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Cryosurgery
01. advanced external cancer
02. Liver tumors
03. skin tumors
04. Breast Cancers
05. menorrhagia
06. bone tumor
07. prostate cancer
08. renal cancer
09. uterine myomas
10. Breast Fibroadenomas
11. lung cancer

Cryosurgery for Breast Cancer

 

Breast cancer is the most common malignant tumor affecting women worldwide. In 2000,approximately 184200 new cases of invasive breast cancer were diagnosed in the United States.In China and South-east Asia, the incidence of breast cancer has been increasing during the recent years. The increased use of breast cancer screening has resulted in more patients with smaller tumors being examined at presentation.
Despite the modest gains made in overall incidence rates,modern treatment of breast cancer has allowed dramatic improvement in quantity and quality of life after the diagnosis of a breast malignancy.The most noteworthy improvements are use of lesser invasive procedures for appropriate patients,improvement of hormonal therapies,and the more effective use of adjuvant cytotoxic therapy.In addition,survival after the diagnosis of metastatic breast cancer has also improved as a result of more effective palliative treatment.The 5-year survival rate for breast cancer at all stages was 63% in 1960,increased to 75% in 1977,and was reported as 82% in 1990[1].


Overview of treatment


The major treatment options for patients with early breast cancer are total mastectomy or conservative resection of the tumor followed by radiotherapy. Multiple randomized trials have demonstrated that there was no significant differences between groups received total mastectomy, lumpectomy or lumpectomy plus radiotherapy in overall survival. Because those results, surgical treatment options in breast cancer treatment have evolved toward more conservative procedures[2]. Either a modified radical mastectomy or partial mastectomy and radiotherapy currently is considered optimal local treatment for patients with stage I or stage II breast cancer[3].
Stage III breast cancer is advanced locally without apparent distant metastases. The clinical course of these patients indicates that most already have occult metastatic disease and suggests the need for early or initial treatment with systemic chemotherapy. Now it is suggested that breast-conserving surgery with chemotherapy and radiotherapy is amenable for this stage of breast cancer.
However, a lumpectomy, while a tremendous improvement over mastectomy, is still an invasive procedure, with potentially undesirable cosmetic results. For this reason, there has been significant interest in less invasive percutaneous ablation.
With the improvements in imaging techniques that have allowed the earlier detection of smaller breast cancers and the desire for improvements in cosmetic outcome, a number of minimally invasive techniques for the treatment of early stage breast cancers are being investigated. Ablative therapies, including laser ablation, focused ultrasound, microwave ablation, radiofrequency ablation, and cryoablation, have been described[4]. All of these techniques have shown promise in the treatment of small cancers of the breast, heir potential advantages of the percutaneous ablation would include better cosmetic results; fewer complications; and a decrease in operating room and anesthesia needs, recovery time, and health care costs. For advanced breast cancer, these techniques can induce reduction in the tumor bulk, and alleviating intractable pain, make a basis for combination therapy.

Cryosurgery for Breast Cancer

Cryosurgery has been developed since the 1960s to destroy benign and malignant tissues and is well established to treat a variety of neoplasms with minimal surgical risk. However, application of cryosurgery for the treatment of breast cancer does not seem to attract much attention and has been performed by just a few active cryosurgeons .

In the Fuda Cancer Hospital Guangzhou where authors work, of a total of 2500 patients with malignancy, 70 had breast cancer: 18 primary advanced and 52 recurrent, who underwent cryosurgery in the period from Mar 2000 to May 2006.

Experimental research of cryosurgery for breast cancer

Staren et al[5] determined the feasibility and efficacy of cryosurgery of experimental breast cancer. Phase 1 was performed in Sprague-Dawley rats with carcinogen-induced mammary adenocarcinomas, phase 2,in DBA/IJ mice with transplantable mammary adenocarcinomas and phase 3,in dogs and sheep. In phase 1, a single, short-term (< 7 minutes) freeze killed only tumors smaller than 1.5 cm in diameter, despite an apparent decrease to -40 degrees C at the periphery of each tumor. In phase 2, varying the peripheral tumor temperature to as low as -70 degrees C, using a single, short-term (< 7 minutes) freeze did not alter the results from phase 1. If the ice ball fully encompassed the tumor, however, maintaining it for at least 15 minutes achieved 100% tumor kill independent of tumor size. In phase 3, creation of a reproducible ultrasound-monitored cryolesion was facilitated when 2 freeze-thaw cycles were performed. No procedure-related complications were noted. In situ breast cryosurgery has been proved to be feasible and efficacious in small and large animal studies.


