Meshes in Implant-Based Breast Reconstruction: The Science and Technology

*Emily Louise Hopwood, Annabelle Xiao Yan Tan and Fiona Jane Tsang-Wright*

## **Abstract**

Breast reconstruction is a common choice post mastectomy or breast-conserving surgery for breast cancer. Reconstructive options currently include implant-based and autologous reconstruction, with adjunctive use of surgical meshes. Acellular dermal matrices (ADMs) of both human and animal origin, and synthetic meshes are well-established for use in implant reconstruction. With ADMs, there is reduced risk of capsular contracture, providing a strong scaffold for prosthetic-based immediate reconstruction. Reduced seroma formation and infection has been demonstrated with synthetic mesh, thus both techniques proving advantageous. Use of mesh in implantbased reconstruction is a quickly evolving field, with hybrid meshes, 3D printed meshes and antibiotic-loaded meshes being investigated within the current literature. Whilst these surgical techniques are relatively new, they provide a new approach to many of the ethical issues currently surrounding use of surgical mesh.

 Introduction**

Breast cancer is one of the most prevalent malignancies in the UK, with 55,000 women and 370 men diagnosed every year in the UK alone [1]. Lifetime risk for women in the UK is currently one in seven, with breast cancer accounting for approximately 50% of all cancer diagnoses in women between the ages of 45–54 years old [2].

Breast cancer involves the breast tissue and may be invasive or non-invasive, with ductal carcinoma in situ (DCIS) being the most common subtype [3]. Current management for breast cancer in the UK may involve breast-conserving surgery or mastectomy, dependent on subtype and whether invasive disease is present [4]. Mastectomy is removal of the breast tissue and may be superseded by adjunctive radiotherapy, which has been demonstrated across the literature to reduce recurrence and mortality in women with lymph node involvement [5]. Following mastectomy, women may opt for delayed or immediate reconstruction, with the current trend in

England towards immediate reconstruction, of which implant-based reconstruction accounts for 53% of cases in the UK [6]. Autologous reconstruction is another method, which may use the extended latissimus dorsi flap and provides good reconstruction for small to medium sized breasts [7]. Alternatively, the deep inferior epigastric perforator flap (DIEP) is another surgical technique deployed in breast reconstruction since 1994 [8] with added advantages of reduced ventral hernias and muscle weaknesses, previously seen with the free transverse rectus abdominus myocutaneous (TRAM) flap. In the TRAM flap, the TRAM muscle is removed from the abdomen and used to create the breast shape, whereas the DIEP flap creates the breast shape from tissue from the abdomen, sparing the abdominal muscle. The perforators of the deep inferior epigastric artery and vein are taken with the tissue and connected to the internal mammary artery and vein in the breast, advantageous due to increased sensory return of the breast compared to device-based reconstruction [9].

In early implant-based reconstruction, the implant was placed subcutaneously under the skin flaps and then the trend moved towards placing the implant in a pocket underneath the pectoralis major muscle [10]. However, there has been a change back to subcutaneous prepectoral implant insertions with the more widespread use of ADMs. There were initially increased complications pre-operatively [11]. Typically, tissue expanders are used first to expand the pocket under the pectoralis major muscle through a subcutaneous fluid injection, as this pocket is usually not large enough initially to house an implant [10]. Once the pocket has enlarged, the tissue expander is replaced in a further operation by a fixed volume implant. Newer combined expander implants can be used which is performed as one operation, reducing the number of operations required, and have good outcomes similar to other reconstructive methods [12] with low complication rates [13]. With an ADM more surgeons use a direct to implant approach, negating the use of a temporary expander in the prepectoral plane [14, 15].

Use of mesh as an adjunct in breast reconstructive surgery has been shown to have many advantages, providing a scaffold for host revascularisation and repopulation of cells, extending the pectoralis major muscle and space for the implant, thus forming a natural inframammary fold at the base of the implants [16]. Mesh reduces amount of tissue dissection required during surgery as well as the incidence of capsular contracture [17]. Despite this, they are also known to increase risk of seroma formation, skin necrosis, infection, and come at a high financial cost [18]. In a bid to reduce costs, use of absorbable vicryl mesh, alongside acellular dermal matrix (ADM), has been reported as safe and may provide a method to reduce material costs, without loss to the patient in terms of outcomes [19, 20].

#### **2. History and development**

Mesh, also referred to as 'matrices' is widely used across surgery in many different disciplines, including in abdominal and perineal wall closures, hernia repairs, colposuspension and rectoplexies. Prosthetic material was first suggested as a method to repair hernia defects in 1890 by Billroth [21] with original materials including silver metal braided as a weave, which led to problems surrounding toxicity due to silver sulphate formation on their surface [22].

Non-metallic materials were first considered for surgical use to repair defects by Koontz and Kimberly in 1959 [23]. However, the authors agreed that non-metallic

materials may better fit the contours needing repair, thus should be considered in some circumstances [23]. Non-metallic materials including Dacron, Nylon and Teflon prove troublesome with infection, loss of tensile strength and rigidity [24], however tantalum gauze, a metallic material which used to be widely used in hernia repairs, escapes this. Marlex mesh was developed later, which had large pores thus incorporated well into tissue, with increased fibroblast activity and scaffold strength [25]. First generation meshes were introduced in 1998 and are based upon polypropene systems with large pores and small surface areas and are categorised into microporous, macroporous, and macroporous meshes with multifilament or microporous components [26].

Second generation meshes have increased tensile strength compared to their first generation counterparts [26]. They are composed of polypropylene (PP), polyester (PL) or expanded polytetrafluoroethylene (e-PTFE) combined with other materials such as titanium, omega 3, polyvinylidene fluoride (PVDF) and poliglecaprone 25 (PGC-25), and reduce formation of adhesions as the visceral and non-visceral sides of the mesh are specific to its function. The visceral side prevents adhesion through its microporous surface whilst the non-visceral side enables growth of parietal tissue through its macropores. Second generation meshes can be either absorbable or permanent.

