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Posts Tagged ‘Cancer Surgery’


Imaging Technology in Cancer Surgery

Author and curator: Dror Nir, PhD

The advent of medical-imaging technologies such as image-fusion, functional-imaging and noninvasive tissue characterisation is playing an imperative role in answering this demand thus transforming the concept of personalized medicine in cancer into practice. The leading modality in that respect is medical imaging. To date, the main imaging systems that can provide reasonable level of cancer detection and localization are: CT, mammography, Multi-Sequence MRI, PET/CT and ultrasound. All of these require skilled operators and experienced imaging interpreters in order to deliver what is required at a reasonable level. It is generally agreed by radiologists and oncologists that in order to provide a comprehensive work-flow that complies with the principles of personalized medicine, future cancer patients’ management will heavily rely on computerized image interpretation applications that will extract from images in a standardized manner measurable imaging biomarkers leading to better clinical assessment of cancer patients.

As consequence of the human genome project and technological advances in gene-sequencing, the understanding of cancer advanced considerably. This led to increase in the offering of treatment options. Yet, surgical resection is still the leading form of therapy offered to patients with organ confined tumors. Obtaining “cancer free” surgical margins is crucial to the surgery outcome in terms of overall survival and patients’ quality of life/morbidity. Currently, a significant portion of surgeries ends up with positive surgical margins leading to poor clinical outcome and increase of costs. To improve on this, large variety of intraoperative imaging-devices aimed at resection-guidance have been introduced and adapted in the last decade and it is expected that this trend will continue.

The Status of Contemporary Image-Guided Modalities in Oncologic Surgery is a review paper presenting a variety of cancer imaging techniques that have been adapted or developed for intra-operative surgical guidance. It also covers novel, cancer-specific contrast agents that are in early stage development and demonstrate significant promise to improve real-time detection of sub-clinical cancer in operative setting.

Another good (free access) review paper is: uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery

Abstract

Pre- and intraoperative diagnostic techniques facilitating tumor staging are of paramount importance in colorectal cancer surgery. The urokinase receptor (uPAR) plays an important role in the development of cancer, tumor invasion, angiogenesis, and metastasis and over-expression is found in the majority of carcinomas. This study aims to develop the first clinically relevant anti-uPAR antibody-based imaging agent that combines nuclear (111In) and real-time near-infrared (NIR) fluorescent imaging (ZW800-1). Conjugation and binding capacities were investigated and validated in vitro using spectrophotometry and cell-based assays. In vivo, three human colorectal xenograft models were used including an orthotopic peritoneal carcinomatosis model to image small tumors. Nuclear and NIR fluorescent signals showed clear tumor delineation between 24h and 72h post-injection, with highest tumor-to-background ratios of 5.0 ± 1.3 at 72h using fluorescence and 4.2 ± 0.1 at 24h with radioactivity. 1-2 mm sized tumors could be clearly recognized by their fluorescent rim. This study showed the feasibility of an uPAR-recognizing multimodal agent to visualize tumors during image-guided resections using NIR fluorescence, whereas its nuclear component assisted in the pre-operative non-invasive recognition of tumors using SPECT imaging. This strategy can assist in surgical planning and subsequent precision surgery to reduce the number of incomplete resections.

