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Cost-effectiveness of ultrasound-guided surgical clips placement for breast cancer localization prior to neoadjuvant chemotherapy
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
Contents lists available at ScienceDirect
The Egyptian Journal of Radiology and Nuclear Medicine journal homepage: www.elsevier.com/locate/ejrnm
Original Article
Cost-effectiveness of ultrasound-guided surgical clips placement for breast cancer localization prior to neoadjuvant chemotherapy Ahmed H. Soliman, Ahmed M. Osman
⁎
Radiology Department – Faculty of Medicine, Ain Shams University, Cairo, Egypt
A R T I C LE I N FO
A B S T R A C T
Keywords: Surgical clips Ultrasound-guided Breast cancer Neoadjuvant chemotherapy
Objective: To evaluate the outcome and the cost value of surgical clips use as guidance for breast cancer localization in patients prepared for neoadjuvant chemotherapy (NAC). Methods: A prospective study of 43 patients confirmed histopathologically to have breast cancer and prepared to receive pre-operative NAC. Surgical clips were inserted via US guidance. The patients were followed up by mammography and US before surgery to evaluate the treatment response meanwhile, assessment of clips location, migration and complications. The overall cost of clips was also calculated. Results: Only 32 patients completed the study; the mean time interval was 32 weeks ± 2 weeks between the clip insertion date and the surgery. The number of the inserted clips was 34 surgical clips. Only two cases showed positive migration yet with no evidence of other complications occurred in our study patients. The average cost of the surgical clips was 145 ± 20 Egyptian pounds (average 8–9 US$). Conclusion: Surgical clips can be used safely to replace the usual commercial markers in the localization of breast cancer before NAC. They showed effective results with no complications, don't interfere with the patients' imaging and of the significant low cost compared to the commercial ones.
1. Introduction Breast malignancy is one of commonest tumor affecting the women, representing 31% of overall tumors affecting the female population. Also, 10% of the females have the risk of developing breast cancer at some stage in their life. The incidence and mortality of breast cancer are directly related to the female age [1,2]. The increase in breast cancer incidence is accompanied by an increase in the clinician and researchers concerns regarding the improvement of diagnostic and therapeutic tools [3]. The treatment options and the characteristics determining the therapy choice in patients with primary advanced breast cancer are becoming variable. New targeted therapies are now available in combination with the usual chemotherapy exerting dramatic change in the treatment strategy of breast cancer over the last 10 years [4]. Neoadjuvant chemotherapy (NAC) made a revolution in the management of patients with operable and inoperable breast cancer. Multiple studies demonstrated the significant response of the primary breast lesion to the NAC with success rates reaching to about 80–90% [5,6]. The value of NAC appeared in decreasing the mortality incidence,
changing the surgical approach as the use of breast conservative surgery and convert the inoperable lesions into operable ones [5,7,8]. The response of breast cancer to NAC assessed using pathologic complete remission (pCR). The American Food and Drug Administration (FDA) made a worldwide large meta-analysis study on approximately 12,000 patients. The prognostic relevance of pCR for recurrence-free survival and overall survival (HR 0.48, p < 0.001) was confirmed. So, the NAC now becomes a new challenging concept for the surgeons and the radiologists as this dramatic pCR hinder proper localization of any residual tissue by the surgeon or even make a satisfactory reconstructive surgery [9]. To avoid these complications, the international breast cancer specialist panel in 2006 and 2010 alarming the importance of radiopaque marker localization into the breast tumor before NAC start. The radiopaque marker implant in the tumor bed became a safe and recommended method for tumor localization before surgical resection or even reconstructive surgery in patients who received NAC [10,11]. In a study by Edeiken et al., the metallic markers were only remaining with a complete absence of the original tumor in 47% of the studied patients with cancer breast [12]. Application of breast markers adds more progress in the field of
Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine. ⁎ Corresponding author. E-mail address: [email protected] (A.M. Osman). https://doi.org/10.1016/j.ejrnm.2018.06.010 Received 14 November 2017; Accepted 20 June 2018 0378-603X/ © 2018 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Please cite this article as: Soliman, A.H., The Egyptian Journal of Radiology and Nuclear Medicine, https://doi.org/10.1016/j.ejrnm.2018.06.010
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
Fig. 1. CONSORT flow diagram showing number of patients at each phase of the study. Table 1 Demonstrates the number and the percentage of the patients according to the ACR classification as well as the response to the NAC.
ACR classification: ACR 1 ACR 2 ACR 3 Response to NAC: Partial Complete Stationary
Number of patients
Incidence (%)
11 15 6
34.38 46.87 18.75
12 14 6
37.50 43.75 18.75
interventional radiology in concerns with breast cancer as such clips are inserted using the ultrasound-guided technique [13]. Many types of commercial clips and markers are widely available and used prior to NAC. However, they are relatively expensive encouraging the researchers to study less expensive alternatives such as standard titanium surgical clips especially in the third world contraries where the health expenses are of high load for the patients [14]. Our study aimed to investigate the feasibility of using surgical clips as tumor localizations markers studying their effectiveness, complications, and influence on the imaging assessment after NAC, and finally the cost of such procedure.