The most recent development of surgical mesh encompasses those made from biological donor sources such as human dermis, bovine or porcine and greatly improve on the issues with second generation meshes, such as adhesion formation [26]. Human ADM was the first biological mesh produced and grafted well with tissues, with reduced rates of infection [27]. However, there are some issues with homografts, including increased risk of eventration, whereby a hernia forms at the same time as scars post surgery, with amount of stretch in the material also increasing over time [27]. Recurrence of hernias and fluid collections are also commonly seen after ADM use in abdominal wall reconstruction [28]. It has been thought in the literature that biological meshes reduce risk of capsular contracture when used in breast surgery, however have been associated with increased incidence of breast implant losses [29].

Matrices were first reported in the literature as being used in aesthetic breast revisions in 2003 to reduce rippling commonly seen with implant use [30], and in 2005 for breast reconstructions to reduce requirement for tissue expansion [31]. Following concerns raised by silicone-gel filled implants manufactured by PIP in 2010 [32], the safety of silicone-gel filled implants has been heavily investigated throughout the literature and they have been deemed as safe [33] and at present are the most common form of implant used in the UK for aesthetic breast augmentation [34] and breast reconstruction [35]. Matrices can be differentiated into biological ADMs and meshes [17]. ADMs are usually human, bovine or porcine derived and are soft tissue grafts containing only extracellular matrix after original cells are removed. They have been used in breast surgery since 2001, originally used for soft tissue coverage and as a structural scaffold for prosthetic-based immediate reconstruction [36] and utilise the prepectoral technique, described above (**Figure 1**) [37]. The patient's own cells will then revascularize the matrix, creating an additional tissue layer [17]. Contrastingly, there are synthetic meshes, which have comparable aesthetic outcomes to ADMs and are lower in cost [16]. Synthetic mesh has been used in breast reconstruction since 2005 with non-absorbable Mersilene mesh being the first [38]. Synthetic mesh is usually available as a sheet of plastic-like material with different

**Figure 1.** *Hand drawn image depicting subpectoral implant-based reconstruction [37].*

sized pores dependent on mesh type, which affects how well the mesh is integrated into the breast tissue [39].

Within the prepectoral approach, ADMs can be used to recreate breasts when either a youthful appearance or ptotic breasts are desired, in a one-stage direct to fixed implant breast reconstruction [14]. The 'tent' technique, where the ADM is sutured to the pectoralis fascia can be utilised to create non-ptotic breasts; the 'enhanced hammock' technique allows for ptotic breast creation to recreate a similar breast where the alternate is already ptotic (**Figure 2**) [40], proving ADMs to be hugely versatile with regards to the final aesthetic appearance. The inferior free ADM edge is sutured a third up the implant edge on the pectoralis fascia, forming the 'hammock' [14]. Both of these techniques further promote a person-centred approach to implant-based reconstruction, with promising aesthetic results for patients due to superior breast symmetry.

*Meshes in Implant-Based Breast Reconstruction: The Science and Technology DOI: http://dx.doi.org/10.5772/intechopen.112995*

**Figure 2.** *Hand drawn image showing prepectoral 'tent' (A) and 'enhanced-hammock' techniques (B) [40].*

## **3. Current types**

#### **3.1 ADMS**

In the UK, single stage direct to implant using animal derived ADM products is the most common form of implant reconstruction [15]. ADMs may be human, bovine or porcine derived and are composed of original dermal collagen matrix, which functions as a scaffold for revascularisation by the host's tissues [41]. Common sources of tissue used in ADM products (**Figure 3**) [42] include skin, small intestinal submucosa, amniotic membrane and peritoneal membrane [42]. First used in burns patients in the 1990s, they are currently applied in plastic and burns reconstructive surgery, skin grafts, orthopaedic surgery and breast reconstruction [42]. Whilst costly initially, they have been shown to be a cost-effective surgical technique with lower cost at 2 years post surgery [43].

#### **3.2 Synthetic**

Synthetic meshes are also used in breast reconstruction and are produced from plastic-like material and may be absorbable, non-absorbable or a mixture of both. Generally, they are lower in cost to ADMs [20]. Some studies have reported reduced or no infection or seroma formation post surgery with synthetic mesh, with aesthetic outcomes and patient satisfaction comparable with both synthetic and biological mesh [16, 44]. Synthetic meshes have poor incorporation into host tissue, which is one drawback to this surgical technique; of all synthetic materials used in meshes, PL is reported as having better incorporation [16].

#### **3.3 Shapes**

Meshes are available in different shapes, patches, plugs and sheets, all designed for various functions. Matrices may be knitted or woven; woven meshes have multiple parallel strands alternatively passed over and under another set of parallel strands, whilst knitted meshes are made using continuous loops of filaments [45]. Knitted meshes are the more traditional approach and are associated with increased post operative complications [46]. Patches and plugs are used in hernia repairs [26, 47], whilst flat sheet meshes are frequently used in implant-based breast reconstructions, notably sub-muscular and prepectoral reconstructions [48].

#### **4. Indications**

Popular indications for use of surgical mesh in breast surgeries are in implant-based total breast reconstructions post mastectomy, for patients with breast cancer or having risk reduction surgery, breast revision surgery, and surgery for congenital asymmetry or deformities. In the UK, biological and synthetic meshes have been used more frequently in ADM assisted procedures since 2013 [49]. Compared to traditional total submuscular techniques, mesh allows for better inframammary fold control and lower pole projection, with increased aesthetic results [50]. Synthetic meshes have been shown to be good substitutes for ADMs in aesthetic surgeries [51]. Lipomodelling is a more historical technique used to create symmetrical breasts in patients with congenital asymmetry [52]. Implants can be used in patients with amastia, uni-or bilateral absence of the breast and nipple-areola complex, Poland syndrome, where there is breast hypoplasia/aplasia and in tuberous breasts, where a fibrous ring blocks the radial development of the inferior mammary pole [53].

