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Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer.

Hohenforst-Schmidt W, Zarogoulidis P, Stopek J, Kosmidis E, Vogl T, Linsmeier B, Tsakiridis K, Lampaki S, Lazaridis G, Mpakas A, Browning R, Papaiwannou A, Drevelegas A, Baka S, Karavasilis V, Mpoukovinas I, Turner JF, Zarogoulidis K, Brachmann J - J Cancer (2015)

Bottom Line: Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect.Future modification of lipiodol might provide a more efficient method of therapy enhancement.Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

View Article: PubMed Central - PubMed

Affiliation: 1. II Medical Clinic, "Coburg" Hospital, University of Wuerzburg, Coburg, Germany.

ABSTRACT
Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (10(6)) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm(3) the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

No MeSH data available.


Related in: MedlinePlus

Control group; T1 sequence: Heterogeneous appearance in the central part of the tumor, low intensity indicates necrosis. T2 sequence: High signal intensity indicates necrosis. The necrosis observed in the center of the tumor is attributed to the necrosis that is normally observed within tumors.
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Figure 6: Control group; T1 sequence: Heterogeneous appearance in the central part of the tumor, low intensity indicates necrosis. T2 sequence: High signal intensity indicates necrosis. The necrosis observed in the center of the tumor is attributed to the necrosis that is normally observed within tumors.

Mentions: The application of microwave energy with spikes has proven to be an efficient method of local therapy for cancer and lung cancer in specific.27-29 A recent study has presented data where this method is efficient and safer for the elderly >75 years old, or for patients not able to undergo chemotherapy.27 The major drawback of this method is the short range of the thermal effect around the tip of each spike, therefore in many cases more than two spikes are inserted in the tumor with 1cm distance from one and another in order to enhance the effect (http://surgical.covidien.com/products/ablation-systems/microwave-ablation/evident-mwa-antennas). 29 Currently the guidance of the spike to the tumor lesion for lung cancer is possible with the assistance of Computed Tomography (CT) or Cone Beam CT, however; novel techniques are currently investigated with that of ultrasound being the newest.30 Furthermore; a three dimensional magnetic guidance system is currently being developed.31 Microwave ablation therapy has proven efficient for lesions <3cm, distant to vessels and recurrence is rare in these situations.32 It has been observed that when the microwave energy is applied for at least three minutes the tissue where the spike/s are inserted expands initially up to 25% and then the contraction takes place.33 Moreover; in a recent study the novel treatment of cryoablation provided superior results when it was compared to radiofrequency ablation or microwave ablation, for hepatocellular carcinoma.34 Possibly this methodology could be persued for lung cancer as well in the future. In another study by Sheng S. et. al. 35 microwave ablation was applied for hepatocellular carcinoma with the addition of recombinant adenovirus p53 gene (rAd-p53) and interleukin-2 intravenously. Complete remission of metastatic lesions to the lung was observed. The concept was to simultaneously stimulate the immune system and target the circulating cancer cells. However; this methodology is extremely costly. Microwave ablation is not without any adverse effects, in the case by Huang G. et. al. 36 invasive aspergillosis occurred after microwave ablation. Our current study was based on the concept that a lipophilic substance, such as lipiodol can enhance the thermal effect of microwave ablation. In the previous study by Solazzo SA et. al. 18 liposomal doxorubicin increased the effect of radiofrequency ablation by inducing tumor destruction by increasing cellular oxidative stress and accelerating apoptotic pathways. In the study by Vogl TJ. et. al. 37 it was observed that the thermal effect of laser-induced thermotherapy increases the activation of tumor-specific T lymphocytes. We therefore chose lipiodol as a lipid solution to investigate and observe whether this compound could enhance the chemotherapy effect of cisplatin or thermal effect of microwave ablation. Our results indicate the toxicity of 45W and 10 minutes application for small tumors (group g; lipiodol, cisplatin and microwave), in a future study we will focus on developing an appropriate model for small animals and tumor volumes. It was observed that lipiodol is a very difficult solution to handle and as observed in the MRI figures 5-12, it is not distributed homogeneously. Based on this observation we conclude that it does not assist at all in the thermal effect of microwave ablation. Moreover; it does not assist in the homogeneous distribution of cisplatin, nor adds a sustained release effect to cisplatin absorption. We used the smallest doses possible for cisplatin and lipiodol, since the tumor model that we chose was very small. One of the major limitations of our study was that we did not have a dose escalation for cisplatin, lipiodol and microwave. Furthermore, it was observed that lipiodol, does not have an effect on its own. It has been proposed that nanoparticles could stimulate the dendritic cells (DC) and activate the immune system locally, because when nanoparticles/solutions of small molecules are inserted locally to the tumor they are recognized as foreign material and the T-cells are stimulated.38 In conclusion; combination of cisplatin and microwave ablation could be applied as a method to enhance local therapy, however; more studies are needed to investigate proper dosage in comparison to tumor size. Additionally, we need a drug that can distribute homogeneously within the tumor after administration. Current chemotherapy drugs are not designed for this purpose.