Fig. 2. A female patient 38 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A and B and diagnosed histopathologically to have invasive duct carcinoma (IDC) grade II. The decision was to take NAC before conservative surgery with the positive clinical response made the mass not more palpable for the surgeon indicating wire application. C image shows the excised malignant specimen with the wire noticed inside (black arrow indicating the wire and the black star indicating the mass) (the nipple is covered by white color tag). 2
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
Fig. 3. A female patient 53 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and diagnosed histopathologically to have invasive duct carcinoma (IDC) grade II with no ductal carcinoma in situ (DCIS). The decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed the surgical clips are migrated outside the remaining lesions, showing positive regressive response to the NAC. The rest of the breast categorized as ACR 1.
2. Patients & Methods
2.3. US-guided clip placement:
• Ultrasound machine: we used Logic P5 ultrasound machine (GE –
2.1. Patients A prospective study conducted on 43 patients who came to the Radiology Department – Intervention unit - Ain Shams University Hospital presented with pathologically proved malignant breast lesion (BIRAD VI). They were prepared to receive NAC before surgery and in need for clip placement for tumor localization over the period from January 2016 to August 2017. Informed written consents were taken from all patients according to the ethical committee regulations. The decision of clip placement was made by a multidisciplinary team including a surgeon, oncologist, radiologist and pathologist after patients' agreement. The maneuver was done by consultant radiologist with 3 years experience in the interventional radiology field.
• •
2.2. Patient preparation No specific preparation needed apart from bleeding profile. Patients with a high bleeding profile or patients with no available histopathological data for the breast lesions were excluded from the study.
3
General Electric Healthcare - USA) during the surgical clip insertion and during the follow-up. Mammography machine: we used Mammomat 1000 mammography machine (Siemens Medical Solutions Company - Germany) during follow up. Technique: All patients were placed in adequate position according to the site of the lesion with both arms elevated uncovering the neck and breast regions. Adequate localization of the breast lesion was done using the US followed by skin sterilization of the affected breast and the expected site of entrance in a circumferential manner. Local anesthesia (Lidocaine 1%) was applied with a dose 10 ml/kg being infiltrated along the skin, epidermal layer as well as along the expected track of needle entrance. A small skin incision was done using scalpel blade size 10. Disposable Guillotine biopsy needle 16 G x 20 cm GTA® was used, where we removed the needle stylet and fit single GRENA® surgical titanium ligation clips into the bore of the needle transducer. The needle was advanced along the anesthetized track directed to the targeted mass, then the stylet was used to diploy the titanium clip 2–4 mm after initial penetration of the mass into the center of the lesion, followed by removal of the whole biopsy needle with the stylet. The sonomammography examination
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
o The surgical clips location in relation to the breast lesion either “within” or “outside” the tumor with an assessment of the degree of migration compared to the last mammography done before NAC. o The degree of artifact exerted by the inserted clips and to what extent interfering with the image interpretation and judgment. The patients were sent back to the Intervention radiology Department prior to surgery to assess whether the lesion disappeared or shrunken and not more palpable to the surgeon for wire localization over the already placed clips after confirmation no migration. The surgical specimens were examined by frozen section intra-operatively and paraffin block post surgery with an assessment of the clips localization. The feedback from the surgeons and pathologist were collected for all patients about the adequate localization of the surgical clips and presence of migration in any case.
Fig. 4. The ultrasound of the same case of Fig. 2 done after clip insertion showing the surgical clips within the tumor mass (white arrow) with no significant artifact interfering with the image interpretation.
was done after finishing to ensure the adequate location of the clips. The wound was covered using Steristrips cover. The whole cost of the procedure was calculated and recorded.
2.5. Analysis of data the analysis of data was done using IBM SPSS statistics (V. 24.0, IBM Corp., USA, 2016). Quantitative and qualitative data are expressed as mean ± SD, frequencies, and percentages. The cost of surgical clips was compared to the commercial clips.
2.4. Follow up after NAC The patients were followed up after finishing the course of the NAC and before the surgery by both US and mammography with the calculation of the time gap between clip placement and the time of surgery. The follow up was done via two experts radiologist in the field of breast imaging with experience at least five years and not involved in the study. The following were assessed during the pre-operative follow up:
3. Results 32 cases out of 43 cases completed the study till the surgery level (Fig. 1). 2 patients were excluded from the study due to inadequate bleeding profile and nonavailable histopathological data about the
Fig. 5. A female patient 48 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and diagnosed histopathologically to have infiltrative ductal carcinoma grade II with decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed the surgical clips are migrated outside the remaining lesions, showing positive regressive response to the NAC. The rest of the breast categorized as ACR 1. 4
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
Fig. 6. A female patient 40 years old presented with right breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and diagnosed histopathologically to have lobular carcinoma with decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed complete response of the tumor to the NAC with radiological disappearance of the tumor. C images shows the surgical clips are still seen in the same site compared to the previous studies (B).