Risk reducing mastectomies may be chosen by women who are at higher genetic risk of developing breast cancer in their lifetime which may include those with the

#### *Meshes in Implant-Based Breast Reconstruction: The Science and Technology DOI: http://dx.doi.org/10.5772/intechopen.112995*

*BRCA1* or *BRCA2* genes or with a previous breast cancer diagnosis in the alternate breast [54] and is well reported as being the most effective way of reducing breast cancer risk in affected women [55]. *BRCA1* and *BRCA2* gene mutations increase a women's risk of breast cancer, with peak incidence at age 41–50 years in *BRCA1* carriers, and 51–60 years in *BRCA2* carriers [56]. For ovarian cancers, cumulative risk increases to 44% for *BRCA1* carriers and 17% for *BRCA2* carriers [56]. Risk reducing contralateral mastectomies have been illustrated as having a 48–63% survival advantage in patients with known *BRCA1* or *BRCA2* mutations [57, 58]. Implants may be placed prepectorally in these patients, and researchers argue that immediate reconstruction may be preferable to maintain self-esteem and aesthetic outcomes [55].


**3.2.7 Techniques**

Follow the preparation of skin: under the ultrasonic or fluoroscopic imaging, once the pelvocalical system is clearly visible, the skin is anesthetized with one percent xylocaine or 0.25 percent bupivicaine. Xylocaine is injected into the skin, subcutaneous tissue, muscle, perinephric space and renal capsule with a small cutaneous incision. Using a needle 2 system, a 18-gauge needle is introduced toward the desired site in the renal pelvis at the more lateral point which is usually along the posterior axillary line. This can be followed and monitored by real-time ultrasound or fluoroscopy. Under fluoroscopic guidance, visualization of desired calyx is demonstrated by injection of air and contrast media. In prone position, air usually floats up to posterior calices that it is the marker for the puncture. (Fig. 16)

Fig. 16. Fluoroscopic imaging: air usually floats up to posterior calices in prone position that it is the marker for the puncture.

When the needle tip enters the collecting system, urine can be aspirated from the needle after the needle stylet is removed. A soft J-tipped guidewire is inserted into the needle and advanced across the caliceal infundibulum to renal pelvis. The choice of guidewires depends on the indication of nephrostomy placement. A Bentson guidewires is commonly used due to a floppy tip and coil atraumatically in collecting system.

Follow the preparation of skin: under the ultrasonic or fluoroscopic imaging, once the pelvocalical system is clearly visible, the skin is anesthetized with one percent xylocaine or 0.25 percent bupivicaine. Xylocaine is injected into the skin, subcutaneous tissue, muscle, perinephric space and renal capsule with a small cutaneous incision. Using a needle 2 system, a 18-gauge needle is introduced toward the desired site in the renal pelvis at the more lateral point which is usually along the posterior axillary line. This can be followed and monitored by real-time ultrasound or fluoroscopy. Under fluoroscopic guidance, visualization of desired calyx is demonstrated by injection of air and contrast media. In prone position, air usually floats up to posterior calices that it is the marker for the puncture.

Fig. 16. Fluoroscopic imaging: air usually floats up to posterior calices in prone position that

When the needle tip enters the collecting system, urine can be aspirated from the needle after the needle stylet is removed. A soft J-tipped guidewire is inserted into the needle and advanced across the caliceal infundibulum to renal pelvis. The choice of guidewires depends on the indication of nephrostomy placement. A Bentson guidewires is commonly

used due to a floppy tip and coil atraumatically in collecting system.

**<IP_ADDRESS> The causes of access failure**

it is the marker for the puncture.

**3.2.7 Techniques**

(Fig. 16)

In special situations, such as an impacted stone in the collecting system, the manipulation often requires small angled-tip catheters and hydrophilic coated wires. Then the needle is removed, and progressively larger dilators are introduced over the guidewire to dilate the access tract to facilitate the placement of soft nephrostomy tube. The size of tract dilatation depends on the goal of percutaneous access. If the goal is to provide external urinary drainage, serial dilators are inserted over the guidewire to dilate the tract to a sufficient size for the nephrostomy tube. The 8 or 10 Fr nephrostomy tube is introduced over the guidewire and optimal position is monitored by ultrasound or fluoroscopy.

The most reliable evidence for the proper placement of the nephrostomy tube can be demonstrated by nephrostogram under fluoroscopic imaging. The guidewire is withdrawn and the nephrostomy tube is secured with skin to prevent dislodging the catheter. The catheter is connected to a urine bag for drainage. (Fig. 17-20) For permanant nephrostomy tube placement, the tract can be further dilated and a regular Foley's catheter can be used.

Fig. 17. Ultrasonic probe for guidance the nephrostomy tube placement.

Fig. 18. Dilators over the guidewire.

Modern Surgical Treatments of Urinary Tract Obstruction 277

Overall success rate of uncomplicated nephrostomy tube placement is over 97% with less success in patients who required percutaneous tract for subsequent endourologic interventions. Factors which affect the success rate of nephrostomy tube placement during endourologic operation are stone burden, degree of hydronephrosis, history of previous open nephrolithotomy, and experience of surgeon. As same as other urologic procedure, a training simulator for ultrasound-guided percutaneous nephrostomy insertion is needed for a safe, non-threatening environment, without risk to patients. Commercial and a gelatin phantoms are available. Skill is required prior to undertaking procedures in patients. (Rock et al., 2010)

Complications following simple nephrostomy tube drainage are minor with a rate approaching 4%. (LeRoy, 1996). The common complications are hemorrhage, infection, improper catheter placement, nephrostomy tube dislodging after initial proper placement, nephrocutaneous fistula, stone formation and post-obstructive diuresis. Initial hematuria is

Small subcapsular hematoma is found about 3% of cases, a complication that is usually resolved without sequelae. Bleeding from iatrogenic arteriovenous-caliceal fistulas occurs in less than 2% and can be managed with angioembolization. (Fig. 21, 22) Pulmary

Preoperative and postoperative angioembolization of arteriovenous fistula follow

Fig. 22. Disappear of fistula after

angioembolization.

**4. Results**

**5. Complications**

percutaneous nephrolithotomy.

of kidney.

Fig. 21. Arteriovenous fistula at middle part

common, but should be cleared in 24 – 48 hours post operatively.