INTRODUCTION
Diagnosis, staging, and surgical planning of colorectal cancer patients increasingly rely on imaging techniques that provide information about tumor biology and anatomical structures [1-3]. Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are preoperative nuclear imaging modalities used to provide insights into tumor location, tumor biology, and the surrounding micro-environment [4]. Both techniques depend on the recognition of tumor cells using radioactive ligands. Various monoclonal antibodies, initially developed as therapeutic agents (e.g. cetuximab, bevacizumab, labetuzumab), are labeled with radioactive tracers and evaluated for pre-operative imaging purposes [5-9]. Despite these techniques, during surgery the surgeons still rely mostly on their eyes and hands to distinguish healthy from malignant tissues, resulting in incomplete resections or unnecessary tissue removal in up to 27% of rectal cancer patients [10, 11]. Incomplete resections (R1) are shown to be a strong predictor of development of distant metastasis, local recurrence, and decreased survival of colorectal cancer patients [11, 12]. Fluorescence-guided surgery (FGS) is an intraoperative imaging technique already introduced and validated in the clinic for sentinel lymph node (SLN) mapping and biliary imaging [13]. Tumor-specific FGS can be regarded as an extension of SPECT/PET, using fluorophores instead of radioactive labels conjugated to tumor-specific ligands, but with higher spatial resolution than SPECT/PET imaging and real-time anatomical feedback [14]. A powerful synergy can be achieved when nuclear and fluorescent imaging modalities are combined, extending the nuclear diagnostic images with real-time intraoperative imaging. This combination can lead to improved diagnosis and management by integrating pre-intra and postoperative imaging. Nuclear imaging enables pre-operative evaluation of tumor spread while during surgery deeper lying spots can be localized using the gamma probe counter. The (NIR) fluorescent signal aids the surgeon in providing real-time anatomical feedback to accurately recognize and resect malignant tissues. Postoperative, malignant cells can be recognized using NIR fluorescent microscopy. Clinically, the advantages of multimodal agents in image-guided surgery have been shown in patients with melanoma and prostate cancer, but those studies used a-specific agents, following the natural lymph drainage pattern of colloidal tracers after peritumoral injection [15, 16]. The urokinase-type plasminogen activator receptor (uPAR) is implicated in many aspects of tumor growth and (micro) metastasis [17, 18]. The levels of uPAR are undetectable in normal tissues except for occasional macrophages and granulocytes in the uterus, thymus, kidneys and spleen [19]. Enhanced tumor levels of uPAR and its circulating form (suPAR) are independent prognostic markers for overall survival in colorectal cancer patients [20, 21]. The relatively selective and high overexpression of uPAR in a wide range of human cancers including colorectal, breast, and pancreas nominate uPAR as a widely applicable and potent molecular target [17,22]. The current study aims to develop a clinically relevant uPAR-specific multimodal agent that can be used to visualize tumors pre- and intraoperatively after a single injection. We combined the 111Indium isotope with NIR fluorophore ZW800-1 using a hybrid linker to an uPAR specific monoclonal antibody (ATN-658) and evaluated its performance using a pre-clinical SPECT system (U-SPECT-II) and a clinically-applied NIR fluorescence camera system (FLARE™).

Fig1 Fig2 Fig3

Robotic surgery is a growing trend as a form of surgery, specifically in urology. The following review paper propose a good discussion on the added value of imaging in urologic robotic surgery:

The current and future use of imaging in urological robotic surgery: a survey of the European Association of Robotic Urological Surgeons

 Abstract

Background

With the development of novel augmented reality operating platforms the way surgeons utilize imaging as a real-time adjunct to surgical technique is changing.

Methods

A questionnaire was distributed via the European Robotic Urological Society mailing list. The questionnaire had three themes: surgeon demographics, current use of imaging and potential uses of an augmented reality operating environment in robotic urological surgery.

Results

117 of the 239 respondents (48.9%) were independently practicing robotic surgeons. 74% of surgeons reported having imaging available in theater for prostatectomy 97% for robotic partial nephrectomy and 95% cystectomy. 87% felt there was a role for augmented reality as a navigation tool in robotic surgery.

Conclusions

This survey has revealed the contemporary robotic surgeon to be comfortable in the use of imaging for intraoperative planning it also suggests that there is a desire for augmented reality platforms within the urological community. Copyright © 2014 John Wiley & Sons, Ltd.

 Introduction

Since Röntgen first utilized X-rays to image the carpal bones of the human hand in 1895, medical imaging has evolved and is now able to provide a detailed representation of a patient’s intracorporeal anatomy, with recent advances now allowing for 3-dimensional (3D) reconstructions. The visualization of anatomy in 3D has been shown to improve the ability to localize structures when compared with 2D with no change in the amount of cognitive loading [1]. This has allowed imaging to move from a largely diagnostic tool to one that can be used for both diagnosis and operative planning.

One potential interface to display 3D images, to maximize its potential as a tool for surgical guidance, is to overlay them onto the endoscopic operative scene (augmented reality). This addresses, in part, a criticism often leveled at robotic surgery, the loss of haptic feedback. Augmented reality has the potential to mitigate this sensory loss by enhancing the surgeons visual cues with information regarding subsurface anatomical relationships [2].

Augmented reality surgery is in its infancy for intra-abdominal procedures due in large part to the difficulties of applying static preoperative imaging to a constantly deforming intraoperative scene [3]. There are case reports and ex vivo studies in the literature examining the technology in minimal access prostatectomy [3-6] and partial nephrectomy [7-10], but there remains a lack of evidence determining whether surgeons feel there is a role for the technology and if so for what procedures they feel it would be efficacious.

This questionnaire-based study was designed to assess first, the pre- and intra-operative imaging modalities utilized by robotic urologists; second, the current use of imaging intraoperatively for surgical planning; and finally whether there is a desire for augmented reality among the robotic urological community.

Methods

Recruitment

A web based survey instrument was designed and sent out, as part of a larger survey, to members of the EAU robotic urology section (ERUS). Only independently practicing robotic surgeons performing robot-assisted laparoscopic prostatectomy (RALP), robot-assisted partial nephrectomy (RAPN) and/or robotic cystectomy were included in the analysis, those surgeons exclusively performing other procedures were excluded. Respondents were offered no incentives to reply. All data collected was anonymous.