with images interpretation. No other complications recorded. The mean cost of surgical clips application was 145 ± 20 LE Egyptian pounds (about 8–9 US $) with the average cost of the needle = 130 LE Egyptian pounds and the clip = 15 LE Egyptian pounds
breast lesion. 4 patients refused to participate in such study and another 2 didn't attend the date of US-guided clip placement. 3 patients were lost during the follow-up stage. The age of the patients ranged from 28 to 76 years old with the mean age ± SD was 51.28 ± 12.2 years. ACR classification of patients revealed that 15 patients classified as ACR 2 representing 46.87% of the cases (Table 1). Two cases showed bilateral malignant breast lesions while the others showed one lesion in both breasts. We used 34 surgical clips to localize 34 lesions within 32 patients. The mean time interval between the insertion date to the time of surgery was 32 weeks ± 2 week. 14 cases showed pCR between the studied patients representing 43.75% while only 6 cases showed stationary course after NAC representing 18.75% (Table 1). 26 patients showed clinical improvement and lesions became no more palpable after NAC representing 81.25% underwent guide wire application before the time of surgery (Fig. 2). Only two cases representing 6.25% showed positive migration on preoperative follows diagnosed when comparing the follow-up mammogram with the old one done before the start of NAC. This is also confirmed by the surgeons' and pathologists' feedback who recorded absent of migration in any other cases. These two cases were categorized as patients with breast type ACR 1 with predominant fatty elements (Figs. 3–6). The radiologists responsible for follow up recorded 3 cases with ultrasound artifacts representing 9.4% yet not interfering
4. Discussion This study demonstrates the significant value of using metallic surgical clips in breast tumor localization in patients undergoing NAC before surgical treatment with a significant reduction in total cost when compared to the commercial clips without significant complications. NAC is a standard pre-operative treatment for breast cancer, especially in locally advanced cases. It is used to convert the inoperable masses into operable one with fewer complications and better cosmetic outcome [14]. Because the unexpected response of the tumor to the NAC which may be adequate up to complete radiological response associated with difficult identification of the tumor site by the surgeon during surgery raises the use of radiopaque markers before NAC start [7,11,15]. In our study, there were 14 cases had a complete radiological response after NAC. This is close to Edeiken et al, who found 47% complete response yet considered high in controversy to other studies such as Dash et al. who found 21.4% out of 28 patients [12,16]. 5
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
effect of the surgical clips on the MRI image and whether it will interfere with the image quality and the judgment of the response to the NAC. The non-use of MRI was due to the high cost as well as the long waiting lists. So, further studies needed including the MRI during preoperative follow up after clip placement. Also, multi-centric study is needed to study this technique over larger number of patients.
In this study, we tried to use the surgical clips instead of the commercial breast markers trying to reduce the cost of this procedure. This was done using US-guided semi-automated technique using a guiding needle (Disposable Guillotine biopsy needle). Multiple studies used the similar semi-automated technique [14,15] which is considered a safe and easy procedure similar to the core needle biopsy done completely under real-time ultrasound and accurately identifying the desired location for the surgical clips insertion with an estimated time of the whole procedure about 7–10 min. This is in controversy to Lee et al. (2005) and Uematsu (2007) who used an automated gun for clip placement [17,18]. The disadvantage of the automated technique is the relatively high cost when compared with the use of disposable biopsy needle. No complications occurred among our study group apart from 2 cases reported having positive migration during preoperative follow up when comparing the preoperative mammogram with the one done before the start of NAC. These two cases observed to have partial response to the NAC and categorized as patients with breast type ACR 1 with predominant fatty elements which may be an explanation for the occurrence of this complication due to redundant breast tissue interfering with the fixation of surgical clips especially after decrease in the size of the mass soft tissue which is an important factor for clip fixation and stability. This result wasn't in agreement with Masroor et al and Youn et al who studied the feasibility of surgical clips use as breast marker and found no cases with clip migration [14,15]. The incidence and occurrence of clip and breast marker migration were discussed in a lot of research works [19,20,21]. During follow up, only 3 cases recorded artifact in the US yet not interfering with the judgment upon the tumor assessment and response to NAC. This is similar to a lot of studies which concluded that the application of surgical clips does not interfere with the radiological assessment of the lesion [11,16,22,23]. Our study revealed that the average cost of the single surgical clip for each patient was 145 ± 20 LE Egyptian pounds at the time of the study which is almost equal to 8–9 US$. This is was almost in agreement with Masroor et al study done in Aga Khan University Hospital, Pakistan since 2014 who found the cost of surgical clips about 9 US$ [14]. Also, this result was close to the study done in South Korea since 2015 with estimated cost was 10 US$ per clip [15]. This is of much low cost when compared to the commercial breast markers of different companies with an estimated price range for clip = 75–200 US$ (average 90 US$) [15]. So, using surgical clips in our study saved about 80–82 US$ for each clip placement when calculated to our study group (34 × 80 US$ = 2720 US$). So, the use of surgical clips of the highly significant low cost compared to the commercial breast marker especially in developing countries as Egypt. Finally due to the adequate response to NAC, 26 cases in our study represented 81.25% had nonpalpable breast masses as mentioned in result section after NAC and subsequently, the decision was to apply breast wire localization for the surgeon over the previously inserted surgical clips. This is the same technique explained by multiple authors as Corsi et al and Sajid et al. [24,25].