Fig. 19. 8 Fr nephostomy catheter inserted through the guidewire.

Fig. 20. The nephrostomy tube is secured with skin.

Further endourologic procedures that will follow temporary nephrostomy tube placement are percutaneous nephrolithotomy for removal of renal and upper ureteral calculi, endopyelotomy for ureteropelvic junction obstruction and infundibulotomy for infundibular stenosis. Percutaneous nephrolithotomy is effective and safe in patients with complex conditions such as underlying medical conditions and previous open nephrolithotomy. (Lojanapiwat, 2006).

Following these procedures, most patients need a larger nephrostomy tube for adequate drainage and tamponing the bleeding point from the nephrostomy tract. Recently tubeless percutaneous nephrolithotomy has been performed in uncomplicated cases with no significant bleeding, no significant extravasation, no distal obstruction and no secondary nephroscopy required. (Lojanapiwat et al., 2001) (Table 5)

276 Chronic Kidney Disease

Fig. 19. 8 Fr nephostomy catheter inserted through the guidewire.

Fig. 20. The nephrostomy tube is secured with skin.

nephroscopy required. (Lojanapiwat et al., 2001) (Table 5)

nephrolithotomy. (Lojanapiwat, 2006).

Further endourologic procedures that will follow temporary nephrostomy tube placement are percutaneous nephrolithotomy for removal of renal and upper ureteral calculi, endopyelotomy for ureteropelvic junction obstruction and infundibulotomy for infundibular stenosis. Percutaneous nephrolithotomy is effective and safe in patients with complex conditions such as underlying medical conditions and previous open

Following these procedures, most patients need a larger nephrostomy tube for adequate drainage and tamponing the bleeding point from the nephrostomy tract. Recently tubeless percutaneous nephrolithotomy has been performed in uncomplicated cases with no significant bleeding, no significant extravasation, no distal obstruction and no secondary

Table 5. Criteria for tubeless percutaneous nephrolithotomy.


*2.2. Microscopic Examination*

Microscopic examination was performed according to von der Ohe et al. [36]. Honeydew elements (HDE) have been counted and the ratio HDE/P (Pollen) is given as the number of honeydew elements over the number of pollen grains from nectariferous plants. Quantitative melissopalynological analysis was based on the method of Yang et al. [37] and results are expressed as total number of all pollen grains (PG) in 10 g honey.


*2.2. Chemistry*

To authenticate the design and the interesting results of the computational studies, the targeted lead compound was synthesized according to Scheme 1. The commercially available material (4-aminobenzoic acid **1**) was first refluxed with methanol and sulfuric acid in accordance with the reported procedure, to afford methyl 4-aminobenzoate **2**. Benzoylation of methyl 4-aminobenzoate **2** was achieved in an ice bath via dropwise addition of benzoyl chloride **3** in DCM in the presence of TEA, to afford compound **4**. Refluxing compound **4** with hydrazine hydrate in ethanol afforded the corresponding acid hydrazide derivative **5**. A mixture of the acid hydrazide derivative **5** and 5-methoxy-1*H*indole-3-carbaldehyde **6** was refluxed in absolute ethanol and a few drops of glacial acetic acid, to afford the final target compound **7**.

The structure of compound **7** (Figure 17) was validated using spectral analysis. The IR spectrum showed absorption bands at 3287 cm−1, and 1645 cm−1 attributed to NH and the amidic carbonyl group, respectively. Moreover, 1H NMR spectra showed singlet signals around *δ* 11.48 and 10.53 ppm, corresponding to the indole NH and the two amidic NH protons. In addition, an up-field sharp singlet signal corresponding to OCH3 protons appeared at *δ* 3.82 ppm. The three protons (6, 7, and 9) of the phenyl ring of the *1H*-indol moiety resonated at *δ* 7.36 (d, *J* = 8.8 Hz), 6.88 (dd, *J* = 8.8, 2.4 Hz), and 7.79 (d, *J* = 2.4 Hz), respectively. At the same time, proton 2 was presented as a sharp singlet, peaking at *δ* 8.01. The characteristic proton, 10, resonated clearly as a sharp singlet signal at *δ* 8.62. Regarding the di para-substituted protons, protons (19, 21) and (18, 22) resonated at *δ* 7.58 (d, *J* = 8.2 Hz) and 7.99 (d, *J* = 8.2 Hz), respectively. Finally, the aromatic protons of

the benzamide moiety resonated at the overlapped areas of 7.68 and 7.96. Matching such findings, the 13C NMR spectra showed characteristic peaks corresponding to the two C=O and OCH3 groups around *δ* 166.34, 162.36, and 55.80 ppm, respectively. The carbons (2, 3, 4, 5, 6, 7, 8, and 9) of the phenyl ring of the *1H*-indol moiety resonated at *δ* (128.3, 112.8, 125.4, 130.4, 112.7, 111.9, 154.8, and 104.6, respectively). The characteristic carbon, 10, resonated at *δ* 154.2. The di para-substituted carbons (19, 21) and (18, 22) resonated at *δ* 119.9 and 128.2, respectively. The aromatic carbons (26, 27, 28, 29, 30, and 31) of the benzamide moiety resonated at *δ* (135.1, 128.2, 128.9, 132.5, 128.9, and 128.2, respectively).

**Scheme 1.** Synthetic pathway of target compound **7**.

**Figure 17.** Chemical structure of compound **7**.


**Abstract**

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. It is characterized by a variable clinical course ranging from mild to fatal disease. It can affect the kidneys. The aim of treatment in SLE is the prevention of flares and the prevention of accumulation of damage to the main organs affected as well as the prevention of drug side effects. The cornerstone of SLE treatment is hydroxychloroquine. Corticosteroids are used both as induction treatment in disease flares as well as in small doses as maintenance treatment. Immunosuppressants, such as azathioprine, methotrexate and mycophenolate mofetil are used as steroid sparing agents. Calcineurin inhibitors, namely tacrolimus and cyclosporin A may also be used as immunosuppressants and steroid sparing agents. Pulse methylprednisolone, along with mycophenolate mofetil and cyclophosphamide are used as induction treatment in lupus nephritis. Rituximab, an anti-CD20 biologic agent may be used in non-renal SLE. In patients insufficiently controlled with hydroxychloroquine, low dose prednisone and/or immunosuppressive agents, belimumab may be used with beneficial effects in non-renal disease and lupus nephritis.