Sabel et al[6] showed that cryosurgery can initiate inflammation and leave tumor-specific antigens intact, which may induce an anti-tumor immune response in experimental breast cancer. To help define the mechanisms involved in the cryoimmunologic response, cryosurgery to surgery in a murine model of breast cancer was compared. Cryoablation led to significantly higher levels of interleukin (IL)-12 and IFN-gamma, but no changes in IL-4 or IL-10. Tumor-specific T-cell responses were evident after cryosurgery in lymphocytes from tumor draining lymph nodes(TDLN) but not from spleen. Cryoablation also increased NK activity compared to surgery.

Indications of cryosurgery
The most important issue for cryosurgery is patient selection. There are selection principles as follows[7,8]:

  • The ideal candidate would have a small solitary invasive breast cancers, smaller than 15 mm with low density on a mammogram and discrete margins and a visible posterior wall at ultrasonography.
  • Small breast tumors but are not candidates for surgery or pharmacologic therapy.
  • Cancers should be unifocal and mammograms should not show any other suspicious lesions. There should be no history of prior breast cancer in the same breast.
  • Invasive lobular carcinoma and cancers with significant amounts of intraductal carcinoma tend to be multifocal, with some foci too small to be seen on current imaging. are not candidates for this treatment. Patients with noncalcified ductal carcinoma-in-situ(DCIS) often are the cause of most cryoablation failures.
  • Those with scattered suspicious calcifications are also not candidates since these calcifications may be associated with intraductal carcinoma.
  • There should not be any other cancers in the same breast and lymph nodes should be clinically negative.
  • Due to limited experience, special forms of breast cancer (mucinous, medullary, apocrine, etc.) should be avoided.
  • Any inoperable stages III and IV cancer, not indicated for conventional surgery, and recurrent breast cancer with multiple and wide-spread lesions, resistant to radio/chemo/endocrine therapy, indicated for cryosurgery. Goals of cryosurgery will depend on the status of the tumor and general condition of the patient, including arresting continuous hemorrhage from an ulcerating tumor, reducing malodorous discharge, reduction in the tumor bulk, and alleviating intractable pain.
  • For inflammatory carcinoma (carcinoma erysipelatodes), which spreads rapidly, cryosurgery with the liquid nitrogen (LN2) spraying technique is the only measure to stop the disease and salvage the patient.
  • Cryosurgery for anaplastic cancer may cause unexpected progression of the disease, thus is contraindicated.

Pre-procedure

Mammograms, ultrasound(US) and US-guided core-needle biopsy should be performed.

Accurate precryoablation determination of tumor size, extent, and margins at mammography and US is probably important in assessment of whether a patient is a candidate for this type of procedure.Preoperative core needle biopsy should be taken to provide
all prognostic testing necessary since ablation will destroy all tumor tissue and testing will be impossible after treatment.
Magnetic resonance (MR) imaging before cryoablation is sometime helpful. MR imaging might depict occult lesions which is no possible to be discovered with other imaging methods and might be helpful to accurately assess tumor extent.

Procedure of cryosurgery

Instrument

LN2 or argon gas–based cryoablation system is often used. This system is designed to create probe temperatures of –160-190°C. Progress in the technology of cryosurgery has provided smaller devices which could achieve ultracold temperatures in a controlled and reliable manner(Figure 1 )[9]. Cryoprobe selection depends upon tumor size and condition.

Figure 1 Cryoablation devices have decreased in size, now desktop size.
Not shown are the argon and helium gas tanks needed for the procedure.(From
Kaufman CS and Rewcastle JC[7]).

  • Cryoprobes of closed-end type, with various outer diameter.
  • Probe-tip adaptors of various size and shape to be equipped with a cryprobe, to obtain good contact with the tumor are selected.
  • Cryosurgical device for spraying LN2 (available as a portable unit) is essential for the treatment of a widespread but not so deeply invasive lesion, such as inflammatory cancer, and is useful for the simultaneous combined methods of freezing with contact and penetration, to expedite the freezing procedure.