Survey design and administration

The questionnaire was created using the LimeSurvey platform (www.limesurvey.com) and hosted on their website. All responses (both complete and incomplete) were included in the analysis. The questionnaire was dynamic with the questions displayed tailored to the respondents’ previous answers.

When computing fractions or percentages the denominator was the number of respondents to answer the question, this number is variable due to the dynamic nature of the questionnaire.

Demographics

All respondents to the survey were asked in what country they practiced and what robotic urological procedures they performed. In addition to what procedures they performed surgeons were asked to specify the number of cases they had undertaken for each procedure.

 Current imaging practice

Procedure-specific questions in this group were displayed according to the operations the respondent performed. A summary of the questions can be seen in Appendix 1. Procedure-nonspecific questions were also asked. Participants were asked whether they routinely used the Tile Pro™ function of the da Vinci console (Intuitive Surgical, Sunnyvale, USA) and whether they routinely viewed imaging intra-operatively.

 Augmented reality

Before answering questions in this section, participants were invited to watch a video demonstrating an augmented reality platform during RAPN, performed by our group at Imperial College London. A still from this video can be seen in Figure 1. They were then asked whether they felt augmented reality would be of use as a navigation or training tool in robotic surgery.

f1

Figure 1. A still taken from a video of augmented reality robot assisted partial nephrectomy performed. Here the tumour has been painted into the operative view allowing the surgeon to appreciate the relationship of the tumour with the surface of the kidney

Once again, in this section, procedure-specific questions were displayed according to the operations the respondent performed. Only those respondents who felt augmented reality would be of use as a navigation tool were asked procedure-specific questions. Questions were asked to establish where in these procedures they felt an augmented reality environment would be of use.

Results

Demographics

Of the 239 respondents completing the survey 117 were independently practising robotic surgeons and were therefore eligible for analysis. The majority of the surgeons had both trained (210/239, 87.9%) and worked in Europe (215/239, 90%). The median number of cases undertaken by those surgeons reporting their case volume was: 120 (6–2000), 9 (1–120) and 30 (1–270), for RALP, robot assisted cystectomy and RAPN, respectively.

 

Contemporary use of imaging in robotic surgery

When enquiring about the use of imaging for surgical planning, the majority of surgeons (57%, 65/115) routinely viewed pre-operative imaging intra-operatively with only 9% (13/137) routinely capitalizing on the TilePro™ function in the console to display these images. When assessing the use of TilePro™ among surgeons who performed RAPN 13.8% (9/65) reported using the technology routinely.

When assessing the imaging modalities that are available to a surgeon in theater the majority of surgeons performing RALP (74%, 78/106)) reported using MRI with an additional 37% (39/106) reporting the use of CT for pre-operative staging and/or planning. For surgeons performing RAPN and robot-assisted cystectomy there was more of a consensus with 97% (68/70) and 95% (54/57) of surgeons, respectively, using CT for routine preoperative imaging (Table 1).

Table 1. Which preoperative imaging modalities do you use for diagnosis and surgical planning?

  CT MRI USS None Other
RALP (n = 106) 39.8% 73.5% 2% 15.1% 8.4%
(39) (78) (3) (16) (9)
RAPN (n = 70) 97.1% 42.9% 17.1% 0% 2.9%
(68) (30) (12) (0) (2)
Cystectomy (n = 57) 94.7% 26.3% 1.8% 1.8% 5.3%
(54) (15) (1) (1) (3)

Those surgeons performing RAPN were found to have the most diversity in the way they viewed pre-operative images in theater, routinely viewing images in sagittal, coronal and axial slices (Table 2). The majority of these surgeons also viewed the images as 3D reconstructions (54%, 38/70).

Table 2. How do you typically view preoperative imaging in the OR? 3D recons = three-dimensional reconstructions

  Axial slices (n) Coronal slices (n) Sagittal slices (n) 3D recons. (n) Do not view (n)  
RALP (n = 106) 49.1% 44.3% 31.1% 9.4% 31.1%
(52) (47) (33) (10) (33)
RAPN (n = 70) 68.6% 74.3% 60% (42) 54.3% 0%
(48) (52) (38) (0)
Cystectomy (n = 57) 70.2% 52.6% 50.9% 21.1% 8.8%
(40) (30) (29) (12) (5)

The majority of surgeons used ultrasound intra-operatively in RAPN (51%, 35/69) with a further 25% (17/69) reporting they would use it if they had access to a ‘drop-in’ ultrasound probe (Figure 2).

f2

Figure 2. Chart demonstrating responses to the question – Do you use intraoperative ultrasound for robotic partial nephrectomy?

Desire for augmented reality

Overall, 87% of respondents envisaged a role for augmented reality as a navigation tool in robotic surgery and 82% (88/107) felt that there was an additional role for the technology as a training tool.