**Keywords:** systemic lupus erythematosus, treatment, hydroxychloroquine, corticosteroids, mycophenolate mofetil, rituximab, belimumab

## **1. Introduction**

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affecting many organ systems. It has a variable course, ranging from a mild course to severe fatal disease. It affects mainly women in the reproductive age. Women of African or Asian origin suffer frequently and present with more severe disease. The treatment of SLE is in the focus of scientific interest as new immune modulating agents have entered the management of the disease.

The therapeutic management of the disease depends mainly on antimalarial agents, namely hydroxychloroquine, corticosteroids, immunosuppressive agents and biologic drugs (**Figures 1** and **2**). The use of hydroxychloroquine is established in SLE. Similarly, the use of corticosteroids has been in the mainstream of lupus treatment for many years. Their use is hindered by their adverse effects, which may occur even with small doses. Immunosuppressive agents such as azathioprine and methotrexate have been used as steroid sparing agents. The use of mycophenolate mofetil (MMF) is also in the mainstream treatment of severe SLE cases or lupus nephritis. Rituximab, an antiCD20 antibody targeting B lymphocytes has also been

#### **Figure 1.**

*Agents involved in systemic lupus erythematosus treatment.*

**Figure 2.** *Agents contributing to the treatment of lupus nephritis.*

applied in the treatment of severe SLE cases. Recently, the use of belimumab has been introduced in the treatment of SLE and is indicated in patients with nonrenal disease and renal disease not responsive to standard treatment. Although, recent advances in treatment have improved prognosis and life expectancy in lupus patients, much progress remains to be achieved. In the present chapter, the use of various treatment modalities for SLE will be discussed. Additionally, the use of supplementary drugs will be reviewed.


*4.1. Experimental Environment*

Hardware: The experiment was carried out on an i7-3770k CPU computer @ 3.50 (turbo: 3.9) GHz, 4 cores (note: during the experimentation, only one core was used, since agents do not implement the multi-core support) and 16 GB RAM.

Software: OS Windows 10 Pro and Java Development Kit 13.0.2. The experiment was set in the latest version of the microRTS environment, acquired from an online source at the time of preparing this article [64]. The microRTS environment comes pre-loaded with the following gameplaying agents: RandomAI, RandomAIBiased, MonteCarlo, IDRTMinimax, IDRTMinimaxRandomized, IDABCD, UCT, PuppetSearchMCTS, and NaiveMCTS. TiamatBot was acquired from the online source [65]. MixedBot (which includes TiamatBot source files but an improved version) was acquired from the online source [66] and was included in the microRTS environment. Every gameplaying agent is used in the experiment as it was acquired from the online source of original authors (i.e., no code or internal parameter was changed for experimental purposes).

Table 4 shows the hyper-parameters used for the validation of every game feature presented in Table 1.

**Table 4.** Hyper-parameters used in the experimentation.

These hyper-parameters are pre-set within the microRTS environment. The only parameter that we changed was iterations, which we set to 50 (before it was set to 10). The standard UnitTypeTable was used where necessary. Note: to validate the GF9\_PARI, we changed the environment from fully observable to partially observable.

The game feature descriptions presented in Table 1 were derived from related works and written independently of a specific game environment, i.e., they can be implemented in any RTS game engine. In Table 5, we present the same game features as those presented in Table 1, although the former are adapted to the microRTS environment and a specific scenario. All game features in Table 5 are written with the assumption that they are valid for the microRTS environment. If the playtesting agent actually manages to invalidate a game feature from the list, it will add to its metric score.

#### *4.2. Adaptation of Gameplaying Agents as Playtesting Agents*

To adapt a gameplaying agent to the playtesting task, we created a non-intrusive component. The component contains information about the scenario (map, position of units and the opponent) and controls the validation procedure by following the playtesting agents' progress (i.e., actions that it executes) and by accessing game environment information (e.g., current game state status). All the information is accessible through well-defined interfaces of the microRTS source code. One of the interface methods is the method that returns the best action for the given game state, and every gameplaying agent operating in the microRTS environment implements it.

#### **Table 5.** microRTS game feature scenario.

When the actions are executed in a game state, it cycles to the next one (i.e., actions change the inner state). During such cycles, our component tests if the Game Feature is valid or invalid. A Game Feature is invalid if the condition that is written in the validation procedure of the game feature in question is not fulfilled. The condition is tested against the information provided from the agent's executed action and the environment's current game state. The validation procedure checks the validity of the game feature, until either the maximum number of cycles is reached, or the game is over (i.e., one of the players has no more units left on the field).

For example, the game feature, GF8\_FANT, is validated by checking if the resulting game state still holds this special unit after the agent has given an order to fire on it. If in any cycle the unit is destroyed, the game feature is invalid.


3.3.3. Influence of the *aF145S* Mutation on ATP Synthase Assembly/Stability

The ATP synthase organizes into a membrane-extrinsic domain (F1) and a domain (FO) largely anchored in the inner membrane [47–49]. The subunit *a* and a ring of identical subunits *c* move protons through the FO. As a result of this, the *c*-ring rotates and provokes conformational changes in the F1 that promote ATP synthesis. In current models, the assembly of ATP synthase starts with formation of F1, followed by its association to the *c*-ring and peripheral stalk subunits that prevent rotation of the catalytic subdomain (αβ3) of F1. The process ends with incorporation of subunit *a* [50]. When incorporation of subunit *a* is compromised, the F1 and the *c*-ring easily dissociate during BN-PAGE analysis of mitochondrial proteins, as was observed in a yeast strain lacking the *ATP6* gene [15,30,51]. In addition to fully assembled monomers and dimers of ATP synthase, free F1 and *c*-ring were detected in mitochondrial samples from the *aF145S* mutant whereas these particles were absent in those from *WT* yeast, as revealed by Western blot with subunit *c* (Atp9) antibodies and by the in-gel F1-mediated ATP hydrolytic activity (Figure 3C). The steady state levels of the mutated subunit *a* were estimated by Western blot (WB) with Atp6 antibodies of mitochondrial proteins resolved in denaturing gels. They were significantly reduced in the mutant vs. *WT* (Figure 3D). Taken together these data show that the *aF145S* change partially compromises a stable incorporation of subunit *a* within ATP synthase.