Thermocouple needles for tissue temperature monitoring are a prerequisite to achieve sufficient cryodestruction of the tumor and to protect adjoining normal tissue. Before starting to freeze, thermocouple needles for tissue temperature monitoring are placed at multiple sites, at least at the three critical points: intratumor, basis of the tumor (invasive front), and juxtatumor normal skin[7] (Figs. 13.3.1a,b) to achieve precise cryodestruction of the tumor and to protect adjacent normal tissue. Tissue temperature down to -50oC to -60oC or lower at the critical points is required to definitely destroy the tumor (3).

Cryosurgery technique

There are following kinds of cryosurgery for breast cancer[7]:

  • Penetration method: Small cross incisions by an electric knife are made at several sites to introduce a cryoprobe. The penetration method is the best of all of the cryosurgical techniques for various size of tumors.
  • Contact method: The most frequently used and safe, with a variety of probe-tip adaptors to fit the size and shape of the tumor. If good contact cannot be obtained because of the rough surface of the tumor, Vaseline may be applied to cover and flatten the surface to obtain certain contact between the probe-tip adaptor and the tumor. Freezing sites are fractionated and overlapped when the tumor is large and wide.
  • Contact method plus spraying method: Frequently used safely for bulky and for wide-spread tumors, to expedite freezing. A heavy-duty apparatus and LN2-spraying machine are utilized simultaneously (Fig. 13.3.2). A Vaseline embankment is prepared to prevent run-off of LN2, which otherwise soaks into the surgical drapes, and thus protect normal skin from unnecessary cold injury when spraying liquid nitrogen (Fig. 13.3.3).
  • Penetration method plus spraying method: For massive tumors, it is the most powerful method, yielding the best depth of freezing. (e) Spraying as the sole method: For small tumors, e.g., skin metastases or recurrence, with a spray cone (closed spray) (Figs. 13.3.4a,b), or direct open spray onto the superficial lesion it is suitable to treat wide spread tumors in a short period of time. However, it must be remembered that the depth of freezing attained will be less than 1cm, although there are some reports (5,6) of successful aggressive freezing of bulky advanced cancer by the open spray alone.

In the sequential freezing, the probe-tip temperature is set at -160oC to -180oC, and duration of the time is 5 to 10 minutes. The ice front should be at least 1cm beyond the margin of the tumor, and generally, two or three freeze-thaw cycles are necessary.

Focus in penetration method of cryoablation for breast cancer
Here, a great attention is paid to introduction of penetration method of cryoablation for breast cancer[8].
The mass of breast is identified by using ultrasound (US), and the most convenient access to the mass is determined in the same way that is typically used for US-guided core-needle breast biopsy. Less than 1 ml of 2% lidocaine is injected into the skin at the planned insertion site, and afterward a small incision is made in the skin by using a scalpel. For local anesthesia, 2–5 ml of 1% lidocaine is injected into the deeper tissues proximal to the mass along the expected course of the cryoprobe.

Thereafter, the cryoprobe is percutaneously inserted through the skin opening, with US guidance, into the center of the mass, and the tip was advanced 1.0–1.5 cm beyond the distal edge of the tumor (Figure 2 ).The cryoprobe is a 2- or 3-mm-diameter vacuum-insulated trocar-tipped instrument, which allows cooling to occur only at its distal 4 cm. Central placement within the tumor is confirmed in two orthogonal planes (parallel to and perpendicular to the axis of the probe) by using US to ensure symmetric placement of the probe prior to activation of the cryoablation system.

Figure 2 Cryoprobe percutaneously placed into tumor continuously visualized
with ultrasound(From Kaufman CS and Rewcastle JC[9]).

In cases in which masses are asymmetrically larger in one plane, the planned trajectory is oriented such that the longitudinal axis of the probe would be in the same plane as the longest dimension of the mass (Figure ). This is done because the ice ball forms more like an oval than a ball; that is, it is longer in the longitudinal plane along the length of the probe. The goal is to create an ice ball to rapidly engulf a tumor plus a circumferential margin of normal tissue.

Figure 1 Longitudinal US images relative to transducer show placement of cryoprobe in tumor (arrows).

Figure 2 Longitudinal US images relative to transducer show placement of cryoprobe in tumor (arrows). Tip (arrowhead) of probe was advanced 1.0-1.5 cm beyond distal aspect of tumor and allowed ice ball to engulf entire tumor.

