DISCUSSION
RFA
RFA represents the most used technique to treat breast cancer with a minimally-invasive approach.
In 1999,
Jeffrey et al.
performed the first study,
enrolling 5 patients,
aged 38-66,with locally advanced invasive breast cancer and treating them with preoperative radiofrequency ablation.
Tumor size ranged from 4 to 7 cm,
as measured by clinical investigation or mammography.
Complete ablation was seen in 4 of 5 enrolled patients,
with no complications[2].
In all other studies,
tumor size ranged from 0.2 to 4 cm and patients’age ranged from 42 to 89 years,
with a predominance of postmenopausal or elderly women.
Percutaneous ablation treatment was conducted under local or general anesthesia,
and when under local,
with preliminary sedation.
US guidance was preferred,
even though Van den Bosch et al.
used an open 0.5T Signa-SP imager (MRI) guidance to perform RFA on 3 women,
aged 47,45 and 60 year old,
with invasive ductal carcinoma[3].
Surgical tumor resection was performed immediately after percutaneous treatment or from 1 to 4 weeks after,
with some exceptions: Pallussière et al.
for instance enrolled women who had undergone neoadjuvant endocrine therapy within the past 6 months,
and then treated them with US-guided RF ablation while under local anesthesia and sedation.
Breast irradiation was not performed and RFA was used as substitute for surgery in this elderly patients (aged >70 years).
Clinical follow-up included US,
mammography,
and dynamic contrast material-enhanced (DCE) MRI every 2 months for 6 months and then every 6 months until 5 years.
After 1 year,
only 1/21 patient presented a local relapse.
Ten women were followed up for 5 years: 3 additional cases presented cancer recurrence outside the ablation zone.
Four patients died during the full follow-up,
two for breast cancer-related causes and two for unrelated causes.[4]
Success ablation percentage varied from 57 to 100%,
considering all 34 studies included in the review.
Cosmesis was reported from good to excellent almost in all studies,
with the exception of Oura et al.
who reported a 6% of fair cosmesis (3/52 patients)[5].
Most frequently reported complications were full thickness skin burn,
skin burn at puncture site,
muscle burn; less frequent were granulomatous mastitis,
late abscess,
and minimal ecchymosis.
Complete ablation rate was in the range of 57-100%,
being the highest reported among the ablation techniques evaluated.
CRYOABLATION
Cryoablation is a “reverse” thermal ablation technique,
which uses extreme cold to freeze a targeted tumor in place of heat.
Most studies taken into account are concerned with clinical experiences on benign lesion ablations.
Women enrolled were aged 28 to 80 years.
Lesion diameters ranged from 0.8 to 4 cm.
All patients received surgical excision from 0 days to 6 weeks after cryoablation.
After a pilot study in 2002[6],
a larger experience was reported by Tafra et al,
who compared surgical results of two methods – cryo-assisted localization (CAL) and needle-wire localization (NWL) - in patients undergoing lumpectomy for breast cancer.
CAL was superior in ease of lumpectomy,
quality of specimens,
acute surgical cosmesis,
short-term cosmesis,
patient satisfaction,
and overall procedure time.
CAL even had a lower invasive positive margin rate (11% vs 20%),
that made this technique preferred as an alternative to standard wire localization.[7]
Pfleiderer demonstrated that the invasive components of small tumours could be treated using cryotherapy,
while remnant DCIS components which may not have been detected prei-nterventionally represented a challenging problem for complete ablation.
In tumours larger than 15 mm two or more cryoprobes should be used to achieve larger iceballs[8].
In another study,
he demonstrated that cryoablation could be successful in breast cancer smaller than15 mm and complete ablation was achieved in 24 (83%) of 29 patients with small breast cancer.[9]
Similar results had been already shown in different studies before.
Twenty-nine women with early-stage breast cancer were treated with cryoablation in a multi-institutional study,
followed by surgical resection 1–4 weeks later.
The results showed that cryoablation successfully destroyed 100% of cancers in all patients with tumor leas than 1 cm.
For tumors >1.5 cm,
cryoablation was not reliable with this technique in terms of complete ablation.[10]
Cryoablation was normally performed under US guidance,
but Morin et al.
and Pusztaszeri et al.
also performed it under MRI guidance even if complete ablation achieved was low,
ranging from 36% (4/13) to 52% (13/25) in patients with invasive breast cancer.[11],[12]
A very important study,
more recent than the others,
has been published in 2009 by Littrup et al.
Their experience is concerned with a feasibility study on breast cryoablation without excision.
Using multiple cryoprobes,
twenty-two breast cancer foci (stages I-IV) were treated in 11 patients who refused surgery.