Enhancement of Intratumoral Chemotherapy with Cisplatin with or without Microwave Ablation and Lipiodol. Future Concept for Local Treatment in Lung Cancer.

Hohenforst-Schmidt W, Zarogoulidis P, Stopek J, Kosmidis E, Vogl T, Linsmeier B, Tsakiridis K, Lampaki S, Lazaridis G, Mpakas A, Browning R, Papaiwannou A, Drevelegas A, Baka S, Karavasilis V, Mpoukovinas I, Turner JF, Zarogoulidis K, Brachmann J - J Cancer (2015)

Control group; T1 sequence: Heterogeneous appearance in the central part of the tumor, low intensity indicates necrosis. T2 sequence: High signal intensity indicates necrosis. The necrosis observed in the center of the tumor is attributed to the necrosis that is normally observed within tumors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4317756&req=5

Figure 6: Control group; T1 sequence: Heterogeneous appearance in the central part of the tumor, low intensity indicates necrosis. T2 sequence: High signal intensity indicates necrosis. The necrosis observed in the center of the tumor is attributed to the necrosis that is normally observed within tumors.
Mentions: The application of microwave energy with spikes has proven to be an efficient method of local therapy for cancer and lung cancer in specific.27-29 A recent study has presented data where this method is efficient and safer for the elderly >75 years old, or for patients not able to undergo chemotherapy.27 The major drawback of this method is the short range of the thermal effect around the tip of each spike, therefore in many cases more than two spikes are inserted in the tumor with 1cm distance from one and another in order to enhance the effect (http://surgical.covidien.com/products/ablation-systems/microwave-ablation/evident-mwa-antennas). 29 Currently the guidance of the spike to the tumor lesion for lung cancer is possible with the assistance of Computed Tomography (CT) or Cone Beam CT, however; novel techniques are currently investigated with that of ultrasound being the newest.30 Furthermore; a three dimensional magnetic guidance system is currently being developed.31 Microwave ablation therapy has proven efficient for lesions <3cm, distant to vessels and recurrence is rare in these situations.32 It has been observed that when the microwave energy is applied for at least three minutes the tissue where the spike/s are inserted expands initially up to 25% and then the contraction takes place.33 Moreover; in a recent study the novel treatment of cryoablation provided superior results when it was compared to radiofrequency ablation or microwave ablation, for hepatocellular carcinoma.34 Possibly this methodology could be persued for lung cancer as well in the future. In another study by Sheng S. et. al. 35 microwave ablation was applied for hepatocellular carcinoma with the addition of recombinant adenovirus p53 gene (rAd-p53) and interleukin-2 intravenously. Complete remission of metastatic lesions to the lung was observed. The concept was to simultaneously stimulate the immune system and target the circulating cancer cells. However; this methodology is extremely costly. Microwave ablation is not without any adverse effects, in the case by Huang G. et. al. 36 invasive aspergillosis occurred after microwave ablation. Our current study was based on the concept that a lipophilic substance, such as lipiodol can enhance the thermal effect of microwave ablation. In the previous study by Solazzo SA et. al. 18 liposomal doxorubicin increased the effect of radiofrequency ablation by inducing tumor destruction by increasing cellular oxidative stress and accelerating apoptotic pathways. In the study by Vogl TJ. et. al. 37 it was observed that the thermal effect of laser-induced thermotherapy increases the activation of tumor-specific T lymphocytes. We therefore