The cryoablation procedure consistes of a double–freeze-thaw protocol. The freezing time is based on the maximum tumor diameter as assessed with US to avoid excessive freezing of uninvolved tissue around smaller lesions. Each freezing cycle is split between a high-freeze and a low-freeze period; the time for each period is determined by using a maximum tumor size. The high-freeze period is 1.5–5.0 times longer than was the low-freeze period, depending on maximum tumor size, with longer durations for larger cancers. The low-freeze period varies from 2 to 4 minutes, and the high-freeze period varies from 6 to 10 minutes. When freezing begins, the cancer is quickly obscured by the shadowing that grows around the probe. During the high-freeze period, the system operates at a 100% duty cycle (argon flows continuously), while during the low-freeze period, it operates at a 10% duty cycle (argon gas flows for 1 second and is off for 9 seconds of every 10-second period). This 10% duty cycle maintains cold temperatures within the ice ball while it slows the overall growth of the ice ball. At formation of the second ice ball, the goal is for the ice ball to encompass the tumor plus an approximately 8–10-mm margin. The time parameters set for the freeze-and-thaw cycles allows a predictable steady growth in the ice ball length and width over time so that the ice ball sizes are appropriate for the cancer size within the time parameters set for the freeze-and-thaw cycles. A passive thaw that lasts 10–12 minutes (depending on the cycle used) is interposed between the two freezing cycles, and an active thaw with helium gas is performed after the second freezing cycle, which thereby facilitates probe removal. The total time involves in the freezing and thawing aspects of the procedure is 30–40 minutes.

During cryoablation, multiple static US images are obtained to document the tumor size and location before probe placement, the probe placement within the tumor, and the maximum length and width of the ice ball. Color Doppler flow imaging may be applied during cryoablation to observe whether blood flow could be seen in the tissue surrounding the ice ball.

The ice ball was readily identifiable as an enlarging hypoechoic circumscribed mass with an echogenic anterior surface and extensive acoustic posterior shadowing(Fig ). Ice ball sizes are directly proportional to cancer sizes,but generally the ablated tissue is slightly smaller than the visualized iceball on ultrasound.

Figure US images depict ice ball formation. At maximum size, ice ball is an oval mass with echogenic anterior surface and dense posterior acoustic shadowing. Distance between margin of ice ball and skin (arrowheads) was greater because of injection of sterile saline, which was intermittently instilled between ice ball and skin to maintain an ice ball-to-skin distance of at least 5 mm to prevent hypothermic injury to skin.
To protect the skin from injury during the procedure, approximately 5–15 ml of sterile saline is injected subcutaneously through a 20-gauge needle whenever the anterior surface of the ice ball is seen to approach within 5 mm of the skin surface at US, and these injections are repeated as necessary. Approximately three to five injections are often needed in each case. The saline increases the distance from the ice ball to the skin; thus, the skin is protected from frostbite. After the probe is withdrawn, pressure is maintained on the breast for approximately 20 minutes, and a pressure dressing is applied to decrease the risk of hematoma formation. Patients are assessed prior to discharge for any evidence of skin injury.


Post-cryosurgery management

Postcryosurgical hemorrhage is often a problem. The wound is covered with a thick gauze dressing after topical application of an antibiotic ointment, and then with sterilized soft cotton sheet wadding, which is usually applied under cast fixation for bone fracture, wrapped in gauze. Wide adhesive plasters with cotton tapes are prepared and applied. Pressure on the wound is given by tying the tapes to each other from three directions over the cotton pads.

Two to three weeks after cryosurgery for advanced breast cancer, necrotomy is done with scissors or an electric knife. Suspicious tumor remnants, if present, are frozen. A mesh skin graft follows to cover the skin defect, one month after the necrotomy. Time is required to observe and confirm no early recurrence of the tumor[7].

Post-cryoablation follow-up
After satisfactory ablation of small breast cancer, the patient should be scheduled for sentinel or axillary node dissection. After completing ablation and node treatment, patient should likely undergo radiation treatment to the breast.Medical oncology evaluation will determine whether patient should also undergo either chemotherapy or hormone therapy. Follow up should include regular imaging at three month intervals for the first two years. If an abnormality is found on imaging, a core needle biopsy of that site should be performed. Thereafter, long term imaging follow up should be given every six months. In addition, routine core needle biopsies should be recommended at regular intervals of several sites within the cryotreated area. These would include biopsy of the central ablated tissue, as well as several peripheral margins to confirm there is no residual disease. Patients with positive biopsies should undergo immediate surgical excision and appropriate medical treatment[9].