References [1] Guraly M, Sahin A. Benign breast diseases: Classification, Diagnosis, and Management. Oncologist 2006;11(5):435–49. [2] VanderWalde A, Hurria A. Early breast cancer in the older woman. Clin Geriatr Med 2012;28:73–91. [3] Guo Y, Cai Y, Cai Z. Differentiation of clinically benign and malignant breast lesions using diffusion-weighted imaging. J Magn Reson Imaging 2002;16(2):172–8. [4] Gerber D. Targeted therapies: A new generation of cancer treatments. Am Fam Physician 2008;77(3):311–9. [5] Adel-Razeq H, Marei L. Current neoadjuvant treatment options for HER2-positive breast cancer. Biologics 2011;5:87–94. [6] Lobbes MB, Prevos R, Smidt M, et al. The role of magnetic resonance imaging in assessing residual disease and pathologic complete response in breast cancer patients receiving neoadjuvant chemotherapy: a systematic review. Insights Imaging 2013;4:163–75. [7] Kaufmann M, Von Minckwitz G, Bear H, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol 2007;18:1927–34. [8] Kim Z, Min SY, Cs Yoon, et al. The basic facts of Korean breast cancer in 2011: results of a nationwide survey and breast cancer registry database. J Breast Cancer 2014;17:99–106. [9] Wang-Lopez Q, Chalabi N, Abrial C, et al. Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer? Critic Rev Oncol/Hematol 2015;95:88–104. [10] Cardoso F, Loibl S, Pagani O, et al. The European society of breast cancer specialists recommendations for the management of young women with breast cancer. Eur J Cancer 2012;48(18):3355–77. [11] Oh JL, Nguyen G, Whitman G, et al. Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy and breast conservation therapy. Cancer 2007;110(11):2420–7. [12] Edeiken BS, Fornage BD, Bedi DG, et al. US-guided implantation of metallic markers for permanent localization of the tumor bed in patients with breast cancer who undergo preoperative chemotherapy. Radiology 1999;213:895–900. [13] Plantade R. Interventional radiology: the corner-stone of breast management. Diagn Interventional Imaging 2013;94(6):575–91. [14] Masroor I, Zeeshan S, Afzal S, et al. Outcome and cost-effectiveness of ultrasonographically guided surgical clip placement for tumor localization in patients undergoing neoadjuvant chemotherapy for breast cancer. Asian Pac J Cancer Prev 2016;16(18):8339–43. [15] Youn I, Choi SH, Kook SH, et al. Ultrasonography-guided surgical clip placement for tumor localization in patients undergoing neoadjuvant chemotherapy for breast cancer. J Breast Cancer 2015;18(1):44–9. [16] Dash N, Chafin S, Johnson R, et al. Usefulness of tissue marker clips in patients undergoing neoadjuvant chemotherapy for breast cancer. Am J Roentgenol 1999;173:911–7. [17] Lee SY, Kook SH, Kwag HJ. The results and usefulness of marker clip placement after ultrasound-guided mammotome excision of breast lesion. J Korean Radiol Soc 2005;52:207–13. [18] Uematsu T. Commercially available titanium clip placement following a sonographically guided core needle biopsy of breast. Breast J 2007;13:624–6. [19] Esserman L, Cura M, DaCosta D. Recognizing pitfalls in early and late migration of clip markers after imaging-guided directional vacuum-assisted biopsy. Radiographics 2004;24(1):147–56. [20] Le-Petross H, Hess K, Knudtson J, et al. Effect of mammography on marker clip migration after stereotactic-guided core needle breast biopsy. Curr Probl Diagn Radiol 2017;46(6):410–4. [21] Jain A, Khalid M, Qureshi M, et al. Stereotactic core needle breast biopsy marker migration: an analysis of factors contributing to immediate marker migration. Eur Radiol 2017;27(11):4797–803. [22] Baron LF, Baron PL, Ackerman SJ, et al. Sonographically guided clip placement facilitates localization of breast cancer after neoadjuvant chemotherapy. Am J Roentgenol 2000;174:539–40. [23] Genson CC, Blane CE, et al. Effects on breast MRI of artifacts caused by metallic tissue marker clips. Am J Roentgenol 2007;188:372–6. [24] Corsi F, Sorrentino L, Sartani A, et al. Preoperative localization and surgical margins in conservative breast surgery. [25] Sajid MS, Parampalli U, Haider Z, et al. Comparison of radioguided occult lesion localization (ROLL) and wire localization for non-palpable breast cancers: a metaanalysis. J Surg Oncol 105(8):852–8.