**8. Treatment**

#### **8.1. From single to multi-modality treatment**

The results of mesothelioma treatment in the 1970s and 1980s were disappointing. Radical surgery alone was associated with high morbidity and mortality, whilst its impact on long term outcomes was questionable [77]. The response rate to chemotherapy was poor amongst most agents and responses were not durable with 80% of patients developing recurrent disease within 2 years. Mesothelioma cells are radiosensitive in the laboratory [104], but the use of radiotherapy to treat mesothelioma was associated with significant toxicity resulting from the extensive volume that needs to be treated and the proximity of vital organs. The disease burden is great from both local progression and distant metastases, but none of the modalities when used alone were effective. In 1980, Karen Antman at the then Sidney Farber Cancer Institute in Boston, proposed the combination of resection with radiotherapy and systemic chemotherapy in limited disease to maximise local control and minimise distant relapse.

Studies of surgery alone have reported that following extrapleural pneumonectomy, local recurrence occurs in a third of patients and distant recurrence in half the patients [105] [106]. Therefore, there was room to improve local control, but systemic control should also be part of the treatment for all patients. Early work focused on adding adjuvant chemotherapy and postoperative radiotherapy after EPP, but compliance with early chemotherapy following lung resection was often poor due to a prolonged postoperative recovery [107]. With this in mind, and the discovery of significant responses from platinum doublets, the Swiss investigators adopted a strategy of neoadjuvant chemotherapy followed by surgery and hemithoracic radiotherapy to ensure all patients received systemic treatment [108]. They showed that surgery after neoadjuvant chemotherapy was safe and outcomes were at least comparable if not improved. With this strategy, compliance with chemotherapy was near 100% and overall compliance with all three treatment modalities was 60-70% [109].

Since then, each of the therapeutic modalities have undergone refinement and a number of groups reported improved outcomes in selected patients undergoing multimodality treatment when compared to historical results. This has led to a number of randomised trials designed to tease out the role of various components of multimodality treatment.

In this section we will review the current state of knowledge on the treatment of mesothelioma. The role and nuances of surgery will be covered in another chapter, and here we will focus on radiation therapy and systemic treatment. We will review the roles of these treatments in palliation and as part of multimodality therapy with radical intent.

#### **8.2. Symptom palliation**

disease and those with partial response, even following optimisation of the cut-off criteria for each group [103]. This has significant implications for the clinical relevance of studies

The results of mesothelioma treatment in the 1970s and 1980s were disappointing. Radical surgery alone was associated with high morbidity and mortality, whilst its impact on long term outcomes was questionable [77]. The response rate to chemotherapy was poor amongst most agents and responses were not durable with 80% of patients developing recurrent disease within 2 years. Mesothelioma cells are radiosensitive in the laboratory [104], but the use of radiotherapy to treat mesothelioma was associated with significant toxicity resulting from the extensive volume that needs to be treated and the proximity of vital organs. The disease burden is great from both local progression and distant metastases, but none of the modalities when used alone were effective. In 1980, Karen Antman at the then Sidney Farber Cancer Institute in Boston, proposed the combination of resection with radiotherapy and systemic chemotherapy in limited disease to maximise local control and minimise distant

Studies of surgery alone have reported that following extrapleural pneumonectomy, local recurrence occurs in a third of patients and distant recurrence in half the patients [105] [106]. Therefore, there was room to improve local control, but systemic control should also be part of the treatment for all patients. Early work focused on adding adjuvant chemotherapy and postoperative radiotherapy after EPP, but compliance with early chemotherapy following lung resection was often poor due to a prolonged postoperative recovery [107]. With this in mind, and the discovery of significant responses from platinum doublets, the Swiss investigators adopted a strategy of neoadjuvant chemotherapy followed by surgery and hemithoracic radiotherapy to ensure all patients received systemic treatment [108]. They showed that surgery after neoadjuvant chemotherapy was safe and outcomes were at least comparable if not improved. With this strategy, compliance with chemotherapy was near 100% and overall

Since then, each of the therapeutic modalities have undergone refinement and a number of groups reported improved outcomes in selected patients undergoing multimodality treatment when compared to historical results. This has led to a number of randomised trials designed

In this section we will review the current state of knowledge on the treatment of mesothelioma. The role and nuances of surgery will be covered in another chapter, and here we will focus on radiation therapy and systemic treatment. We will review the roles of these treatments in

compliance with all three treatment modalities was 60-70% [109].

to tease out the role of various components of multimodality treatment.

palliation and as part of multimodality therapy with radical intent.

which use response as their primary outcome measure instead of survival.

**8. Treatment**

relapse.

**8.1. From single to multi-modality treatment**

140 Principles and Practice of Cardiothoracic Surgery

The symptoms of mesothelioma are severe and debilitating, leaving many patients miserable for their remaining time. In particular, the severity of pain and breathlessness exceeds that in non-small cell lung cancer patients [110].

Early on in the disease, breathlessness is due to pleural effusion compressing the lung and can be managed effectively by drainage. If the lung reexpands following drainage, pleurodesis can prevent reaccumulation. Most studies concern the management of malignant pleural effusions in general which include some cases of mesothelioma. Randomised trials for the use of sclerosant (drainage alone vs drainage with sclerosant), between different sclerosants and between techniques (bedside vs thoracoscopic) for malignant pleural effusions in general favoured the use of talc pleurodesis and thoracoscopy [111] [112]. One subsequent large randomised trial did suggest equivalence between bedside talc slurry and thoracoscopic talc pleurodesis [113], but the frequent need to obtain tissue for diagnosis usually favours the thoracoscopic approach. The recurrence rate following thoracoscopic pleurodesis remains however at 20-30%.