The greatest desire for augmented reality was among those surgeons performing RAPN with 86% (54/63) feeling the technology would be of use. The largest group of surgeons felt it would be useful in identifying tumour location, with significant numbers also feeling it would be efficacious in tumor resection (Figure 3).

f3

Figure 3. Chart demonstrating responses to the question – In robotic partial nephrectomy which parts of the operation do you feel augmented reality image overlay would be of assistance?

When enquiring about the potential for augmented reality in RALP, 79% (20/96) of respondents felt it would be of use during the procedure, with the largest group feeling it would be helpful for nerve sparing 65% (62/96) (Figure 4). The picture in cystectomy was similar with 74% (37/50) of surgeons believing augmented reality would be of use, with both nerve sparing and apical dissection highlighted as specific examples (40%, 20/50) (Figure 5). The majority also felt that it would be useful for lymph node dissection in both RALP and robot assisted cystectomy (55% (52/95) and 64% (32/50), respectively).

f4

Figure 4. Chart demonstrating responses to the question – In robotic prostatectomy which parts of the operation do you feel augmented reality image overlay would be of assistance?

f5

Figure 5. Chart demonstrating responses to the question – In robotic cystectomy which parts of the operation do you feel augmented reality overlay technology would be of assistance?

Discussion

The results from this study suggest that the contemporary robotic surgeon views imaging as an important adjunct to operative practice. The way these images are being viewed is changing; although the majority of surgeons continue to view images as two-dimensional (2D) slices a significant minority have started to capitalize on 3D reconstructions to give them an improved appreciation of the patient’s anatomy.

This study has highlighted surgeons’ willingness to take the next step in the utilization of imaging in operative planning, augmented reality, with 87% feeling it has a role to play in robotic surgery. Although there appears to be a considerable desire for augmented reality, the technology itself is still in its infancy with the limited evidence demonstrating clinical application reporting only qualitative results [3, 7, 11, 12].

There are a number of significant issues that need to be overcome before augmented reality can be adopted in routine clinical practice. The first of these is registration (the process by which two images are positioned in the same coordinate system such that the locations of corresponding points align [13]). This process has been performed both manually and using automated algorithms with varying degrees of accuracy [2, 14]. The second issue pertains to the use of static pre-operative imaging in a dynamic operative environment; in order for the pre-operative imaging to be accurately registered it must be deformable. This problem remains as yet unresolved.

Live intra-operative imaging circumvents the problems of tissue deformation and in RAPN 51% of surgeons reported already using intra-operative ultrasound to aid in tumour resection. Cheung and colleagues [9] have published an ex vivo study highlighting the potential for intra-operative ultrasound in augmented reality partial nephrectomy. They report the overlaying of ultrasound onto the operative scene to improve the surgeon’s appreciation of the subsurface tumour anatomy, this improvement in anatomical appreciation resulted in improved resection quality over conventional ultrasound guided resection [9]. Building on this work the first in vivo use of overlaid ultrasound in RAPN has recently been reported [10]. Although good subjective feedback was received from the operating surgeon, the study was limited to a single case demonstrating feasibility and as such was not able to show an outcome benefit to the technology [10].

RAPN also appears to be the area in which augmented reality would be most readily adopted with 86% of surgeons claiming they see a use for the technology during the procedure. Within this operation there are two obvious steps to augmentation, anatomical identification (in particular vessel identification to facilitate both routine ‘full clamping’ and for the identification of secondary and tertiary vessels for ‘selective clamping’ [15]) and tumour resection. These two phases have different requirements from an augmented reality platform; the first phase of identification requires a gross overview of the anatomy without the need for high levels of registration accuracy. Tumor resection, however, necessitates almost sub-millimeter accuracy in registration and needs the system to account for the dynamic intra-operative environment. The step of anatomical identification is amenable to the use of non-deformable 3D reconstructions of pre-operative imaging while that of image-guided tumor resection is perhaps better suited to augmentation with live imaging such as ultrasound [2, 9, 16].

For RALP and robot-assisted cystectomy the steps in which surgeons felt augmented reality would be of assistance were those of neurovascular bundle preservation and apical dissection. The relative, perceived, efficacy of augmented reality in these steps correlate with previous examinations of augmented reality in RALP [17, 18]. Although surgeon preference for utilizing augmented reality while undertaking robotic prostatectomy has been demonstrated, Thompson et al. failed to demonstrate an improvement in oncological outcomes in those patients undergoing AR RALP [18].

