Nanoknife Ablation Doubles Survival in Pancreatic Cancer

Alexander M. Castellino, PhD

September 01, 2015

Irreversible electroporation (IRE) — a tissue ablation technique — appears to double median survival compared with historical controls for patients with locally advanced pancreatic cancer (LAPC), according to data extracted from six surgical centers in the United States. The results were published in the September issue of the Annals of Surgery.

"The appropriate and precise use of IRE in appropriately selected patients with locally advanced pancreatic cancer can result in a median overall survival close to 24 months, which is nearly double the survival rate with the best new chemotherapy and chemoradiotherapy," the investigators write in their discussion.

"This study demonstrates that IRE, in conjunction with standard of care, may substantially prolong the survival rates of patients with locally advanced pancreatic cancer," lead author Robert C. G. Martin II, MD, PhD, director of surgical oncology at the University of Louisville, Kentucky, said in a statement.

"While additional research is needed, ablation may represent an addition to the current standard of care for stage 3 pancreatic cancer patients whose only treatment options until now have been chemotherapy or a combination of chemoradiation therapy," he added.

IRE is a novel, nonthermal, tissue-ablation modality that delivers microsecond pulses of direct current to create permanent defects in cell membranes of targeted tissues and spares other tissues and connective tissue in blood vessels. In this study, IRE was delivered by the Nanoknife system (AngioDynamics).

The six surgical centers that participated in the study included the University of Louisville, the Cleveland Clinic, the Henry Ford Hospital in Detroit, the Piedmont Hospital in Atlanta, the Swedish Medical Center in Denver, and the Cancer Treatment Centers of America in Atlanta.

"This report of our 200-patient review is the single largest evaluation to date and further confirms the smaller series that have been published with the use of this treatment in patients with pancreatic adenocarcinoma," Dr Martin and colleagues write in their discussion.

Study Details

This was a registry study. Clinical data on patients treated for LAPC were retrieved from an institutional review board–approved, prospectively maintained soft tissue ablation registry.

Two hundred patients with confirmed LAPC first received induction therapy (chemotherapy, chemoradiation, or both) per institution protocol. Approximately 1 month after completion of induction treatment, patients were restaged with repeat triple-phase CT scan and serum tumor markers.

The decision to perform IRE with the Nanoknife system was made in appropriate patients. Patients' comorbidities, previous therapy, and intraoperative preresection margin assessment were used to determine whether surgical resection was possible; in these patients, IRE was used for tumor margin attenuation (n = 50).

"IRE was not used when an R2 resection could occur; and those patients underwent an IRE without resection," Dr Martin and investigators state. LAPC with IRE (in situ) was undertaken in 150 patients.

Perioperative 90-day outcomes, local failure, and overall survival were end points of the study.

Study Results

Median age of patients was 62 years (range: 27 - 88 years), median Charlston comorbidity index was 4, and median Groningen frailty indicator was 2.

For LAPC patients in the group who underwent IRE alone (the in situ arm), tumors were more often located in the pancreatic head (63%); for patients undergoing both resection and IRE (the margin arm), the tumors were more often located in the pancreatic body/neck (75%).

All patients received chemotherapy (either with FOLFIRINOX [5-fluorouracil, leucovorin, irinotecan, and oxaliplatin] or gemcitabine-based chemotherapy), and approximately half the patients also received radiation therapy.

With a median follow-up of 29 months, three patients experienced IRE failure at 3 months, and six patients had local recurrence at the ablation site.

Median overall survival from IRE treatment was 23 months for patients in the LAPC resection and IRE (margin) arm and 18 months for patients in the LAPC IRE in situ arm.

Gastrointestinal complaints were the most common adverse events (eight patients in the LAPC resection with IRE group and 38 in the LAPC with IRE in situ group); 90-day mortality was only seen in the LAPC with IRE in situ group (2%).

Morbidity associated with IRE was similar in comparison with morbidity associated with extending chemotherapy beyond induction treatment, as determined on the basis of data from another study. However, "the morbidity of IRE delivery system is mitigated by the significant improvement in overall survival and local PFS," Dr Martin and colleagues write.

Pointing out the limitations of the study, Dr Martin and colleagues noted that in this registry study, variability in post-IRE imaging protocols between centers was expected, and "local recurrence or persistent disease based on RECIST criteria may be underestimated, as conventional imaging has significant limitations in detecting viable tumor."

Patient Selection

"Dr Martin and colleagues are to be congratulated in studying a novel technology, irreversible electroporation, in a multidisciplinary treatment plan for the approximately one-third of patients with pancreas cancer who present with locally advanced disease. They have demonstrated both reasonable safety and excellent local control with this approach," Jeffrey A. Drebin, MD, PhD, from the Department of Surgery, University of Pennsylvania Health System, Philadelphia, Pennsylvania, writes in a discussion published with the study.

Dr Drebin also raised a question about patient eligibity: how many patients who were initially considered for this approach ultimately did not meet requirements for IRE?