Clinical comment
Marilyn et al[8] represented the nine patients in a prospective multi-institutional trial to evaluate the effectiveness of a cryoablation system in the treatment of small invasive breast malignancies .
Patients had solitary lesions of 1.8 cm or smaller that were visible at US. No procedure was prematurely terminated because of patient discomfort or patient request, and no patient needed any conscious sedation or postprocedural narcotic pain medications. There were no major or minor complications, which included immediate or periprocedural complications. Despite the close margins of some tumors to either the skin or the chest wall, no skin injury occurred. Between 14 and 23 days after the cryoablation procedure, the tumor sites in eight of nine patients were excised by using conventional lumpectomy with wire localization guidance, and in one patient, lumpectomy was performed with palpation. Histology of specimens showed that seven (78%) of nine patients had no residual cancer; specimens contained fat necrosis. One patient had a small focus of invasive cancer; one had extensive multifocal ductal carcinoma in situ. No residual invasive cancer occurred in tumors 17 mm or smaller or in cancers without spiculated margins at US.
Pfleiderer et al[10] investigated the potential and feasibility of ultrasound-guided cryotherapy in breast cancer. Fifteen female patients with 16 breast cancers (mean tumour diameter 21+/-7.8 mm) were treated. A 3-mm cryo probe was placed in the tumour under ultrasound guidance. Two freeze/thaw cycles with durations of 7-10 min and 5 min, respectively, were performed. The patients underwent surgery within 5 days and the specimens were evaluated histologically. The mean diameter of the iceball was 28+/-2.7 mm after the second freezing cycle. No severe side effects were observed. Five tumours with a diameter below 16 mm did not show any remaining invasive cancer after treatment. Two of these had ductal carcinoma in situ (DCIS) in the surrounding tissue. In 11 patients cryotherapy of tumours reaching diameters of 23 mm or more resulted in incomplete necrosis. This study shows that the invasive components of small tumours can be treated using cryotherapy. Remnant DCIS components which may not be detected preinterventionally represent a challenging problem for complete ablation. In tumours larger than 15 mm two or more cryo probes should be used to achieve larger iceballs.

Sabel et al[11] reported that twenty-nine patients with ultrasound-visible primary invasive breast cancer </=2.0 cm were enrolled. Twenty-seven (93%) successfully underwent ultrasound-guided cryoablation with a tabletop argon gas-based cryoablation system with a double freeze/thaw cycle. Standard surgical resection was performed 1 to 4 weeks after cryoablation.There were no complications to the procedure or postprocedural pain requiring narcotic pain medications. Cryoablation successfully destroyed 100% of cancers <1.0 cm. For tumors between 1.0 and 1.5 cm, this success rate was achieved only in patients with invasive ductal carcinoma without a significant ductal carcinoma-in-situ (DCIS) component. For unselected tumors >1.5 cm, cryoablation was not reliable with this technique.

Roubidoux et al[12] determined the mammographic and ultrasonographic (US) findings at cryoablation of small solitary invasive breast cancers and compare them with presence of residual malignancy after treatment. Nine patients with small solitary invasive breast cancers diagnosed at core biopsy were treated with US-guided cryoablation and a 2.7-mm cryoprobe. Mean cancer size was 12 mm (range, 8-18 mm); four were palpable. Ice balls (maximal mean size, 4.4 cm) were formed around cancers. Before excision, eight patients underwent mammography; all had new focal densities (maximum size, 2.5-5.0 cm) at cancer sites. Six patients underwent preexcisional US; 100% of them had new hyperechogenicity in tissue surrounding cancer site. Seven (78%) of nine patients had no residual cancer; specimens contained fat necrosis. One patient had a small focus of invasive cancer; one had extensive multifocal ductal carcinoma in situ. Patients with BI-RADS category 1 or 2 densities on mammograms or nonpalpable tumors had no residual malignancy. No residual invasive cancer occurred in tumors 17 mm or smaller or in cancers without spiculated margins at US.

Clinical experience in 29 patients with breast cancer was reviewed byKaufman and Rewcastle[9,13], demonstrating effectiveness in properly chosen patients. All tumors under 1 cm in size were completely destroyed. Grade one tumors were less likely to have residual disease after ablation than other grades (0% vs. 58%). Patients who had negative lymph nodes were less likely to have residual disease than those with positive nodes (21% vs. 80%). The treated site was excised two weeks after cryosurgery, gross examination of the tissues showed a hemorrhagic firm mass at the treatment site which engulfed the target tumor (Figure 5). The histologic findings reveal complete cellular necrosis in the cryosurgery treated areas (Figure 6). Gradual resorption of this necrotic debris correlates with the mammogram and ultrasound over time.

