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Pathologic Analysis of Ex Vivo Plasma Energy Tumor Destruction in Patients With Ovarian or Peritoneal Cancer

Sonoda, Yukio MD; Olvera, Narciso BS; Chi, Dennis S. MD; Brown, Carol L. MD; Abu-Rustum, Nadeem R. MD; Levine, Douglas A. MD

International Journal of Gynecological Cancer: November 2010 - Volume 20 - Issue 8 - p 1326-1330
doi: 10.1111/IGC.0b013e3181f3bf04
Ovarian Cancer

Introduction: Cytoreduction of all visible disease has been associated with improved survival in patients with advanced-stage ovarian or peritoneal cancer. This is best achieved by minimizing injury to normal tissues. We report on the tumor destruction potential, in an ex vivo model, of a novel energy source that uses an electrically neutral beam of pure plasma to vaporize tissue.

Methods: Tumors were harvested from patients undergoing primary surgical cytoreduction for ovarian or peritoneal cancer. Specimens were divided into 1-cm3 sections and treated with pure plasma energy for 2 or 4 seconds using standardized power settings. Bright-field microscopy was used to measure the depth of tissue vaporization and lateral thermal damage (LTD).

Results: The mean (SD) tissue vaporization depth was 2.7 (1.3) mm (n = 96). Lateral thermal damage was minimal at all tissue interaction settings (0.13 [0.031] mm). Lateral thermal damage was approximately 5% of the depth of tissue vaporization. Tissue interaction time was a more powerful predictor of vaporization than power. When tissue interaction time increased from 2 to 4 seconds, depth of vaporization and LTD increased by 1.7 and 0.03 mm, respectively (P < 0.001 for both). When power was increased from low to high settings, depth of vaporization increased by 0.6 mm (P = 0.02), and LTD did not change.

Conclusions: Plasma energy can effectively vaporize ovarian and peritoneal cancer cells. Greater power and tissue interaction time results in more tumor vaporization while maintaining minimal LTD. This is an attractive characteristic of plasma energy that may be useful for eradicating tumor from visceral surfaces.

Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.

Received April 5, 2010, and in revised form July 6, 2010.

Accepted for publication July 25, 2010.

Address correspondence and reprint requests to Douglas A. Levine, MD, Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. E-mail: gynbreast@mskcc.org.

This study was supported in part by an unrestricted research grant from PlasmaSurgical.

This article was presented at the 40th Annual Meeting of the Society of Gynecologic Oncologists, San Antonio, TX.

Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal's Web site (www.ijgc.com).

Year after year, ovarian cancer has the highest mortality of all gynecologic malignancies in the United States. In 2010, there will be an estimated 21,880 new cases of ovarian cancer diagnosed, and 13,850 deaths from this disease.1 The high death rate is a direct reflection of the number of cases that present with widespread disease.

Unlike most other solid cancers, despite widespread metastases, surgical cytoreduction is traditionally performed in this situation and consistently associated with survival benefit. Griffiths2 first demonstrated the potential benefit of surgical debulking in cases of advanced ovarian cancer. His initial study demonstrated a significant survival benefit for patients in whom residual disease could be minimized to less than 1.5 cm in greatest diameter. The standard of care for advanced epithelial ovarian and peritoneal cancer is to perform maximal cytoreductive surgery with the intent to remove all large-volume disease. This has led to the current definition of optimal residual disease as no remaining tumor nodule greater than 1 cm in maximal diameter.3,4

Recently, the current approach to optimal debulking has been challenged, and a growing body of literature is accumulating to support the concept that complete gross resection is associated with more favorable outcomes.5-7 In many cases, setting the bar at this level requires meticulous technique and removal of numerous gross cancer metastases. Aggressive surgical procedures are often used to eliminate bulky disease, yet residual superficial peritoneal and serosal metastases often remain. Removing these metastases can be challenging. To accomplish these goals, gynecologic oncologists must use a variety of surgical techniques and varied surgical devices. These procedures can also be applicable to serous borderline tumors and low-grade serous carcinomas that frequently have superficial peritoneal implants. Several common techniques have been previously described in the literature including excision and thermal ablation with electrocautery or, more recently, argon beam coagulation.8 Although a number of methods are available to perform thermal ablation, each has specific benefits and limitations (Table 1).