As the disease progresses, a trapped lung develops where the visceral tumour forms a constricting cortex over the lung preventing pleural apposition. Talc pleurodesis in such situations risks infection from long term drainage and contamination of a fixed space. VATS pleurectomy and decortication has been advocated as a palliative procedure which does not aim for complete macroscopic clearance, but tries to achieve lung reexpansion. There seems to be some short-term improvement in pain and dyspnoea [114] without detriment to survival [115] [116]. Recruitment to the randomised trial for VATS decortication (MesoVATS) has now closed, and the results should be available in the near future [117].

Recently, the use of long term tunnelled pleural catheters for effusions with underlying trapped lung has shown promise with very short hospital stay, low morbidity and better patient tolerability. It compared favourably with bedside talc slurry [118]. Even in patients with trapped lung, long term drainage could ultimately result in pleural symphysis, and the drain could eventually be removed in a fifth of patients [119]. Furthermore, chemotherapy can safely continue in the presence of such drains.

As the disease progresses, the effusion disappears and is replaced by a constricting tumour and a contracted hemithorax. Management of breathlessness at this stage is difficult. A palliative pleurectomy could be performed to relieve the restriction on ventilation and chest wall pain but there is significant morbidity associated with such an extensive operation. On the other hand, self-help breathlessness management techniques and opioids can help to relieve the sensation of dyspnoea.

Pain is also a significant symptom that could be difficult to manage. In addition to the WHO pain ladder, radiotherapy can improve chest wall pain in 50-60% patients [120] although unfortunately in most cases the relief is not sustained [121]. There is some suggestion that hyperthermia may increase the response rate to radiotherapy for pain control [122]. In addition, there is a significant neuropathic component to the pain, so early referral to a specialist pain management team may help to improve the quality of life in the final months.

The question of whether palliative chemotherapy has additional benefit on top of best supportive treatment was addressed by a three-armed randomised trial [123]. This was an important landmark - whilst there were numerous phase II trials addressing different chemo‐ therapy agents, prior to this trial there were no randomised evidence to show that chemother‐ apy was beneficial over best supportive care, and most retrospective comparisons suffered from significant selection bias. Unfortunately, the trial experienced slow accrual and was revised to amalgamate two chemotherapy arms, which then also closed early from falling recruitment following the results of other randomised trials. This rendered it underpowered to show a survival difference. The trial was also criticised for employing non-standard chemotherapy regimens which may have led to nonsignificant results [124]. Within these limitations, it concluded the addition of chemotherapy did not improve symptoms or quality of life to any significant degree, in part because the few symptoms which improved were outweighed by the significant morbidity associated with chemotherapy.

basis of this, Berghmans and colleagues carried out a metaanalysis, grouping studies into four subgroups: those which contained cisplatin without doxorubicin, doxorubicin without cisplatin, both doxorubicin and cisplatin and those that contained neither agents [131]. The composite response rate was highest for the two groups that contained cisplatin, with a higher response rate in the group that contained also doxorubicin (28.5%). On the other hand, doxorubicin alone (11.3%) was not better than trials which contained neither cisplatin nor

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143

A more recent metaanalysis [132] found the combined intention-to-treat (ITT) response rate for phase II single agent trials was indeed highest for cisplatin (20.0%) whilst almost all other classes of drugs including the anthracyclines had a rate of <10%. When used in combination, the non-platinum combination regimens had a slight improvement over single agents (overall response rate of 10.4%), but still remained some way behind single-agent cisplatin. On the other hand, certain combination therapies containing cisplatin appeared to show an improve‐ ment on single-agent cisplatin such as with anthracyclines (32.4%) and gemcitabine/irinotecan

These trials seemed to suggest that cisplatin is the more potent agent, and that combination therapy could improve on the results of single-agent cisplatin. Nevertheless, these phase II trials were hampered by their non-comparative nature, and the use of response rate as a surrogate outcome whilst often without reporting of survival outcomes. In fact, these respons‐ es were rarely sustained, and the link between radiological response and improved survival

Gemcitabine is a false nucleotide antimetabolite that gets misincorporated into DNA and hence interferes with DNA synthesis and repair. It showed broad activity against many solid and haematological malignancies, and has been evaluated in mesothelioma. The single agent trials were however inconsistent, with three trials showing widely differing response rates of 0%, 7% and 31% [133] [134] [135]. The overall ITT response rate was a disappointing 6.9%. There was significant heterogeneity in patient selection, chemotherapy dose and schedule, and

Cisplatin and gemcitabine are synergistic in the killing of neoplastic cells *in vitro* [136]. It is efficacious for several malignancies including non small cell lung cancer for which it became a standard of care prior to 2008 [137]. In a single institution phase II study from Australia, Byrne and colleagues administered a 6-cycle regimen of cisplatin and gemcitabine to 21 patients with confirmed mesothelioma. Tumour response was assessed by what was to become the modified RECIST criteria. There was an impressive 47.6% response rate that exceeded the results of both drugs as single agents, and a number of patients, including non-responders, found symptom relief [138]. This led to a multicentre phase II study of 53 patients using the same regimen [139]. However, the overall response rate this time was only 33% with a median duration of response of 5.4 months; the overall survival from diagnosis was a median of 17.3 months. In Europe, a phase II trial using a different dosing and scheduling regimen, obtained a response rate of 16% for the 25 patients using the WHO criteria for assessment [140].

doxorubicin (11.6%), suggesting cisplatin was the active agent.

response evaluation to explain some of the differences seen.

(26.1%).

is tenuous.

*8.3.2. The antimetabolites*

The role of chemotherapy was indirectly addressed by other studies. The MED trial rando‐ mised 43 malignant mesothelioma (M) patients with stable symptoms to early (E) chemother‐ apy or to delayed (D) chemotherapy when there was symptom progression. It found patients who received early chemotherapy had a longer freedom from symptom progression and a better quality of life; furthermore, despite the small number of patients, there was a trend towards prolonged survival in the early chemotherapy group [125]. In addition to this study, a number of comparative randomised phase III studies found benefit for one regimen over another. Unless the control arms led to worse outcome than best supportive care, which is unlikely, these studies indirectly showed that a benefit for chemotherapy exists. Together, they showed that chemotherapy not only has a role in palliation as well as improving survival, but that it should be given early rather than late, and before symptoms worsen.