Both nerve sparing and apical dissection require a high level of registration accuracy and a necessity for either live imaging or the deformation of pre-operative imaging to match the operative scene; achieving this level of registration accuracy is made more difficult by the mobilization of the prostate gland during the operation [17]. These problems are equally applicable to robot-assisted cystectomy. Although guidance systems have been proposed in the literature for RALP [3-5, 12, 17], none have achieved the level of accuracy required to provide assistance during nerve sparing. In addition, there are still imaging challenges that need to be overcome. Although multiparametric MRI has been shown to improve decision making in opting for a nerve sparing approach to RALP [19] the imaging is not yet able to reliably discern the exact location of the neurovascular bundle. This said, significant advances are being made with novel imaging modalities on the horizon that may allow for imaging of the neurovascular bundle in the near future [20].

 

Limitations

The number of operations included represents a significant limitation of the study, had different index procedures been chosen different results may have been seen. This being said the index procedures selected were chosen as they represent the vast majority of uro-oncological robotic surgical practice, largely mitigating for this shortfall.

Although the available ex vivo evidence suggests that introducing augmented reality operating environments into surgical practice would help to improve outcomes [9, 21] the in vivo experience to date is limited to small volume case series reporting feasibility [2, 3, 14]. To date no study has demonstrated an in vivo outcome advantage to augmented reality guidance. In addition to this limitation augmented reality has been demonstrated to increased rates of inattention blindness among surgeons suggesting there is a trade-off between increasing visual information and the surgeon’s ability to appreciate unexpected operative events [21].

 

Conclusions

This survey shows the contemporary robotic surgeon to be comfortable with the use of imaging to aid intra-operative planning; furthermore it highlights a significant interest among the urological community in augmented reality operating platforms.

Short- to medium-term development of augmented reality systems in robotic urology surgery would be best performed using RAPN as the index procedure. Not only was this the operation where surgeons saw the greatest potential benefits, but it may also be the operation where it is most easily achievable by capitalizing on the respective benefits of technologies the surgeons are already using; pre-operative CT for anatomical identification and intra-operative ultrasound for tumour resection.

 

Conflict of interest

None of the authors have any conflicts of interest to declare.

Appendix 1

Question Asked Question Type
Demographics
In which country do you usually practise? Single best answer
Which robotic procedures do you perform?* Single best answer
Current Imaging Practice
What preoperative imaging modalities do you use for the staging and surgical planning in renal cancer? Multiple choice
How do you typically view preoperative imaging in theatre for renal cancer surgery? Multiple choice
Do you use intraoperative ultrasound for partial nephrectomy? Yes or No
What preoperative imaging modalities do you use for the staging and surgical planning in prostate cancer? Multiple choice
How do you typically view preoperative imaging in theatre for prostate cancer? Multiple choice
Do you use intraoperative ultrasound for robotic partial nephrectomy? Yes or No
Which preoperative imaging modality do you use for staging and surgical planning in muscle invasive TCC? Multiple choice
How do you typically view preoperative imaging in theatre for muscle invasive TCC? Multiple choice
Do you routinely refer to preoperative imaging intraoperativley? Yes or No
Do you routinely use Tilepro intraoperativley? Yes or No
Augmented Reality
Do you feel there is a role for augmented reality as a navigation tool in robotic surgery? Yes or No
Do you feel there is a role for augmented reality as a training tool in robotic surgery? Yes or No
In robotic partial nephrectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
In robotic nephrectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
In robotic prostatectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
Would augmented reality guidance be of use in lymph node dissection in robotic prostatectomy? Yes or No
In robotic cystectomy which parts of the operation do you feel augmented reality image overlay technology would be of assistance? Multiple choice
Would augmented reality guidance be of use in lymph node dissection in robotic cystectomy? Yes or No
*The relevant procedure related questions were displayed based on the answer to this question

References

1. Foo J-L, Martinez-Escobar M, Juhnke B, et al.Evaluating mental workload of two-dimensional and three-dimensional visualization for anatomical structure localization. J Laparoendosc Adv Surg Tech A 2013; 23(1):65–70.

2. Hughes-Hallett A, Mayer EK, Marcus HJ, et al.Augmented reality partial nephrectomy: examining the current status and future perspectives. Urology 2014; 83(2): 266–273.

3. Sridhar AN, Hughes-Hallett A, Mayer EK, et al.Image-guided robotic interventions for prostate cancer. Nat Rev Urol 2013; 10(8): 452–462.

4. Cohen D, Mayer E, Chen D, et al.Eddie’ Augmented reality image guidance in minimally invasive prostatectomy. Lect Notes Comput Sci 2010; 6367: 101–110.

5. Simpfendorfer T, Baumhauer M, Muller M, et al.Augmented reality visualization during laparoscopic radical prostatectomy. J Endourol 2011; 25(12): 1841–1845.

6. Teber D, Simpfendorfer T, Guven S, et al.In vitro evaluation of a soft-tissue navigation system for laparoscopic prostatectomy. J Endourol 2010; 24(9): 1487–1491.