TABLE 1

TABLE 1

Pure plasma energy is a new technology that achieves optimal coagulation with minimal tissue damage. This form of coagulation does not require conduction of an electrical current through the patient. Instead, a low-voltage electrical current (30 V) is used only to ionize argon gas to form plasma. Very high temperatures are then created within the plasma but at a very low mass flow rate. The argon plasma transfers this heat (kinetic) energy to coagulate tissue for rapid and complete hemostasis. The surface temperature of the affected coagulated tissue is approximately 100°C. This high temperature causes the liquid component of the tissue to vaporize.

In this report, we describe the tumor destruction potential of pure plasma energy to vaporize tissue in an ex vivo model. We demonstrate its clinical use in a supplemental video (Video 1, http://links.lww.com/IGC/A18). We also test the hypothesis that tissue interaction time is a greater determinant of tissue destruction than energy level. Finally, we unexpectedly identify a unique property of plasma energy in which the lateral thermal spread is relatively insensitive to tissue interaction time and energy level.

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METHODS

Patient Population

Specimens were collected from a single comprehensive cancer center between February and June of 2007 under institutional review board-approved protocols. Cases included 4 women found to have pathologically confirmed invasive high-grade serous ovarian or peritoneal adenocarcinoma. These patients all had advanced-stage disease at the time of primary cytoreductive surgery. No patients had received prior treatment with surgery, chemotherapy, or radiation. Cases were classified according to the International Federation of Gynecology and Obstetrics staging system. All cases were stage IIIC or IV.

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Tissue Processing

Fresh omental tumors were obtained in the operating room and immediately processed after being accessioned in the pathology laboratory. Specimens were divided into multiple 1-cm3 sections and treated with pure plasma energy from generation 1 of the PlasmaJet (PlasmaSurgical, Roswell, Ga) for 2 or 4 seconds using one of several standardized power settings. The power settings tested were 70%, 75%, 85%, and 90%. The energy device handpiece was mounted onto a fixed manifold at a standardized distance of 10 mm between the source and the tissue. Specimens were then formalin fixed for at least 48 hours and paraffin embedded after being treated with pure plasma energy. Specimens were then bisected at the point of maximal tissue damage and stained with hematoxylin and eosin according to standard protocols. Bright-field microscopy was used to visualize the tissues, and an optical micrometer was used to measure the depth of tissue vaporization and adjacent thermal damage. The depth of tissue vaporization was measured from the parallel surface of the tissue section to the point of deepest tissue destruction (Fig. 1). Because all tumors were divided with a scalpel into 1-cm3 section, each specimen had a flat surface from which to measure depth of vaporization. Lateral thermal damage was measured as the largest distance between the carbon eschar to the point of viable tissue cellularity. All combinations of tissue interaction time and power settings were repeated in triplicate for each patient specimen, resulting in 12 data points for each combination of power setting and tissue interaction time.

FIGURE 1

FIGURE 1

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Data Analysis

Standard 2-sided statistical tests were used to assess relationships between study variables. The Student's t test and linear regression were used to investigate the interaction between depth of vaporization, power, and tissue interaction time. Additional analyses were performed using Pearson correlation and visualized with scatter plots. Statistical analyses were performed using SPSS version 14 (SPSS Inc, Chicago, IL). Significance was considered when P < 0.05.

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RESULTS

Ninety-six specimens were analyzed. The tissue vaporization depth varied from 0.9 to 6.1 mm (mean [SD], 2.7 [1.3] mm). The lateral thermal damage was minimal at all tissue interaction settings (mean [SD], 0.13 [0.031] mm; range, 0.08-0.2 mm). The lateral thermal damage overall was approximately 5% of the depth of tissue vaporization (Table 2). Both tissue interaction time and power were associated with depth of vaporization.

TABLE 2

TABLE 2

The mean (SD) depths of vaporization were 1.84 (0.51) at 2 seconds of tissue interaction time and 3.51 (1.37) mm at 4 seconds (P < 0.001). The lateral thermal damage was slightly greater at 4 seconds than 2 seconds (0.15 [0.027] vs 0.12 [0.027] mm; P < 0.001). When tissue interaction time increased from 2 to 4 seconds, depth of vaporization increased by 1.7 mm, and lateral thermal damage increased by 0.03 mm. For each additional second of tissue interaction time, depth of vaporization increased by 0.84 mm.