Figure Gross photographs of serial slices of excised breast cancer treated
with cryosurgery two weeks earlier. The hemorrhagic treatment area is well defined, surrounded with benign fatty breast tissue. (From Technol Cancer Resear Treat2004;3:174)

Figure Histology of recently treated breast cancer with cryosurgery. Necrosis of tumor tissue is noted without any viable cells at 400X. (From Technol Cancer Resear Treat2004;3:174)

Tanaka[7,14] reported 52 had breast cancer,including 10 primary advanced and 42 recurrent, who underwent cryosurgery in the period from July 1968 to January 2000. All the patients were referred as incurable cancer: advanced and unresectable, resistant to radiotherapy, chemotherapy, and endocrine therapy, or debilitated with associated systemic diseases. Three and five-year survival was 40.0% after cryosurgery(Table 13.3.1). This figure is not disappointing, given the patients’ severe condition.
During Jul 2001 to Dec 2005,42 patients with advanced breast cancer received percutaneous cryosurgery in Fuda Cancer Hospital Guangzhou. Among the 42 cases,15 were given cryosurgery plus systemic chemotherapy,27 were given cryosurgery,chemotherapy and endocrine therapy. The results are as in Table .No significant difference was seen between both groups of patients. Overall, one-,two, three and four-year survival was 71%,64%,53.5% and 45.5%,respectively.

Therapy

Cases

1-year survival

2-year sulvival

3-year survival

4-year survival

Cryo +Chemo

15

68%

63%

56%

47%

Cryo+Chemo+Endoc

27

74%

65%

51%

44%

Total

42

72%

64%

53.5%

45.5%

Discussion
Cryoablation technique has its origins in the 1800s when advanced carcinomas of the breast and uterine cervix were treated with iced saline solution. Cryosurgery has been explored as a radical modality for small breast cancer, and a salvage treatment for locally advanced unresectable breast cancers that are resistant to radiation therapy and chemotherapy and recurrent breast cancers[4,5].
Why consider alternatives to surgical lumpectomy
The standard treatment for breast cancer has progressed from mastectomy to breast conservation (lumpectomy with radiation) over the last 20 years. Multiple studies in the US and Europe have confirmed the long term equivalence of these two treatments for the properly chosen candidate[15,16]. Given that surgical lumpectomy is a relatively minor operation and the deficit in the breast is small, why explore
alternative treatments

Even though lumpectomy is not a major operation, it still involves a surgical incision, excision, anesthesia, postoperative pain, recovery and potential adverse cosmetic
impact. Women wish to have their cancer properly treated, while at the same time they wish to have the least invasive method that will achieve proper treatment. As
the size of detected primary tumors continues to decrease with wide spread mammographic screening, both physicians and women want to have an alternative to a surgical procedure.

For tumors that are small, it should be possible to effectively treat the entire tumor with a surrounding margin of normal tissue using ablative techniques. If the tumor (plus margin) treated is the same that would have been excised, then ablation should achieve the same results as lumpectomy while being less invasive.

Comparing surgical lumpectomy with in situ ablation
A surgical lumpectomy is considered the gold standard for local breast cancer care. The tumor is surgically removed with a margin of normal breast tissue in an operating room
under sedation or general anesthesia. Margins are pathologically examined within 24 hours and the scar tissue slowly resolves over the next 3-6 months. Return to normal activity occurs in a few days to a week at most.

In contrast, in situ ablation, such as cryosurgery, destroys the breast tumor and a surrounding margin within the breast without incision or excision. Ablated tissues are left in the breast for resorption over time. Since the tissue is destroyed with ablation, all information regarding the tumor must be obtained before hand using tissue biopsy and imaging techniques. Complete pathology of the margins cannot be performed since the tissue is not excised and that information must be obtained indirectly. Follow up is therefore dependent on imaging techniques as well as needle biopsy of the treated site. Due to the percutaneous nature of the procedure, a large incision
is avoided as is much of the associated scarring.

Cryoablation versus heat generating ablation methods
There are several types of ablation techniques. The common process among all types is the transfer of thermal energy into or out of a small defined area to achieve heating or cooling and destruction of all viable cells within that area. Currently there are several forms of heating tissue that include radiofrequency, laser, microwave, and focused ultrasound but there only one effective method of cryoablation. Different thermal ablation technologies are differentiated by how they generate heat or cold, deliver or remove energy to the targeted tissue, how the energy is propagated through the tissue and how the procedure is monitored. These differences result in varying ability of the different technologies to uniformly ablate in situ.

