSC progression or side effects after ECT. It is important to emphasize that although long term tumor control was not achieved in all patients, reducing possible side effects and consequent quality of life in patients with short life expectancy is of paramount importance. Thus, a reduced BLM dose in ECT should be considered as a treatment modality in elderly patients with comorbidities, where overall life expectancy is poor.

One of the future perspectives of ECT should be an orientation towards individual patients and tumors. For example, some studies have already shown that differences between tumor vascularization have an impact on BLM pharmacokinetics and therefore on antitumor response.16 The exact dose to achieve maximal antitumor response with minimal side effects should be determined according to tumor histology and patients’ overall health. Hence, in Updated Standard Operating Procedures for ECT a compromised creatinine level was proposed as a guide for using a reduced dose of BLM.3 In our study average creatinine levels during ECT procedure were normal in both groups. It should be noted that the production of creatinine is decreased due to age-related reduction in skeletal muscle mass; thus, plasma creatinine level is an inaccurate indicator of glomerular filtration rate in the elderly population, where the reduction of lean body mass is prominent.7 We presume that creatinine is not a reliable marker in applying a reduced dose of BLM in the group of elderly patients and it must be interpreted in concordance with other methods such as bioelectrical impedance analysis, which is used for body composition measurements.

We are aware that a low number of patients in our study is one of the drawbacks of the study. Even though this study raises some important clinical questions, which need to be addressed. In the future, randomized studies with a larger cohort of patients, treated with reduced doses of BLM, are needed to evaluate the appropriate indications and clinical significance of de-escalated dose BLM in ECT treatment.