7. Teber D, Guven S, Simpfendörfer T, et al.Augmented reality: a new tool to improve surgical accuracy during laparoscopic partial nephrectomy? Preliminary in vitro and in vivo Eur Urol 2009; 56(2): 332–338.

8. Pratt P, Mayer E, Vale J, et al.An effective visualisation and registration system for image-guided robotic partial nephrectomy. J Robot Surg 2012; 6(1): 23–31.

9. Cheung CL, Wedlake C, Moore J, et al.Fused video and ultrasound images for minimally invasive partial nephrectomy: a phantom study. Med Image Comput Comput Assist Interv 2010; 13(Pt 3): 408–415.

10. Hughes-Hallett A, Pratt P, Mayer E, et al.Intraoperative ultrasound overlay in robot-assisted partial nephrectomy: first clinical experience. Eur Urol 2014; 65(3): 671–672.

11. Nakamura K, Naya Y, Zenbutsu S, et al.Surgical navigation using three-dimensional computed tomography images fused intraoperatively with live video. J Endourol 2010; 24(4): 521–524.

12. Ukimura O, Gill IS. Imaging-assisted endoscopic surgery: Cleveland clinic experience. J Endourol2008; 22(4):803–809.

13. Altamar HO, Ong RE, Glisson CL, et al.Kidney deformation and intraprocedural registration: a study of elements of image-guided kidney surgery. J Endourol 2011; 25(3): 511–517.

14. Nicolau S, Soler L, Mutter D, Marescaux J. Augmented reality in laparoscopic surgical oncology. Surg Oncol2011; 20(3): 189–201.

15. Ukimura O, Nakamoto M, Gill IS. Three-dimensional reconstruction of renovascular-tumor anatomy to facilitate zero-ischemia partial nephrectomy. Eur Urol2012; 61(1): 211–217.

16. Pratt P, Hughes-Hallett A, Di Marco A, et al. Multimodal reconstruction for image-guided interventions. In:Yang GZ, Darzi A (eds) Proceedings of the Hamlyn symposium on medical robotics: London. 2013; 59–61.

17. Mayer EK, Cohen D, Chen D, et al.Augmented reality image guidance in minimally invasive prostatectomy. Eur Urol Supp 2011; 10(2): 300.

18. Thompson S, Penney G, Billia M, et al.Design and evaluation of an image-guidance system for robot-assisted radical prostatectomy. BJU Int 2013; 111(7): 1081–1090.

19. Panebianco V, Salciccia S, Cattarino S, et al.Use of multiparametric MR with neurovascular bundle evaluation to optimize the oncological and functional management of patients considered for nerve-sparing radical prostatectomy. J Sex Med 2012; 9(8): 2157–2166.

20. Rai S, Srivastava A, Sooriakumaran P, Tewari A. Advances in imaging the neurovascular bundle. Curr Opin Urol2012; 22(2): 88–96.

21. Dixon BJ, Daly MJ, Chan H, et al.Surgeons blinded by enhanced navigation: the effect of augmented reality on attention. Surg Endosc 2013; 27(2): 454–461.

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Author: Ziv Raviv, PhD

Introduction

Sarcoma is a general class of cancers of mesenchymal cells that form connective tissues. Sarcoma can start in any part of the body and can be formed in the bones or in soft tissues. Sarcomas are rare cancers as compared to the more common epithelial cancers (carcinomas). Around 15,000 new cases of sarcomas diagnosed in the United States every year. Both children and adults can develop a sarcoma, however, while in adults it accounts for only about 1% of all cancers, sarcoma represents around 15% of all cancers in children.

There are tens of different types of sarcomas. This fact makes a particular type of sarcoma to be even rarer. Being sarcoma an uncommon cancer, it is strongly recommended for patients diagnosed with sarcoma to get consultant and treatment for the disease in sarcoma centers, or at list be treated by an oncologist physician that had experienced with sarcomas.

As stated, sarcomas are cancers of connective tissues, namely tissues that connect the body, holding it together. These tissues include: bones, cartilage, muscle, nerve, blood and lymph vessels, and fat. Therefore, sarcomas nomenclature is based according to the normal tissue type they most closely resemble (as opposed to carcinomas where the nomenclature is based upon the organ or part of the body where cancer is originated). Few examples: Osteosarcoma (OS) – cancer of bones origin; Chondrosarcoma – cancer of cells that produce cartilage; Fibrosarcoma – cancer derived from fibrous connective tissues cells; Rhabdomyosarcoma (RMS) –  cancer from skeletal muscle progenitors; Liposarcoma – cancer that arises in fat cells, etc.