Patients were treated only under local anesthesia; US guidance or both computed tomography and US guidance was used.
No significant complications,
retraction,
or scarring were noted.
Biopsies at the margins of the cryoablation site immediately after cryoablation and at follow-up were all negative.
No local recurrences have been noted at an average imaging follow-up of 18 months.[13]
Cryotherapy seems more successful in treating invasive than in situ disease.
Complete success ablation varied from 50-100%,
while complications occurred were skin burn at probe entry site,
skin ulceration and necrosis –reported in 45% in Pusztaszeri’ experience- and minimal discomfort.
Cosmesis and patient satisfaction declared ranged from good to excellent.
LASER ABLATION
Recruitment age range varied,
unexpectedly,
from 18 to 90 years; tumor size from 0.4 to 6 cm in diameter.
Surgical resection was performed immediately after or with a maximum of 70 days of delay.
Studies were mostly performed in order to evaluate safety and feasibility of LA to treat breast cancer.
Dowlatshahi et al.
reported the largest clinical experience with LA for breast cancer by enrolling fifty-four patients (50 with invasive breast carcinoma,
4 with in-situ) with malignant lesion diameter range 0.5-2.2 cm.
Complete ablation rate was 70%.[14]
The most recent study from Klimberg et al.,
aimed to demonstrate the feasibility of a mini-invasive ablation techniques comparing LA to RFA as post-percutaneous excision treatment for sterilization and widening of surgical margins.
Participants with unicentric invasive ductal cancer ≤1.5 cm were randomized to treatment for margin ablation,
then followed by immediate lumpectomy.
While RFA arm showed 100% success in ablation,
LA demonstrated unpredictability of the ablation zone and residual live tumor.[15]
Apart from skin burn,
two severe complications were noted after LA treatment.
Van Esser et al.
reported pneumothorax,[16],
whilst gaseous rupture of the tumor was noted by Akimov et al.[17]
Complete ablation rate was in the range of 13-91%,
thus underlining a potential role to change the paradigm for local treatment of breast cancers.
MICROWAVE ABLATION
Age of women included in papers dealing with MWA ranged from 47 to 82 years,
while lesions treated were mostly core-needle biopsy-proven invasive carcinomas.
Tumor size ranged from 0.8 to 8 cm,
even though in most recent studies tumors treated were smaller (3 cm or less in diameter).
The first pilot study was published in 2002 by Gardner et al.
Their experience is concerned with 10 patients with 1 to 8 cm malignant lesion who underwent MWA followed by mastectomy.
Necrosis was noted in 40% of the specimens (4/10),
and apoptosis in 60% (6/10),
but no evidence of complete ablation was observed[18].
In a subsequent prospective,
non-randomized dose-escalation study,
among twenty-five women with affected by invasive breast cancers who underwent MWA,
pathological necrosis was finally detected in 17 patients (68%),
including 2 patients with complete ablation[19].
In May 2012,
41 patients with core-needle biopsy-proved breast cancers 3.0 cm or less in diameter were recruited to undergo US-guided percutaneous MWA followed by immediate mastectomy.
Thirty-seven out of 41 cases (90%) showed complete tumor coagulation.
Of 38 cases diagnosed with invasive ductal carcinoma,
36 (95%) showed complete tumor coagulation[20].
Reported complications were mild pain during treatment,
slight thermal injuries to the skin and pectoralis major muscle,
skin burn,
and skin erythema.
HIFU
HIFU is a promising and the only truly-non-invasive ablation technique proposed to date.
It employs extracorporeal ultrasound energy to ablate the conformal confluent volume of a targeted tumor at depth,
without any needle insertion.
The first HIFU-treated case was reported by Hüber et al[21].Since then,
the largest series to date,
is still the one of Wu and colleagues,
who performed a prospective,
randomized clinical trial on 48 women with biopsy-proven invasive breast cancer to assess the therapeutic effects of HIFU on tumor cell death and procedure-related complications.
Women were randomized to undergo modified radical mastectomy (25 women) or HIFU followed by modified radical mastectomy 1 to 2 weeks later (23 women).
All tumors were at least 2 cm from the nipple and .5 cm from the chest wall or skin.
The tumor plus a rim of 1.5 to 2 cm of normal-appearing tissue were ablated.
The main symptom seen after HIFU was breast edema,
which resolved in all patients 7 to 10 days postprocedure.
Fourteen of the 23 HIFU patients experienced minor local pain,
warmth,
or a sensation of heaviness; however,
only 4 required prescription oral analgesics.
On resection,
the ablated area was firmer than normal tissue and a rim of congestion representing an inflammatory reaction to thermal ablation was seen.