5. Conclusion The use of breast marker is mandatory before NAC start with the use of surgical clips is of high value being effective with no evidence of complication and of course of the significant low cost compared with the commercial breast clips. 6. Limitations We didn't follow up the patients using MRI to study the artifact
6
Contents lists available at ScienceDirect
The Egyptian Journal of Radiology and Nuclear Medicine journal homepage: www.elsevier.com/locate/ejrnm
Original Article
Cost-effectiveness of ultrasound-guided surgical clips placement for breast cancer localization prior to neoadjuvant chemotherapy Ahmed H. Soliman, Ahmed M. Osman
⁎
Radiology Department – Faculty of Medicine, Ain Shams University, Cairo, Egypt
A R T I C LE I N FO
A B S T R A C T
Keywords: Surgical clips Ultrasound-guided Breast cancer Neoadjuvant chemotherapy
Objective: To evaluate the outcome and the cost value of surgical clips use as guidance for breast cancer localization in patients prepared for neoadjuvant chemotherapy (NAC). Methods: A prospective study of 43 patients confirmed histopathologically to have breast cancer and prepared to receive pre-operative NAC. Surgical clips were inserted via US guidance. The patients were followed up by mammography and US before surgery to evaluate the treatment response meanwhile, assessment of clips location, migration and complications. The overall cost of clips was also calculated. Results: Only 32 patients completed the study; the mean time interval was 32 weeks ± 2 weeks between the clip insertion date and the surgery. The number of the inserted clips was 34 surgical clips. Only two cases showed positive migration yet with no evidence of other complications occurred in our study patients. The average cost of the surgical clips was 145 ± 20 Egyptian pounds (average 8–9 US$). Conclusion: Surgical clips can be used safely to replace the usual commercial markers in the localization of breast cancer before NAC. They showed effective results with no complications, don't interfere with the patients' imaging and of the significant low cost compared to the commercial ones.
1. Introduction Breast malignancy is one of commonest tumor affecting the women, representing 31% of overall tumors affecting the female population. Also, 10% of the females have the risk of developing breast cancer at some stage in their life. The incidence and mortality of breast cancer are directly related to the female age [1,2]. The increase in breast cancer incidence is accompanied by an increase in the clinician and researchers concerns regarding the improvement of diagnostic and therapeutic tools [3]. The treatment options and the characteristics determining the therapy choice in patients with primary advanced breast cancer are becoming variable. New targeted therapies are now available in combination with the usual chemotherapy exerting dramatic change in the treatment strategy of breast cancer over the last 10 years [4]. Neoadjuvant chemotherapy (NAC) made a revolution in the management of patients with operable and inoperable breast cancer. Multiple studies demonstrated the significant response of the primary breast lesion to the NAC with success rates reaching to about 80–90% [5,6]. The value of NAC appeared in decreasing the mortality incidence,
changing the surgical approach as the use of breast conservative surgery and convert the inoperable lesions into operable ones [5,7,8]. The response of breast cancer to NAC assessed using pathologic complete remission (pCR). The American Food and Drug Administration (FDA) made a worldwide large meta-analysis study on approximately 12,000 patients. The prognostic relevance of pCR for recurrence-free survival and overall survival (HR 0.48, p < 0.001) was confirmed. So, the NAC now becomes a new challenging concept for the surgeons and the radiologists as this dramatic pCR hinder proper localization of any residual tissue by the surgeon or even make a satisfactory reconstructive surgery [9]. To avoid these complications, the international breast cancer specialist panel in 2006 and 2010 alarming the importance of radiopaque marker localization into the breast tumor before NAC start. The radiopaque marker implant in the tumor bed became a safe and recommended method for tumor localization before surgical resection or even reconstructive surgery in patients who received NAC [10,11]. In a study by Edeiken et al., the metallic markers were only remaining with a complete absence of the original tumor in 47% of the studied patients with cancer breast [12]. Application of breast markers adds more progress in the field of
Peer review under responsibility of The Egyptian Society of Radiology and Nuclear Medicine. ⁎ Corresponding author. E-mail address: [email protected] (A.M. Osman). https://doi.org/10.1016/j.ejrnm.2018.06.010 Received 14 November 2017; Accepted 20 June 2018 0378-603X/ © 2018 The Egyptian Society of Radiology and Nuclear Medicine. Production and hosting by Elsevier. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
Please cite this article as: Soliman, A.H., The Egyptian Journal of Radiology and Nuclear Medicine, https://doi.org/10.1016/j.ejrnm.2018.06.010
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
Fig. 1. CONSORT flow diagram showing number of patients at each phase of the study. Table 1 Demonstrates the number and the percentage of the patients according to the ACR classification as well as the response to the NAC.
ACR classification: ACR 1 ACR 2 ACR 3 Response to NAC: Partial Complete Stationary
Number of patients
Incidence (%)
11 15 6
34.38 46.87 18.75
12 14 6
37.50 43.75 18.75
interventional radiology in concerns with breast cancer as such clips are inserted using the ultrasound-guided technique [13]. Many types of commercial clips and markers are widely available and used prior to NAC. However, they are relatively expensive encouraging the researchers to study less expensive alternatives such as standard titanium surgical clips especially in the third world contraries where the health expenses are of high load for the patients [14]. Our study aimed to investigate the feasibility of using surgical clips as tumor localizations markers studying their effectiveness, complications, and influence on the imaging assessment after NAC, and finally the cost of such procedure.
