Percutaneous Tumor Ablation: Cryoablation Facilitates Targeting of Free Epirubicin-Ethanol-Ioversol Solution Interstitially Coinjected in a Rabbit VX2 Tumor Model.

This acute study was aimed at exploring the ability of a cryoablative lesion to drive the distribution of a concomitant in situ injection of a free epirubicin-ethanol-ethiodol-methylene blue mixture. We report the feasibility and safety of this new percutaneous computed tomography-guided combinatorial ablative procedure on VX2 tumors. Eight New Zealand white rabbits bearing 16 tumors on both side of the back muscle were randomly selected and treated on the same day with the following procedures: (1) 8 concomitant cryoablation and interstitial chemotherapy and (2) 8 intratumor marginal chemotherapy. For the latter, an injection needle was positioned at the inner distal margin of a first selected tumor side, where the chemotherapy was delivered during 5 serial sequences. For the concomitant therapy, a single cryoneedle maintained the ice front at the tumor margin, where a needle delivered the drug dose during 5 freeze-injection-thaw sequences. Enhanced computed tomography scans on days 3, 7, and 10 assessed the tumor contours and the tracer localization. Two rabbits were killed on days 0, 3, 7, and 10 for gross and histopathological analyses. During the concomitant therapy, ioversol was distributed at the tumor and iceball margins along with the methylene blue. Enhanced computed tomography on days 3, 7, and 10 showed a focal enlarging defect of the tumor marginal enhancing rim. The rim coincided with focal necrosis at histopathology. During the intratumor chemotherapy procedure, computed tomography showed that the tracers distributed mostly over the tumor mass. No marginal necrosis was detected at histopathology. On day 10, the tumor size for the intratumor chemotherapy group was twice that of the concomitant therapy group. No adverse events were observed. In this VX2 tumor model, our image-guided concomitant therapy is feasible and may enhance the effectiveness of a free epirubicin tracer mixture at the tumor margin.

Intratumoral chemotherapy for lung cancer: re-challenge current targeted therapies.

Strategies to enhance the already established doublet chemotherapy regimen for lung cancer have been investigated for more than 20 years. Initially, the concept was to administer chemotherapy drugs locally to the tumor site for efficient diffusion through passive transport within the tumor. Recent advances have enhanced the diffusion of pharmaceuticals through active transport by using pharmaceuticals designed to target the genome of tumors. In the present study, five patients with non-small cell lung cancer epidermal growth factor receptor (EGFR) negative stage IIIa-IV International Union Against Cancer 7 (UICC-7), and with Eastern Cooperative Oncology Group (ECOG) 2 scores were administered platinum-based doublet chemotherapy using combined intratumoral-regional and intravenous route of administration. Cisplatin analogues were injected at 0.5%-1% concentration within the tumor lesion and proven malignant lymph nodes according to pretreatment histological/cytological results and the concentration of systemic infusion was decreased to 70% of a standard protocol. This combined intravenous plus intratumoral-regional chemotherapy is used as a first line therapy on this short series of patients. To the best of our knowledge this is the first report of direct treatment of involved lymph nodes with cisplatin by endobronchial ultrasound drug delivery with a needle without any adverse effects. The initial overall survival and local response are suggestive of a better efficacy compared to established doublet cisplatin-based systemic chemotherapy in (higher) standard concentrations alone according to the UICC 7 database expected survival. An extensive search of the literature was performed to gather information of previously published literature of intratumoral chemo-drug administration and formulation for this treatment modality. Our study shows a favorable local response, more than a 50% reduction, for a massive tumor mass after administration of five sessions of intratumoral chemotherapy plus two cycles of low-dose intravenous chemotherapy according to our protocol. These encouraging results (even in very sick ECOG 2 patients with central obstructive non-small cell lung cancer having a worse prognosis and quality of life than a non-small cell lung cancer in ECOG 0 of the same tumor node metastasis [TNM]-stage without central obstruction) for a chemotherapy-only protocol that differs from conventional cisplatin-based doublet chemotherapy by the route, target site, and dose paves the way for broader applications of this technique. Finally, future perspectives of this treatment and pharmaceutical design for intratumoral administration are presented.

Ultrasound guided combined cryoablation and microencapsulated 5-Fluorouracil inhibits growth of human prostate tumors in xenogenic mouse model assessed by luminescence imaging.

Modern approaches to minimally invasive ablative treatment of solid tumors involve the use of miniature instruments and combined treatments. These can be enhanced with ultrasound imaging that depicts tumor margins; facilitates guidance, delivery, and dosage of local chemotherapy; and can monitor the effectiveness of the treatment. This paper describes the advantages of ultrasound guided cryosurgery combined with local chemotherapy delivered in multilamellar, echogenic microcapsules of 5-FU ("microcaps") using a xenograft tumor model. Genetically engineered bioluminescent human prostate tumor cells, DU-145(Luc+), were implanted subcutaneously into athymic nude mice. Experiments were designed to mimic the situation where palliative cryoablation spares a portion of the tumor so that the combined effect of cryosurgery and focal injections of chemotherapeutic microcapsules could be evaluated. Eighteen (18) tumors were treated with percutaneous partial cryoablation or interstitial chemoablation, or a combination of both. A single F/T cycle was applied to tumor and micro-encapsulated chemotherapy is delivered at outer margin of frozen tumor in two opposite sites. Results show that the tumor and cryosurgical kill zone contours were seen with both the bio-luminescence assay (BLI) and ultrasonography (US). US can easily detect as little as 2 microl of echogenic microcaps, and monitor their lifetime in the tumor tissue. BLI was determinant in showing that minute amounts of microcapsule chemotherapy (38.7 ng of 5-FU/g tumor) dramatically inhibited tumor growth starting within two days after injection. The mean BLI emitted by control tumors was 5.6 times greater at Day 4 than the BLI measurements from tumors treated with 5-FU microcaps (p=0.036). By Day 7, BLI values from the control tumors were still 2.7 times greater than those treated with 5-FU microcaps (p<0.01). In tumors treated by partial cryoablation, the mean BLI of viable tumor cells was 20 times less at day 3 (p=0.05) and 46% less at day 7 than the non-treated tumors. The combined treatment produced a dramatic inhibition of tumor growth that lasted throughout the 7-day study. The BLI measured from viable tumor cells in non-treated tumors was 34 times greater at day 3 and more than 350 times greater at day 7 than those treated by combined cryoablation and 5-FU microcaps. The results demonstrated, for the first time, that a single moderate freeze of a human prostate tumor combined with bi-focal peripheral microcapsule chemotherapy (5-FU) has a better and longer inhibitory effect on tumor growth compared to the growth inhibition rendered by cryosurgery or local microcapsule chemo-therapy alone. This shows promise for a new, focal, combined ablative modality using US guided deposition of microencapsulated drug(s) and echogenic markers deposited in the hypothermic margin of tumors which could enhance the efficacy of cryoablation of prostate cancers.