When comparing the 2 lowest power settings with the 2 highest power settings, we found that there was an increase in depth of vaporization at the higher power setting (2.36 [1.23] vs 2.98 [1.37] mm; P = 0.023); however, there was no significant difference in lateral thermal spread between the low and high power settings (0.13 [0.030] vs 0.13 [0.33] mm; P = 0.87). When power was increased from low to high settings, depth of vaporization increased by 0.6 mm, but adjacent thermal damage did not change. For each 10% power increase, depth of vaporization increased by 0.4 mm.

Depth of vaporization was more strongly correlated with tissue interaction time (r 2, 0.40) than power (r 2, 0.06). Tissue interaction time was 2.6-fold more powerful a predictor of depth of vaporization than power setting. An unexpected and remarkable characteristic of pure plasma energy is that while tissue vaporization increases, the lateral thermal damage remains relatively stable over a range of power settings and tissue interaction times. In fact, the percentage of lateral thermal spread actually decreases when comparing the greatest depth of vaporization with the least (Table 2). The lateral thermal spreads were 7% of the least depth of vaporization and 3% of the maximal depth of vaporization. An online supplemental video demonstrates pure plasma energy being used in a clinical setting (see Video, Supplemental Digital Content 1, http://links.lww.com/IGC/A18).

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DISCUSSION

Surgical cytoreduction for advanced ovarian cancer remains a cornerstone in the management of this disease. In 1975, Griffiths2 published his sentinel article demonstrating that survival time was inversely proportional to the amount of residual disease. Recently, this traditional goal of cytoreductive surgery for ovarian cancer has been challenged.

Chi et al5 reported on 465 patients with bulky International Federation of Gynecology and Obstetrics stage IIIC epithelial ovarian cancer at a single institution. In an attempt to maintain a homogeneous cohort, the authors excluded patients with stage IIIC disease based on nodal metastases alone, fallopian tube, primary peritoneal, and borderline tumors. Multivariate analysis identified the amount of residual disease as a significant prognostic factor. Patients were classified into 1 of 5 categories of residual disease: no gross disease, 0.5 cm or less, 0.6 to 1.0 cm, 1 to 2 cm, and 2 cm or greater. Statistical comparison of these 5 categories revealed significantly different survival between patients with no gross residual disease, residual disease of 1 cm or less, and residual disease greater than 1 cm. With a median survival of 106 months for the patients with no gross residual disease, the authors concluded that complete gross resection should be the goal of surgery. Others have reported a similar correlation of improved survival with complete cytoreduction.3,9

To achieve a higher rate of optimal cytoreduction, different strategies are required of the surgeon. In particular, the incorporation of extensive upper abdominal procedures such as diaphragm peritonectomy/resection, splenectomy, distal pancreatectomy, liver resection, resection of porta hepatis disease, and cholecystectomy have been demonstrated to improve optimal cytoreduction rates without significantly increasing complications or length of hospital stay.10 Despite these aggressive procedures to eliminate bulky disease, it is not uncommon to have multiple residual subcentimeter superficial peritoneal and serosal metastases remaining. Removing these metastases can be a tedious process requiring additional operative time. Multiple energy sources have been used to eliminate peritoneal metastases, as reported in the gynecologic oncology literature. Sharp dissection, carbon dioxide laser, electrocautery, cavitron ultrasonic surgical aspiration, and argon beam coagulation have been used for superficial peritoneal implant elimination.11 These procedures are also applicable to select cases of serous borderline tumors and low-grade serous carcinomas that can have superficial peritoneal implants.

Recently, Bristow et al12 described the use of argon beam coagulation to achieve complete gross cytoreduction in patients with advanced-stage ovarian cancer. Using this energy source, the authors were able to achieve microscopic residual disease in 74.2% of cases in which it was used compared with 28.6% of cases in which this technique was not used (P < 0.004). In a histopathologic analysis of tumor destruction with the argon beam coagulator, the same group demonstrated that the destruction of tumor tissue was dependent upon power setting and tissue interaction time.8 In that report, the ratio of carbonized eschar to coagulative necrosis remained constant. This suggests that for each resulting eschar produced, the underlying coagulative necrosis was of an equivalent or greater degree. The degree of eschar and coagulative necrosis both increased proportionally with higher power. This could be an issue when trying to estimate the amount of underlying thermal damage during tumor destruction.