Fig. 2. A female patient 38 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A and B and diagnosed histopathologically to have invasive duct carcinoma (IDC) grade II. The decision was to take NAC before conservative surgery with the positive clinical response made the mass not more palpable for the surgeon indicating wire application. C image shows the excised malignant specimen with the wire noticed inside (black arrow indicating the wire and the black star indicating the mass) (the nipple is covered by white color tag). 2
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
Fig. 3. A female patient 53 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and diagnosed histopathologically to have invasive duct carcinoma (IDC) grade II with no ductal carcinoma in situ (DCIS). The decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed the surgical clips are migrated outside the remaining lesions, showing positive regressive response to the NAC. The rest of the breast categorized as ACR 1.
2. Patients & Methods
2.3. US-guided clip placement:
• Ultrasound machine: we used Logic P5 ultrasound machine (GE –
2.1. Patients A prospective study conducted on 43 patients who came to the Radiology Department – Intervention unit - Ain Shams University Hospital presented with pathologically proved malignant breast lesion (BIRAD VI). They were prepared to receive NAC before surgery and in need for clip placement for tumor localization over the period from January 2016 to August 2017. Informed written consents were taken from all patients according to the ethical committee regulations. The decision of clip placement was made by a multidisciplinary team including a surgeon, oncologist, radiologist and pathologist after patients' agreement. The maneuver was done by consultant radiologist with 3 years experience in the interventional radiology field.
• •
2.2. Patient preparation No specific preparation needed apart from bleeding profile. Patients with a high bleeding profile or patients with no available histopathological data for the breast lesions were excluded from the study.
3
General Electric Healthcare - USA) during the surgical clip insertion and during the follow-up. Mammography machine: we used Mammomat 1000 mammography machine (Siemens Medical Solutions Company - Germany) during follow up. Technique: All patients were placed in adequate position according to the site of the lesion with both arms elevated uncovering the neck and breast regions. Adequate localization of the breast lesion was done using the US followed by skin sterilization of the affected breast and the expected site of entrance in a circumferential manner. Local anesthesia (Lidocaine 1%) was applied with a dose 10 ml/kg being infiltrated along the skin, epidermal layer as well as along the expected track of needle entrance. A small skin incision was done using scalpel blade size 10. Disposable Guillotine biopsy needle 16 G x 20 cm GTA® was used, where we removed the needle stylet and fit single GRENA® surgical titanium ligation clips into the bore of the needle transducer. The needle was advanced along the anesthetized track directed to the targeted mass, then the stylet was used to diploy the titanium clip 2–4 mm after initial penetration of the mass into the center of the lesion, followed by removal of the whole biopsy needle with the stylet. The sonomammography examination
The Egyptian Journal of Radiology and Nuclear Medicine xxx (xxxx) xxx–xxx
A.H. Soliman, A.M. Osman
o The surgical clips location in relation to the breast lesion either “within” or “outside” the tumor with an assessment of the degree of migration compared to the last mammography done before NAC. o The degree of artifact exerted by the inserted clips and to what extent interfering with the image interpretation and judgment. The patients were sent back to the Intervention radiology Department prior to surgery to assess whether the lesion disappeared or shrunken and not more palpable to the surgeon for wire localization over the already placed clips after confirmation no migration. The surgical specimens were examined by frozen section intra-operatively and paraffin block post surgery with an assessment of the clips localization. The feedback from the surgeons and pathologist were collected for all patients about the adequate localization of the surgical clips and presence of migration in any case.
Fig. 4. The ultrasound of the same case of Fig. 2 done after clip insertion showing the surgical clips within the tumor mass (white arrow) with no significant artifact interfering with the image interpretation.
was done after finishing to ensure the adequate location of the clips. The wound was covered using Steristrips cover. The whole cost of the procedure was calculated and recorded.
2.5. Analysis of data the analysis of data was done using IBM SPSS statistics (V. 24.0, IBM Corp., USA, 2016). Quantitative and qualitative data are expressed as mean ± SD, frequencies, and percentages. The cost of surgical clips was compared to the commercial clips.
2.4. Follow up after NAC The patients were followed up after finishing the course of the NAC and before the surgery by both US and mammography with the calculation of the time gap between clip placement and the time of surgery. The follow up was done via two experts radiologist in the field of breast imaging with experience at least five years and not involved in the study. The following were assessed during the pre-operative follow up:
3. Results 32 cases out of 43 cases completed the study till the surgery level (Fig. 1). 2 patients were excluded from the study due to inadequate bleeding profile and nonavailable histopathological data about the
Fig. 5. A female patient 48 years old presented with left breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and diagnosed histopathologically to have infiltrative ductal carcinoma grade II with decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed the surgical clips are migrated outside the remaining lesions, showing positive regressive response to the NAC. The rest of the breast categorized as ACR 1. 4
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Fig. 6. A female patient 40 years old presented with right breast upper outer quadrant malignant mass lesion as seen in A1 (CC view) and A2 (MLO view) and diagnosed histopathologically to have lobular carcinoma with decision was to take NAC before conservative surgery. B images show the CC (B1) and MLO (B2) views of the breast after surgical clips insertion showing the surgical clips within the tumor mass. C images representing the mammography images after NAC end showed complete response of the tumor to the NAC with radiological disappearance of the tumor. C images shows the surgical clips are still seen in the same site compared to the previous studies (B).