chose lipiodol as a lipid solution to investigate and observe whether this compound could enhance the chemotherapy effect of cisplatin or thermal effect of microwave ablation. Our results indicate the toxicity of 45W and 10 minutes application for small tumors (group g; lipiodol, cisplatin and microwave), in a future study we will focus on developing an appropriate model for small animals and tumor volumes. It was observed that lipiodol is a very difficult solution to handle and as observed in the MRI figures 5-12, it is not distributed homogeneously. Based on this observation we conclude that it does not assist at all in the thermal effect of microwave ablation. Moreover; it does not assist in the homogeneous distribution of cisplatin, nor adds a sustained release effect to cisplatin absorption. We used the smallest doses possible for cisplatin and lipiodol, since the tumor model that we chose was very small. One of the major limitations of our study was that we did not have a dose escalation for cisplatin, lipiodol and microwave. Furthermore, it was observed that lipiodol, does not have an effect on its own. It has been proposed that nanoparticles could stimulate the dendritic cells (DC) and activate the immune system locally, because when nanoparticles/solutions of small molecules are inserted locally to the tumor they are recognized as foreign material and the T-cells are stimulated.38 In conclusion; combination of cisplatin and microwave ablation could be applied as a method to enhance local therapy, however; more studies are needed to investigate proper dosage in comparison to tumor size. Additionally, we need a drug that can distribute homogeneously within the tumor after administration. Current chemotherapy drugs are not designed for this purpose.

Bottom Line: Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect.Future modification of lipiodol might provide a more efficient method of therapy enhancement.Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

View Article: PubMed Central - PubMed

Affiliation: 1. II Medical Clinic, "Coburg" Hospital, University of Wuerzburg, Coburg, Germany.

ABSTRACT
Novel therapies for lung cancer are being explored nowadays with local therapies being the tip of the arrow. Intratumoral chemotherapy administration and local microwave ablation have been investigated in several studies. It has been previously proposed that lipiodol has the ability to modify the microenvironment matrix. In our current study we investigated this theory in BALBC mice. In total 160 BALBC mice were divided in eight groups: a) control, b) cisplatin, c) microwave, d) microwave and lipiodol, e) cisplatin and lipiodol, f) microwave and cisplatin, g) lipiodol and h) lipiodol, cisplatin and microwave. Lewis lung carcinoma cell lines (10(6)) were injected into the right back leg of each mouse. After the 8th day, when the tumor volume was about 100mm(3) the therapy application was initiated, once per week for four weeks. Magnetic resonance imaging was performed for each tumor when a mouse died or when sacrificed if they were still alive by the end of the experiment (8-Canal multifunctional spool; NORAS MRI products, Gmbh, Germany). Imaging and survival revealed efficient tumor apoptosis for the groups b,c,d,e and f. However; severe toxicity was observed in group h and no follow up was available for this group after the second week of therapy administration. Lipiodol in its current form does assist in a more efficient way the distribution of cisplatin, as the microwave apoptotic effect. Future modification of lipiodol might provide a more efficient method of therapy enhancement. Combination of drug and microwave ablation is possible and has an efficient apoptotic effect.

No MeSH data available.


Related in: MedlinePlus