  • Watch a Dana-Farber Cancer Institute – About Sarcoma Video

Soft tissues sarcoma (STS)

Among sarcomas, the group of soft tissues sarcoma (STS) is the largest one, consists of many different types of cancers that origin in soft connective tissues that support and connect overall body parts. STSs account for less than 1% of all new cancer cases where about 11,000 new cases are diagnosed each year in the US, and about 4,000 people are dying from it each year.  STS can occur almost anywhere in the body: about 60% of STSs occur in an arm or leg, 30% in the trunk (torso) or abdomen, and 10% in the head or neck. Because there are many different types of STS, it is more of a family of related cancer diseases then a single one. The specific types of STS are often named according to the normal tissue cells they most closely resemble (see introduction), however, some STSs do not look like any type of normal tissue and are thought to arise from stem cells.  In addition to their tissue resemblance name, STS are characterized with grades and stages (Table I) where low-grade STSs are often local tumors that grow more slowly and are treated surgically (although radiation therapy or chemotherapy may be used occasionally), and intermediate – and high-grade STSs are tumors that are more likely to metastasize and are treated with a combination of surgery, chemotherapy and/or radiation therapy.

Figure 1. STS of the thigh muscle just above the knee.

soft_tissue_sarcoma_leg

Taken from the Mayo Clinic webpage.

Table I: Sarcoma Staging System according to AJCC

Stage

Grade

Size

Location 

Metastasis

IA

Low

< 5cm

Superficial or Deep

No

IB

Low

≥ 5cm

Superficial

No

IIA

Low

≥ 5cm

Deep

No

IIB

High

< 5cm

Superficial or Deep

No

IIC

High

≥ 5cm

Superficial

No

III

High

≥ 5cm

Deep

No

IV

Any

Any

Any

Yes

Adapted from sarcomahelp.org

Diagnosis

In their early stages, STSs usually do not stimulate any symptoms and can grow unnoticed. This is because STSs are grown within soft connective tissues which are elastic and flexible, thus the tumor can develop quite large before being felt and cause any symptoms. The first noticeable symptom is usually a painless lump or swelling, however, since most lumps are not sarcoma they are often misdiagnosed. Eventually, the tumor interferes with normal body activities and cause pain by pressing against nerves and muscles, or if the sarcoma is located at the abdomen the tumor can induce abdominal pains or constipation. Therefore, when STS is suspected it should be examined for any unusual lumps growing to define whether they are malignant even if symptoms are not present, preferred by a sarcoma specialist. There are no standard screening tests for sarcoma. Usually a biopsy of the suspected tumor is taken to evaluate if indeed it is malignant and to define its type and grade. In addition, molecular testing of the tumor could be performed to identify specific genes unique to the tumor. Finally, imaging tests may be used to find out whether the cancer has metastasized.

Prognosis and current treatment

The five-year survival rate for localized-low grade sarcomas is 83%; 54% for intermediate sarcomas (spread to regional lymph nodes); and 16% for high grade STSs that have spread to distant parts of the body to form metastasis. Survival is depended also on tumor size, location, type, mitotic rate, and whether it is superficial or deep.

Surgery

Treatment options depend on the type and stage of cancer, possible side effects, and the patient’s preferences and overall health. Treatment can be a long and arduous process for many patients. Usually STSs are treated with surgery whenever it is possible. Should the tumor is not removable by surgery it may be possible to control its growth with radiation therapy. For a sarcoma that can be surgically removed, radiation therapy and/or chemotherapy may be given before or after surgery to reduce tumor recurrence. Small STSs can usually be effectively eliminated by surgery alone. However, sarcomas larger than 5 cm are often treated with a combination of surgery and radiation therapy or chemotherapy before surgery – to shrink the tumor and make its removal easier, or during and after surgery – to eradicate any remaining microscopic tumor cells. In addition, radiation and chemotherapy pre-surgical treatment might facilitate less surgery, preserving the limbs if the tumor is located in the arms or legs (limb-sparing surgery). Historically, STSs were treated with amputation; however, nowadays at least 90% of tumors are removed using limb-sparing surgery. In intermediate-high stages, chemotherapy and radiation therapy may also be used to reduce the size of the sarcoma or relieve pain and other symptoms.

Radiotherapy

The most commonly used radiation form is external beam radiation. Another mean of post surgically radiation is brachytherapy. This technique allows for high doses of radiation over a short period of time. The decision to use radiation before and/or after surgery is not standardized and may be changed on an individual case basis; Table II describes the choices of using radiation with surgery.

Table II: The advantages and disadvantages of the timing of radiotherapy

T2_aClick on table to enlarge

Adapted from sarcomahelp.org

Proton therapy (also called proton beam therapy), a type of radiation treatment that uses protons rather than x-rays is also being adapted to treat sarcoma. This mode of radiotherapy allows target the radiation much more focused at the tumor site and thus is much protective to surrounding healthy tissue. This procedure however, is currently only available in a few specialized cancer centers in the US. In addition, particle therapy treatment with heavier charged particles such as carbon ions is being used and studied for the treatment of sarcomas in Japan and Germany.