Radiofrequency and laser ablation are the two most common types of heat generating ablation used for breast cancer[17,18].
Once the radiofrequency probe is placed, multiple prongs are deployed from the needle tip into the tumor. Radiofrequency current is passed through the probe and adjacent tissue which induces ion movement in tissue and frictional heat which
further propagates the heat into the tissue via conduction.

Laser ablation utilizes a laser fiber placed within the tumor to generate heat via the photothermal effect. Propagation of heat is also via conduction and tumor necrosis occurs by increasing tissue temperature[19,20].

Microwave ablation utilizes antennae to focus microwave energy at the tumor site. Heating occurs with absorption of microwave energy by the target tissue[21]. A more controlled method of heat ablation is high intensity focused ultrasound
(HIFU)[22,23]. Treatment is accomplished by systematically marching through the target volume pulsing and depositing energy at different locations until the entire tumor has been ablated. Early trials of both microwave and focused ultrasound treatment of breast cancer have been reported.

All techniques that raise tissue temperature to achieve cell destruction have some similar concerns regarding breast cancer treatment. Since breast tissue is made of both fatty and stromal elements, heat conduction (tissue impedance) within the heated tissue varies and may not be predictable or symmetric [24]. Variation in the measured size of ablation volume occurs despite using identical heating elements[25,26]. This in turn may lead to potential under or over-treatment. In addition, elevated tissue temperatures cause pain unless adequate anesthesia is present. Sedation or general anesthesia has been typically used for heat based ablation methods .
Use of local anesthetic alone has been reported, but a significant volume of anesthetic is required and may alter the heating characteristics of the procedure and onsequently the biologic effect. Further, real time intraoperative visualization with ultrasound is difficult. Lack of real time monitoring may make targeting less recise[27].

All thermal ablation therapies can effectively destroy tissue if properly employed. Thus, we expect that it will be the secondary characteristics of ablation techniques that will be decisive in choosing between them (Table I). Many aspects of cryosurgery make it an attractive and seemingly ideal choice as a preferred ablative therapy for breast cancer.
Because of the inherent anesthetic properties of extreme cooling, patients have no sensation during their treatment.
No anesthetic is necessary after the probe is placed in the tumor. This allows cryosurgery to be performed in the office without the costs or side effects of sedation or anesthesia.
Further, the ability to accurately visualize and monitor the procedure in real time helps ensure the prescribed thermal injury is properly administered.

Table Advantages of cryosurgery compared with heat generating ablation
technologies.

Office based treatment Small size of treating and monitoring equipment
No pain associated with cooling No anesthesia needed for ablation
Real-time visualization with ultrasound Tumors close to the skin can be treated
Fibroadenoma experience projects long term imaging findings Imaged lesion resorbs over time without increased scar formation

As a primary treatment for small breast cancer
As a primary treatment for small breast cancer, there are several advantages of cryoablation.

  • Up to one-half of small breast cancer detected by using mammographic screening might be treated with cryoablation. It is suggest that the ideal candidate would have a tumor smaller than 15 mm with low density on a mammogram and discrete margins and a visible posterior wall at US.
  • The efficacy of cryosurgery for small breast cancer is comparable with lumpectomy.
  • Patients experience very little pain; hence, only local anesthesia with lidocaine is necessary, and the technical aspects of the procedure are very similar to those of US-guided core-needle breast biopsy.
  • Cosmetic outcome would be very positive, as scarring is minimal. The lack of skin injury despite proximity to the skin (as close as 5 mm in our series of patients) is promising.
  • The reduced morbidity and mortality compared with those of surgery and compared with those of nonsurgical options in patients who are not candidates for surgical therapy are also advantages.
  • There is also some evidence that cryoablation may induce an immunologic response that may be potentially beneficial to the patient[28-29].