with images interpretation. No other complications recorded. The mean cost of surgical clips application was 145 ± 20 LE Egyptian pounds (about 8–9 US $) with the average cost of the needle = 130 LE Egyptian pounds and the clip = 15 LE Egyptian pounds
breast lesion. 4 patients refused to participate in such study and another 2 didn't attend the date of US-guided clip placement. 3 patients were lost during the follow-up stage. The age of the patients ranged from 28 to 76 years old with the mean age ± SD was 51.28 ± 12.2 years. ACR classification of patients revealed that 15 patients classified as ACR 2 representing 46.87% of the cases (Table 1). Two cases showed bilateral malignant breast lesions while the others showed one lesion in both breasts. We used 34 surgical clips to localize 34 lesions within 32 patients. The mean time interval between the insertion date to the time of surgery was 32 weeks ± 2 week. 14 cases showed pCR between the studied patients representing 43.75% while only 6 cases showed stationary course after NAC representing 18.75% (Table 1). 26 patients showed clinical improvement and lesions became no more palpable after NAC representing 81.25% underwent guide wire application before the time of surgery (Fig. 2). Only two cases representing 6.25% showed positive migration on preoperative follows diagnosed when comparing the follow-up mammogram with the old one done before the start of NAC. This is also confirmed by the surgeons' and pathologists' feedback who recorded absent of migration in any other cases. These two cases were categorized as patients with breast type ACR 1 with predominant fatty elements (Figs. 3–6). The radiologists responsible for follow up recorded 3 cases with ultrasound artifacts representing 9.4% yet not interfering
4. Discussion This study demonstrates the significant value of using metallic surgical clips in breast tumor localization in patients undergoing NAC before surgical treatment with a significant reduction in total cost when compared to the commercial clips without significant complications. NAC is a standard pre-operative treatment for breast cancer, especially in locally advanced cases. It is used to convert the inoperable masses into operable one with fewer complications and better cosmetic outcome [14]. Because the unexpected response of the tumor to the NAC which may be adequate up to complete radiological response associated with difficult identification of the tumor site by the surgeon during surgery raises the use of radiopaque markers before NAC start [7,11,15]. In our study, there were 14 cases had a complete radiological response after NAC. This is close to Edeiken et al, who found 47% complete response yet considered high in controversy to other studies such as Dash et al. who found 21.4% out of 28 patients [12,16]. 5
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effect of the surgical clips on the MRI image and whether it will interfere with the image quality and the judgment of the response to the NAC. The non-use of MRI was due to the high cost as well as the long waiting lists. So, further studies needed including the MRI during preoperative follow up after clip placement. Also, multi-centric study is needed to study this technique over larger number of patients.
In this study, we tried to use the surgical clips instead of the commercial breast markers trying to reduce the cost of this procedure. This was done using US-guided semi-automated technique using a guiding needle (Disposable Guillotine biopsy needle). Multiple studies used the similar semi-automated technique [14,15] which is considered a safe and easy procedure similar to the core needle biopsy done completely under real-time ultrasound and accurately identifying the desired location for the surgical clips insertion with an estimated time of the whole procedure about 7–10 min. This is in controversy to Lee et al. (2005) and Uematsu (2007) who used an automated gun for clip placement [17,18]. The disadvantage of the automated technique is the relatively high cost when compared with the use of disposable biopsy needle. No complications occurred among our study group apart from 2 cases reported having positive migration during preoperative follow up when comparing the preoperative mammogram with the one done before the start of NAC. These two cases observed to have partial response to the NAC and categorized as patients with breast type ACR 1 with predominant fatty elements which may be an explanation for the occurrence of this complication due to redundant breast tissue interfering with the fixation of surgical clips especially after decrease in the size of the mass soft tissue which is an important factor for clip fixation and stability. This result wasn't in agreement with Masroor et al and Youn et al who studied the feasibility of surgical clips use as breast marker and found no cases with clip migration [14,15]. The incidence and occurrence of clip and breast marker migration were discussed in a lot of research works [19,20,21]. During follow up, only 3 cases recorded artifact in the US yet not interfering with the judgment upon the tumor assessment and response to NAC. This is similar to a lot of studies which concluded that the application of surgical clips does not interfere with the radiological assessment of the lesion [11,16,22,23]. Our study revealed that the average cost of the single surgical clip for each patient was 145 ± 20 LE Egyptian pounds at the time of the study which is almost equal to 8–9 US$. This is was almost in agreement with Masroor et al study done in Aga Khan University Hospital, Pakistan since 2014 who found the cost of surgical clips about 9 US$ [14]. Also, this result was close to the study done in South Korea since 2015 with estimated cost was 10 US$ per clip [15]. This is of much low cost when compared to the commercial breast markers of different companies with an estimated price range for clip = 75–200 US$ (average 90 US$) [15]. So, using surgical clips in our study saved about 80–82 US$ for each clip placement when calculated to our study group (34 × 80 US$ = 2720 US$). So, the use of surgical clips of the highly significant low cost compared to the commercial breast marker especially in developing countries as Egypt. Finally due to the adequate response to NAC, 26 cases in our study represented 81.25% had nonpalpable breast masses as mentioned in result section after NAC and subsequently, the decision was to apply breast wire localization for the surgeon over the previously inserted surgical clips. This is the same technique explained by multiple authors as Corsi et al and Sajid et al. [24,25].
