Combined local and systemic bleomycin administration in electrochemotherapy to reduce the number of treatment sessions

Electrochemotherapy (ECT) is an ablative approach that is rapidly growing, both in human and veterinary medicine. ECT is based on administration of bleomycin followed by application of an electric field on the tumor that enhances cell permeability to the drug. This technique can increase bleomycin cytotoxicity by 1000 fold. The effectiveness of ECT is approximately 80% objective response (OR) rate.1,2

A meta-analysis of ECT clinical studies in human oncology showed that the overall OR rates vary from 62.6% and 82.2% OR rate depending also on the route of the drug administration, being either intravenous or intratumoral.3 Despite its success related to its low cost and minimum side effects, ECT still has room for improvement. Even with such a high response rate there are 20% of cases on which attention must be focused in order to improve the outcome of the treatment.

The application of ECT in companion animals showed the same pattern of success as in humans, with many studies demonstrating its high efficiency, with a very similar response rate to that of human patients.4,5

The use of companion animals with spontaneous tumors as models for tumor treatment therapy became a generalized practice due to its many advantages. The most important is that these tumors behave similarly to human ones and are thus better preclinical models for testing new therapies. As these animals were exposed to environmental carcinogens, they developed the tumors in the context of an intact immune system that has the same tumor-host interactions.6,7

A study on melanomas in dogs conducted by Spugnini et al. reported 80% effectiveness.8 Another study by Tamzali et al. on spontaneouslyoccurring tumors showed very high effectiveness when treating sarcoid tumors in equines using ECT with local cisplatin in up to 6 sessions of ECT.9 A ganglioneuroblastoma case was published in which a cat with a very small tumor was treated with up to 3 sessions of ECT in order to obtain an OR.10 In large tumors, however, it is often the case that no OR is possible with a single treatment session.11,12

Systemic bleomycin administration consists of injecting the drug into a vein, thus allowing the drug to reach the tumor through the bloodstream and diffuse from the vessels into the tumor.13 On the other hand, local bleomycin administration consists of directly injecting the drug into the tumor tissue, thus allowing it to diffuse from the injecting point to the target. Multiple injections into the tumor can provide an adequate coverage in small tumors13, but the case of large tumors is different where it is very difficult to homogeneously cover them. Tumor vasculature is structurally and functionally abnormal; blood vessels leak and are tortuous, dilated, and saccular and have a random pattern of interconnection.14 In solid tumors, these aberrant vessels determine an increase in the liquid outlet out of these, together with the contribution of the compression caused by the proliferation of cancer cells, leading to an increase in interstitial hydrostatic pressure.15 The heterogeneous flow of blood and interstitial hypertension pose a serious obstacle to the antineoplastic agents, especially in the case of large tumors with a broader vascular system that are more likely to have areas of tumor that cannot be reached by the systemic route.16,17 This characteristic of tumor vessels could lead to an insufficient bleomycin distribution when administered systemically. Repeated ECT sessions could lead to modifications in the characteristics of the tumors, such as its size reduction and changes in its vasculature that improve treatment response after each session. For these reasons, performing many treatment sessions can improve the results obtained in the first session, increasing, however, the cost of the treatment and its risks related to multiple anesthetic procedures. To address this problem, here, we propose combined bleomycin administration, both systemic and local, using companion animals as models for ECT tumor treating.

The aim of this study was to determine whether it is possible to reduce the number of treatment sessions using a combined administration of bleomycin (both systemic and local) vs. systemic bleomycin administration alone in ECT. Accordingly, for the purpose of this work, we selected companion animals with spontaneous tumors.

The total dose of bleomycin in combined treatment was slightly higher than that of systemic administration alone; in both cases, no toxicity or side effects were reported. Table 1 shows the response of the patients in which combined treatment was performed in the second session. Table 2 shows the control group, for which patients the second session was a repetition of the first procedure.

The responses obtained with combined bleomycin administration were significantly different from those of systemic administration alone in selected cases (p < 0.01). In the combined administration group the following response were obtained: CR 54% (6), PR 36% (4), SD 10% (1). In the control group the obtained response were: CR 0% (0), PR 19% (2), SD 63% (7), PD 18% (2). Figure 1 shows a case treated using combined intravenous and intratumoral bleomycin administration in which a CR was obtained.

Figure 1.

The OR rates obtained were significantly better when using combined treatment compared with the standard ECT treatment (p < 0.01). As seen in Figure 2, in the combined group, 91% (10) of OR (CR+PR) were obtained, and 19% (2) were obtained in the control group.

Figure 2.

It is worth noting that no complete responses were obtained in the control group with two sessions of ECT, as opposed to 54% of CR obtained when applying combined treatment in the second session.

The average tumor size in the control group was 99.9 cm3, while it was 58.5 cm3 in the combined group. In general, the patients were at a lower stage of the disease in the control group compared with the combined group.

ECT is based on a physical phenomenon, electroporation, which acts directly on cell membranes, which accounts for its effectiveness in practically all histological types of tumors. In our experience with veterinary patients, we found that large tumors have poorer responses and require further sessions to obtain an objective response. Our hypothesis was that the abnormal vasculature of large tumors impedes proper drug distribution when it is administered intravenously, even though this route of drug administration is prescribed for tumors of this size in standard operating procedure (SOP).13

Based on this hypothesis, we decided to make an approach by combining both systemic and local bleomycin administration to improve drug distribution in the tumor. In this way, local administration can cover areas where vasculature proves insufficient. There are many reasons against considering using a local injection alone to improve results. According to literature, in tumors above 2 cm in diameter, intravenous administration is recommended.13 It is highly challenging to provide proper drug distribution in the tumor by using local administration only, because during its local application, it is easy to leave sections without the adequate drug concentration, and sometimes it is even impossible to reach the base of the lesion.

It is worth mentioning that some authors obtained good response rates with several treatment repetitions. These repetitions lead to changes in the tumor that can improve drug distribution in later applications.12,19–22 Here, we obtained good results with only one repetition.

Tamzali et al. obtained very good results with a local injection of cisplatin in multiple applications treating sarcoids. It is important to take into account that this kind of tumors behave like benign tumors, thus giving a veterinarian time to perform multiple treatments. Our scenario is different since these kinds of tumors are significantly large, and the survival of the patients is compromised, so we need to reduce the tumor as fast as possible in order to improve their quality of life. Frequently, patients with large tumors are in bad clinical shape, so it is important to reduce the number of treatment sessions in order to reduce the risk of anesthetic procedures. On the other hand, costs are also a very important issue, as performing many sessions of treatment increases the cost of the procedure, and makes it rather impossible with our resources.

The fact that the tumors in the combined group were smaller could contribute to better responses achieved, but we also have to consider that the stages were higher. Tumor size rather than disease stage is likely to be a better prognostic factor in ECT, but this speculation is yet to be confirmed.

Further study is needed in order to determine in difficult cases whether practitioners should firstly try ECT with systemic bleomycin alone, or directly apply ECT with its combined systemic and local administration. Since the dose of bleomycin used is very low, the greatest risk of the ECT procedure lies in the application of anesthesia. Reducing anesthesia procedures outweighs the risk of adverse reactions related to the accumulated dose of bleomycin.23,24