"Randomized trials of both FOLFIRINOX and gemcitabine-Abraxane chemotherapy combinations show an approximately 6-month median progression-free survival in metastatic patients. If the same is true in locally advanced disease, half or more of patients might never become eligible for IRE because they will progress in that 6-month interval," Dr Drebin pointed out.

Dr Martin responded that at his institution, 75% of patients with stage 3 LAPC were eligible for consideration, owing to tumor size (patients with tumors > 5 cm were ineligible for IRE in situ and were only eligible for resection with IRE if microscopic margins were positive).

After induction therapy, approximately 10% to 15% were ineligible because of disease progression. And finally, some patients become ineligible because they are frail and cannot maintain or improve their performance status, Dr Martin stated. Patients need to be motionless during the procedure and so must undergo general endotracheal anesthesia, he explained.

Median survival was 6.8 months for patients who were ineligible for IRE, Dr Martin said.

Keith D. Lillemoe, MD, from the Department of Surgery at the Massachusetts General Hospital, Boston, and editor-in-chief of Annals of Surgery, was another discussant.

One of his questions focused on whether more patients were candidates for IRE in an era of FOLFIRIFOX neoadjuvant therapy, which is associated with excellent tumor response and an ability to undertake an R0 resection.

Dr Lillimoe said: "[P]ostneoadjuvant therapy imaging [has] become almost useless in predicting who can and cannot undergo resection." He indicated that operative dissection was helpful in deciding when not to resect.

"What this means is that we are now taking patients to the OR whom we might not have attempted resection in the past," he added.

Dr Martin echoed the sentiment that more patients were being taken to the OR. He responded: "We are finding that preoperative CT or even MRI is not as definitive, and we are strengthened more with these patients to take them to the operating room for possible resection, because we have the use of IRE either for margin accentuation or for IRE in situ if indeed they are unresectable at exploration."

"To that end, the need for defining unresectability at the time of operation must be extensively evaluated," he added.

Dr Martin also said that tumor resectability could be defined through extensive dissection or with the use of high-quality, high-definition, and motion-compensated angular compound ultrasound imaging, which is critical for defining vessel invasion vs abutment.

"We utilize intraoperative ultrasound extensively through that incision, before we extend it, if we think there's a greater degree of surgical resectability," he said.

In the post-article discussion, Dr Lillemoe said: "[Although the] paper is not definitive as to the role of this exciting new therapy for locally advanced pancreatic cancer, it does give us hope that follow-up studies, perhaps even a multicenter, randomized trial, might someday follow."

Dr Martin and colleagues agree. "These results need to be confirmed through a randomized trial of chemotherapy and radiation therapy compared with chemotherapy, IRE, and radiation therapy," they note.

IRE: The Procedure and Its Challenges

The IRE system consists of an IRE generator and up to six electrode probes (for a review: Jourabchi et al, Gastrointest Interv. 2014;3:8-18).

The generator is capable of delivering between 100 V and 3000 V of energy in 90 to 100 pulses. Maximum pulse length is 100 microseconds.

Electrode probes are typically 15 cm long and 16 to 19 gauge in diameter. They are inserted in the tissue to be ablated. The number of probes is dependent on the size and shape of the zone to be ablated.

In the study, the operating surgeon determined the number of probes that determined the electroporation zone along the margin where microscopic disease was possibly present. A median of two probes (range: two to four) were used for LAPC resection with IRE; for LAPC with IRE in situ, a median of four probes (range: four to six) were used.

IRE is minimally invasive and is performed with ultrasound or CT guidance. Following the procedure, imaging techniques are used to assess tissue ablation.

Electric fields generated during tissue ablation are complex, and treatment protocols are in place to determine electric field distribution, which is dependent on electrode configuration, pulse parameters, and tissue heterogeneity.

But the procedure is challenging, and there is a learning curve. "The results that we present here with IRE treatment demand that complete electroporation be achieved through precise biology understanding, precise tumor size selection, and precise IRE energy delivery," Dr Martin and colleagues state.

Incomplete electroporation can lead to a change in the biology of a local tumor, they point out.

The investigators admit that IRE imposes technical demands. "The requirements to place these multiple monopolar probes in precise spacing (plus or minus 5.0 mm maximum), precise depth (plus or minus 5.0 mm maximum), and in appropriate bracketing of the soft tissue retroperitoneal tumor that is commonly seen with pancreatic adenocarcinoma can be difficult," they state.

Although a learning curve is involved, optimal access for the placement of the probes in pancreatic head tumors and pancreatic neck tumors is known to be reproducible, they indicate.

"This study was conducted in a small number of centers that have optimized this technique and overcome the learning curve," Dr Martin and colleagues write.

"The technical demands of this therapy are one of the reasons for the slow adoption [of IRE], which could be viewed as both a benefit and a limitation," they add.

However, "a true trimodality therapy of chemotherapy, radiation therapy, and IRE treatment does seem to provide the optimal disease control which has translated into optimistic and impressive overall survival results," Dr Martin and colleagues conclude.

Dr Martin and another study investigator are paid consultants for AngioDynamics, which provided an unrestricted educational grant to the Soft Tissue Ablation Registry.

Ann Surg. 2015;262:486-494. Abstract


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