Accurate precryoablation determination of tumor size, extent, and margins at mammography and US is probably important in assessment of whether a patient is a candidate for this type of procedure. Ductal carcinoma in situ(DCIS) has a high failure rate of cryosurgery. MR imaging might depict DCIS that is occult with other imaging methods. MR imaging and/or an additional biopsy in patients who do not have fat density on mammograms might be helpful to accurately assess tumor extent and the possibility of occult DCIS.
After cryoablation, there was increased echogenicity at US and increased density at mammography; these findings were observed in areas that approximated location and size of the ice ball. Tumor size, mammographic density, and US characteristics may be indicators of likelihood of complete cryoablation.
It is noted that the posterior margin is less discernible because of the shadowing during cryoablation, and this may be a limitation in the evaluation of whether the tumor has been completely encased.
In addition, the fat necrosis in the tumor site would limit subsequent imaging or clinical breast examinations. There is new extensive hyperechogenicity around the tumor after cryosurgery. Correspondingly, vague but focal density up to 5.0 cm in size also occurred on mammography. These changes, which correspond to the coagulative necrosis and possible fat necrosis due to cryoablation.


As a palliation therapy for advanced breast cancer


As a palliation therapy for advanced breast cancer, cryosurgery is indicated for inoperable stages III and IV cancer, no amenable to conventional surgery, and recurrent breast cancer with multiple and wide-spread lesions, resistant to radio/chemo/endocrine therapy, and in particular, inflammatory carcinoma. Goals will vary from palliation of the disease to intention to cure. These will depend on the status of the tumor and general condition of the patient. Palliation includes arresting continuous hemorrhage from an ulcerating tumor, reducing malodorous discharge, reduction in the tumor bulk, and alleviating intractable pain. It deserves special mention that (1) this maneuver is safe even for patients debilitated with the disease, and (2) in an urgent problem, to stop very rapidly spreading disease, e.g., inflammatory cancer. It is suggested that the only exception is anaplastic breast cancer which is contraindicated, because cryosurgery for this may cause unexpected progression of the disease.

Future research using cryosurgery in breast cancer

Current trials have shown the tissue is thoroughly destroyed within the circumference of cryoablation treatment. Most of the failures
are due to disease unknown to be present by imaging
studies at sites outside the treatment area. It is clear that improvements in pretreatment imaging will allow to choose better candidates for cryoablation.

Since residual debris can be identified for up to 1 year after cryosurgery, it is necessary to look for an ideal method to confirm if there is no residual cancer at the treatment site. Multiple imaging exams, including mammograms, ultrasound, and MRI as well as intermittent core needle biopsies of the treatment site are of important significance. The junction between the debris and untreated tissue will be the most likely site to biopsy.

Most metastases of breast cancer are manifest with the first 5 years of diagnosis,but late relapses are frequent and may occur 10 even 20 years after the diagnosis of the primary disease. Therefore, measures to prevent relapse continues to be of great interest.
These patients who have their local breast cancer treatment utilizing cryoablation would also be treated with the remaining components of care for breast cancer. Those additions would include breast radiation, lymph node evaluation, and appropriate systemic treatment with either hormone therapy or chemotherapy.

It is important to state that the benefits of adjuvant systemic therapy are specially substantial for advanced breast cancer. Cryochemotherapy, a new mode of anticancer regimen,is suggested[30]. It is reported that mitomychin C, which is trapped within or in the periphery of the tumor in high concentration, has multiplied anticancer effect in combination with the destructive effect of cryosurgery,when administered intravenously as a bolus or by drip infusion, either during cryosurgery or within one hour of the cryosurgery. Administration of the agents intratumorally or within the periphery of the tumor before the second cycle of the freezing is unproblematic and is recommended for the treatment of a solid tumor.

It have been observed that reduction in size of the unresected tumor or spontaneous regression of multiple metastatic lymph nodes (confirmed by biopsy) occurred after cryosurgery, and adjunctive use of proper biological response modifiers (BRM) resulted in growth arrest of the tumor in a patient with an advanced bilateral breast cancer, that suggest cryoimmunointensification[31,32]. Therefore, the relative benefits of such therapy can be reliably predicted.

Conclusion

Cryosurgery is uniquely suited to treat breast cancer since it is so visible on real time ultrasound and causes essentially no pain with its use. For early stage breast cancer, cryoablation is a safe, well-tolerated office-based procedure. Ability to find appropriate
candidates for this type of procedure will determine its usefulness. Candidates that have unifocal breast cancer with margins that are accurately defined with imaging studies will benefit from this office based new modality. For the advanced breast cancer, cryosurgery as one of combination therapies, has a good palliative efficacy. It is encouraged that continued research in this area to confirm the expected benefits of cryosurgery for women with breast cancer.
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