Chemotherapy

Chemotherapy is often used when a sarcoma has already spread and can be given before surgery or, after surgery as adjuvant chemotherapy to destroy any microscopic tumor cells remained after surgery.  In addition, when a tumor is considered non-operable, cycles of chemotherapy could be performed in order to shrink the tumor and make it necrotic to enable its removal by operation.

  • Watch a STS chemo + surgery Video

Different drugs are used to treat different subtypes of sarcoma. The types of chemotherapy that are used alone or in combination for most STSs include doxorubicin and ifosfamide that are the most common chemotherapy drugs employed for STS, as well as other ordinary chemotherapy drugs. The drug trabectedin, approved for use in Europe, is given for patients with advanced STS when conventional chemotherapy fails. Trabectedin has been shown to have high activity levels in the treatment of a specific subtype of liposarcoma (myxoid/round cell liposarcoma). Other chemotherapy drugs that are only used for certain subtypes of STS include: paclitaxel, docetaxel for Angiosarcoma; as well as vincristine, etoposide, actinomycin, and cyclophosphamide for Rhabdomyosarcoma and Ewing sarcoma.

Experimental chemotherapy drugs include Eribulin, a drug approved for treatment of breast cancer that has shown promising results in early clinical trials. In addition, new versions of sarcoma standard chemotherapy that cause fewer side effects are being studied in ongoing clinical trials. For instance, the three new versions of ifosfamide: palifosfamide, glufosfamide, and TH-302.

Targeted therapy

As genetic and molecular cancer research has evolved, targeted treatment to sarcoma became available. Targeted treatment to sarcoma intends to inhibit the growth and spread of cancer cells by hitting specific proteins, mainly by blocking the action of protein kinases.

Imatinib, a tyrosine-kinase inhibitor was approved in 2002 by the FDA for the treatment of gastrointestinal stromal tumor (GIST) in advanced stages and it is now the standard first-line treatment for GIST. In 2006, sunitinib multi-target receptor tyrosine kinase (RTK) inhibitor was also approved for the treatment of GIST when imatinib fails. Imatinib has been approved recently for use for patients with GIST after initial surgery, to try to prevent recurrence of the tumor. Imatinib is approved also for the treatment of advanced stage dermatofibrosarcoma protuberans (DFSP). Pazopanib, another multi-targeted inhibitor of receptor tyrosine kinase, has also been approved for patients with advanced STS as well as for use in sarcomas other than liposarcoma and GIST in conditions where standard chemotherapy is not working. Regorafenib is a new kinase inhibitor with significant activity in patients with advanced GIST who have already been treated with imatinib and suntinib. The FDA is currently reviewing a phase III clinical trial of this drug.

Closing remarks

Research efforts are made in order to elucidate new sarcoma-specific molecular targets. Studying sarcomas unique genetic fingerprints and understanding their value to sarcoma, not only can assist developing new drugs, but also may help better prediction of patients’ prognosis. To find the most effective treatment, tests to identify the genes, proteins, and other sarcoma-associated factors need to be developed and performed to give a better matched treatment for each patient.  However, being sarcoma a highly diverse group of cancers make these efforts a hard task. These issues will be discussed further in future post(s) to be published in Pharmaceutical Intelligence.

Resources

  1. http://www.cancer.net
  2. http://www.sarcomahelp.org
  3. http://www.cancer.gov
  4. http://sarcomaalliance.org
  5. http://www.sarcoma.org.uk
  6. http://www.mayoclinic.com

Additional related references

  1. Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Casali, PG & Blay, JY. Ann Oncol. 2010 May;21 Suppl 5:v198-203.
  2. Chemotherapy in adult soft tissue sarcoma. Jain A, Sajeevan KV, Babu KG, Lakshmaiah KC. Indian J. Cancer. 2009 Oct-Dec;46(4):274-87.
  3. State-of-the-art approach in selective curable tumours: soft tissue sarcoma. Judson I. Ann Oncol. 2008 Sep;19 Suppl 7:vii166-9.
  4. Soft tissue sarcomas of adults: state of the translational science. Borden EC, et al. Clin Cancer Res. 2003 Jun;9(6):1941-56.
  5. Management of soft-tissue sarcomas: an overview and update. Singer S, Demetri GD, Baldini EH, Fletcher CD. Lancet Oncol. 2000 Oct;1:75-85.

Videos

  1. http://www.youtube.com/watch?v=J35GBjTxzIE
  2. http://www.youtube.com/watch?v=f97oWMANXDw

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