Traditional electrosurgery uses high voltage to coagulate tissue. This current travels from the surgical handpiece through the patient and back to the generator via a grounding pad. Argon beam coagulation also uses an electrical current that flows from a handpiece via an argon gas stream through the patient to a grounding pad. Both forms of electrosurgery use high-voltage currents to achieve tissue destruction. Plasma technology uses low-voltage energy to produce a more energetic and extensive argon plasma. When this plasma reaches tissue, it gives up its energy as heat, resulting in tissue destruction.

In this report, we demonstrate that plasma energy can effectively vaporize ovarian and peritoneal cancer cells. Greater power and tissue interaction time results in more tumor vaporization while maintaining minimal thermal spread. In comparison with a previous report studying the argon beam coagulator, pure plasma energy seems to have a similar ability to vaporize tumor but with a narrower range of lateral thermal damage.8 This is an attractive characteristic of plasma energy that may be useful for eradicating tumor off visceral surfaces.

This report is limited by the modest number of individual tumor specimens studied over a predefined range of power settings and tissue interaction times. One important variable that was not addressed by the current study is distance from the handpiece to the tissue. In this study, this variable was fixed at 10 mm for reproducibility purposes and clinically seems to be a reasonable working distance. Clearly, at closer distances, all metrics would be increased, and at greater distances, the energy would be diffusely spread over a larger tissue area. Both of these changes can have useful attributes during a surgical procedure. When higher temperatures are needed to destroy more tissue, a closer range may be appropriate. For use on more delicate surfaces where a smaller margin for error is available, a greater range from handpiece to tissue may be advisable. As this study was performed on ex vivo specimens, an evaluation of this technology with respect to clinical outcomes in ovarian carcinoma is warranted.

As surgeons begin to push the limits of cytoreductive surgery for ovarian cancer, data are accumulating showing that the goal of cytoreductive surgery may in fact be a complete resection of all gross disease. The tedious process of peritoneal implant elimination can be time consuming and physically exhausting. Several reports using different techniques to facilitate this process have been described. This report demonstrates that in an ex vivo model, plasma energy can be used for effective tissue destruction while minimizing lateral thermal damage. This may be an attractive characteristic when the surgeon is attempting to eliminate tumor from underlying structures. The use of this form of energy in cytoreductive surgery warrants further investigation.

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REFERENCES

1. American Cancer Society. Cancer Facts & Figures 2010. Atlanta, GA: American Cancer Society; 2010.
2. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr. 1975;42:101-104.
3. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.
4. Bristow RE, Tomacruz RS, Armstrong DK, et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20:1248-1259.
5. Chi DS, Eisenhauer EL, Lang J, et al. What is the optimal goal of primary cytoreductive surgery for bulky stage IIIC epithelial ovarian carcinoma (EOC)? Gynecol Oncol. 2006;103:559-564.
6. Ozols RF, Bundy BN, Greer BE, et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003;21:3194-3200.
7. Winter WE 3rd, Maxwell GL, Tian C, et al. Prognostic factors for stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007;25:3621-3627.
8. Bristow RE, Smith Sehdev AE, Kaufman HS, et al. Ablation of metastatic ovarian carcinoma with the argon beam coagulator: pathologic analysis of tumor destruction. Gynecol Oncol. 2001;83:49-55.
9. Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol. 1998;69:103-108.
10. Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol. 2009;114:26-31.
11. Eisenkop SM, Nalick RH, Wang HJ, et al. Peritoneal implant elimination during cytoreductive surgery for ovarian cancer: impact on survival. Gynecol Oncol. 1993;51:224-229.
12. Bristow RE, Montz FJ. Complete surgical cytoreduction of advanced ovarian carcinoma using the argon beam coagulator. Gynecol Oncol. 2001;83:39-48.
Keywords:

Plasma energy; Tumor destruction; Pathologic analysis; Ovarian cancer

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