On histopathologic examination,
tumors showed coagulative necrosis with nuclear disruption as well as significant vascular disruption and vessel occlusion[22].
The initial use of MRI-guided HIFU ablation for patients with invasive breast cancer was reported by Gianfelice et al.that observed a complete ablation in 4 (24%) of 17 patients,
as revealed by hystopathologic analysis on specimens.
Zippel et al.
also found similar results in another feasibility study,
with complete ablation in 2 (20%) of 10 patients with infiltrating breast cancer[23] .
MRI-guided HIFU was even used by Furusawa et al.
that found 100% necrosis of the ablated tumor in 15 (53.5%) of 28 evaluable patients with breast cancer,
95–97% necrosis in 10 (35.8%) of 28,
and less than 95% necrosis in 3 of 28 (10.7%).[24]
In 2003,
the first experience with HIFU as sole-treatment in adjunct to chemotherapy was reported by Gianfelice et al[25].
who followed up for 13–39 months 24 patients considered to be at increased surgical risk or who refused surgery,
treating them with MRI-guided HIFU device,
including 10 patients undergoing a second HIFU due to residual tumor cells.
Core biopsy showed 19 of 24 patients (79%) had negative biopsy results after 1 or 2 HIFU sessions.
In 2005,
a second experience with HIFU as the only prechemo/radiotherapy-treatment was described by Wu et al.
who reported a prospective phase III clinical trial,
in which twenty-two patients with breast cancer underwent ultrasound-guided HIFU ablation with conservative intent for the primary lesions,
followed by chemotherapy,
radiation therapy,
and tamoxifen therapy.
This is even the first example of long-term survival data experience with HIFU: the five-year disease-free survival and recurrence-free survival rates were 95% and 89%,
respectively.
The cosmetic result was judged to be good to excellent by 94% of patients.[26]
Furusawa et al.reported another important follow-up results in 21 patients who underwent MRI-guided HIFU (MRgFUS) treatment.
Core-needle biopsy led to the definitive diagnosis. Irradiation was not applied to all the 21 cases after MRgFUS.
Axillary lymph node metastases were examined by dissection or sentinel lymph node biopsy.
Recurrence or abnormal area of residual cancer was treated with Re-MRgFUS or ablated by usual surgery.
Age range was 34-72 years,
median tumor diameter was 15 mm.
Seventeen patients were treated once,
and four patients twice.
Patients were followed-up for 3-26 months.
One case of recurrence of pure mucinous carcinoma was experienced and no evidences of recurrence were obtained through MRI for the rest of 20 cases.[27]
In 2010,
Orsi,
F.
and Orgera G reported a series of HIFU treatment on selected breast cancer and surgical resection 1 to 6 weeks after treatment in order to evaluate histological findings,
such as residual viable tumour and coagulative necrosis extension.
All HIFU treatments were performed in a single session under local anaesthesia plus monitored anaesthesia care),
although at the beginning of experience,
general anaesthesia was used in order to avoid any possible external effects disturbing the treatment such as pain,
discomfort and involuntary movements.
Only 16 out of 58 patients (age range 41-74 years),
initially included according to clinical reports at the first medical visit,
were selected and then treated by means of USgHIFU.
Tumour lesions ranged from 5 to 15 mm.
The overall treatment time,
defined as the time from the beginning to the end of HIFU energy emission,
ranged from 8 minutes to 1 hour 55 minutes.
No side effects were observed after the HIFU treatment.
Only soft local mammary edema was noted overlying the lesion. Between 1 and 6 weeks from the HIFU treatment,
patients underwent conserving surgery associated to sentinel lymph-node biopsy or complete axillary dissection,
if the sentinel lymph-node was metastatic.
Microscopic examination showed tumour cells with typical characteristics of coagulation necrosis induced by thermal energy[28].
Complete ablation rate ranged from 20-100%.
Skin burn and moderate pain after procedure may be encountered.
CONCLUSION
Percutaneous ablation approaches have been shown to be technically feasible for the treatment of primary breast cancer.
If compared with the standard surgical treatment,
these minimally invasive techniques represent a low-invasive option in terms of incision,
scarring,
and pain.
While RFA obtained the best results in terms of safety and complete ablation rates,
HIFU is the most promising treatment that needs no skin incision,
thus representing a real non-invasive ablation technique.
However,
complete ablation and complication rate are extremely variable,
with skin and pectoralis burn,
discomfort and pain being the most frequently reported.
The incidence is not low,
even if it has been evaluated in an early stage of technical devolvement.
These techniques may offer a curative treatment to patients who are not suitable for surgery.
They also may reduce morbidity related to overtreatment with less psychological affections,
better cosmetic results,
and shorter hospital stay.