References [1] Guraly M, Sahin A. Benign breast diseases: Classification, Diagnosis, and Management. Oncologist 2006;11(5):435–49. [2] VanderWalde A, Hurria A. Early breast cancer in the older woman. Clin Geriatr Med 2012;28:73–91. [3] Guo Y, Cai Y, Cai Z. Differentiation of clinically benign and malignant breast lesions using diffusion-weighted imaging. J Magn Reson Imaging 2002;16(2):172–8. [4] Gerber D. Targeted therapies: A new generation of cancer treatments. Am Fam Physician 2008;77(3):311–9. [5] Adel-Razeq H, Marei L. Current neoadjuvant treatment options for HER2-positive breast cancer. Biologics 2011;5:87–94. [6] Lobbes MB, Prevos R, Smidt M, et al. The role of magnetic resonance imaging in assessing residual disease and pathologic complete response in breast cancer patients receiving neoadjuvant chemotherapy: a systematic review. Insights Imaging 2013;4:163–75. [7] Kaufmann M, Von Minckwitz G, Bear H, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006. Ann Oncol 2007;18:1927–34. [8] Kim Z, Min SY, Cs Yoon, et al. The basic facts of Korean breast cancer in 2011: results of a nationwide survey and breast cancer registry database. J Breast Cancer 2014;17:99–106. [9] Wang-Lopez Q, Chalabi N, Abrial C, et al. Can pathologic complete response (pCR) be used as a surrogate marker of survival after neoadjuvant therapy for breast cancer? Critic Rev Oncol/Hematol 2015;95:88–104. [10] Cardoso F, Loibl S, Pagani O, et al. The European society of breast cancer specialists recommendations for the management of young women with breast cancer. Eur J Cancer 2012;48(18):3355–77. [11] Oh JL, Nguyen G, Whitman G, et al. Placement of radiopaque clips for tumor localization in patients undergoing neoadjuvant chemotherapy and breast conservation therapy. Cancer 2007;110(11):2420–7. [12] Edeiken BS, Fornage BD, Bedi DG, et al. US-guided implantation of metallic markers for permanent localization of the tumor bed in patients with breast cancer who undergo preoperative chemotherapy. Radiology 1999;213:895–900. [13] Plantade R. Interventional radiology: the corner-stone of breast management. Diagn Interventional Imaging 2013;94(6):575–91. [14] Masroor I, Zeeshan S, Afzal S, et al. Outcome and cost-effectiveness of ultrasonographically guided surgical clip placement for tumor localization in patients undergoing neoadjuvant chemotherapy for breast cancer. Asian Pac J Cancer Prev 2016;16(18):8339–43. [15] Youn I, Choi SH, Kook SH, et al. Ultrasonography-guided surgical clip placement for tumor localization in patients undergoing neoadjuvant chemotherapy for breast cancer. J Breast Cancer 2015;18(1):44–9. [16] Dash N, Chafin S, Johnson R, et al. Usefulness of tissue marker clips in patients undergoing neoadjuvant chemotherapy for breast cancer. Am J Roentgenol 1999;173:911–7. [17] Lee SY, Kook SH, Kwag HJ. The results and usefulness of marker clip placement after ultrasound-guided mammotome excision of breast lesion. J Korean Radiol Soc 2005;52:207–13. [18] Uematsu T. Commercially available titanium clip placement following a sonographically guided core needle biopsy of breast. Breast J 2007;13:624–6. [19] Esserman L, Cura M, DaCosta D. Recognizing pitfalls in early and late migration of clip markers after imaging-guided directional vacuum-assisted biopsy. Radiographics 2004;24(1):147–56. [20] Le-Petross H, Hess K, Knudtson J, et al. Effect of mammography on marker clip migration after stereotactic-guided core needle breast biopsy. Curr Probl Diagn Radiol 2017;46(6):410–4. [21] Jain A, Khalid M, Qureshi M, et al. Stereotactic core needle breast biopsy marker migration: an analysis of factors contributing to immediate marker migration. Eur Radiol 2017;27(11):4797–803. [22] Baron LF, Baron PL, Ackerman SJ, et al. Sonographically guided clip placement facilitates localization of breast cancer after neoadjuvant chemotherapy. Am J Roentgenol 2000;174:539–40. [23] Genson CC, Blane CE, et al. Effects on breast MRI of artifacts caused by metallic tissue marker clips. Am J Roentgenol 2007;188:372–6. [24] Corsi F, Sorrentino L, Sartani A, et al. Preoperative localization and surgical margins in conservative breast surgery. [25] Sajid MS, Parampalli U, Haider Z, et al. Comparison of radioguided occult lesion localization (ROLL) and wire localization for non-palpable breast cancers: a metaanalysis. J Surg Oncol 105(8):852–8.
5. Conclusion The use of breast marker is mandatory before NAC start with the use of surgical clips is of high value being effective with no evidence of complication and of course of the significant low cost compared with the commercial breast clips. 6. Limitations We didn't follow up the patients using MRI to study the artifact
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