#### **8.3. Chemotherapy**

MPM is a particularly aggressive condition which responds poorly to treatment and chemo‐ therapy is no exception. In the rush to make an impact, numerous studies have been carried out and almost all agents have been tried. Yet amongst these, most are small, noncomparative phase II studies, so attempts to draw conclusions about the efficacy of each treatment were frustrated by heterogeneity of the populations and variations in treatment schedules, assess‐ ment of response and reporting of outcomes, not to mention selection and publication biases. Frequently, promising outcomes in smaller trials were not replicated in larger and better conducted trials.

#### *8.3.1. Towards cisplatin-based chemotherapy*

In general, the single agent studies have been hard pressed to obtain response rates of over 20% and complete responses were rare. Of the single agent chemotherapy trials, many agents such as the vinca alkaloids (with the exception of vinorelbine) had no efficacy, and responders were few for the alkylating agents [126] [127] [128] [129]. The three classes of agents which showed some degree of response, albeit with response rates that rarely exceeded 20%, were the anthracyclines, platinum compounds and the antimetabolites/antifolates [130]. On the basis of this, Berghmans and colleagues carried out a metaanalysis, grouping studies into four subgroups: those which contained cisplatin without doxorubicin, doxorubicin without cisplatin, both doxorubicin and cisplatin and those that contained neither agents [131]. The composite response rate was highest for the two groups that contained cisplatin, with a higher response rate in the group that contained also doxorubicin (28.5%). On the other hand, doxorubicin alone (11.3%) was not better than trials which contained neither cisplatin nor doxorubicin (11.6%), suggesting cisplatin was the active agent.

A more recent metaanalysis [132] found the combined intention-to-treat (ITT) response rate for phase II single agent trials was indeed highest for cisplatin (20.0%) whilst almost all other classes of drugs including the anthracyclines had a rate of <10%. When used in combination, the non-platinum combination regimens had a slight improvement over single agents (overall response rate of 10.4%), but still remained some way behind single-agent cisplatin. On the other hand, certain combination therapies containing cisplatin appeared to show an improve‐ ment on single-agent cisplatin such as with anthracyclines (32.4%) and gemcitabine/irinotecan (26.1%).

These trials seemed to suggest that cisplatin is the more potent agent, and that combination therapy could improve on the results of single-agent cisplatin. Nevertheless, these phase II trials were hampered by their non-comparative nature, and the use of response rate as a surrogate outcome whilst often without reporting of survival outcomes. In fact, these respons‐ es were rarely sustained, and the link between radiological response and improved survival is tenuous.

#### *8.3.2. The antimetabolites*

The question of whether palliative chemotherapy has additional benefit on top of best supportive treatment was addressed by a three-armed randomised trial [123]. This was an important landmark - whilst there were numerous phase II trials addressing different chemo‐ therapy agents, prior to this trial there were no randomised evidence to show that chemother‐ apy was beneficial over best supportive care, and most retrospective comparisons suffered from significant selection bias. Unfortunately, the trial experienced slow accrual and was revised to amalgamate two chemotherapy arms, which then also closed early from falling recruitment following the results of other randomised trials. This rendered it underpowered to show a survival difference. The trial was also criticised for employing non-standard chemotherapy regimens which may have led to nonsignificant results [124]. Within these limitations, it concluded the addition of chemotherapy did not improve symptoms or quality of life to any significant degree, in part because the few symptoms which improved were

The role of chemotherapy was indirectly addressed by other studies. The MED trial rando‐ mised 43 malignant mesothelioma (M) patients with stable symptoms to early (E) chemother‐ apy or to delayed (D) chemotherapy when there was symptom progression. It found patients who received early chemotherapy had a longer freedom from symptom progression and a better quality of life; furthermore, despite the small number of patients, there was a trend towards prolonged survival in the early chemotherapy group [125]. In addition to this study, a number of comparative randomised phase III studies found benefit for one regimen over another. Unless the control arms led to worse outcome than best supportive care, which is unlikely, these studies indirectly showed that a benefit for chemotherapy exists. Together, they showed that chemotherapy not only has a role in palliation as well as improving survival, but

MPM is a particularly aggressive condition which responds poorly to treatment and chemo‐ therapy is no exception. In the rush to make an impact, numerous studies have been carried out and almost all agents have been tried. Yet amongst these, most are small, noncomparative phase II studies, so attempts to draw conclusions about the efficacy of each treatment were frustrated by heterogeneity of the populations and variations in treatment schedules, assess‐ ment of response and reporting of outcomes, not to mention selection and publication biases. Frequently, promising outcomes in smaller trials were not replicated in larger and better

In general, the single agent studies have been hard pressed to obtain response rates of over 20% and complete responses were rare. Of the single agent chemotherapy trials, many agents such as the vinca alkaloids (with the exception of vinorelbine) had no efficacy, and responders were few for the alkylating agents [126] [127] [128] [129]. The three classes of agents which showed some degree of response, albeit with response rates that rarely exceeded 20%, were the anthracyclines, platinum compounds and the antimetabolites/antifolates [130]. On the

outweighed by the significant morbidity associated with chemotherapy.

that it should be given early rather than late, and before symptoms worsen.

**8.3. Chemotherapy**

142 Principles and Practice of Cardiothoracic Surgery

conducted trials.

*8.3.1. Towards cisplatin-based chemotherapy*

Gemcitabine is a false nucleotide antimetabolite that gets misincorporated into DNA and hence interferes with DNA synthesis and repair. It showed broad activity against many solid and haematological malignancies, and has been evaluated in mesothelioma. The single agent trials were however inconsistent, with three trials showing widely differing response rates of 0%, 7% and 31% [133] [134] [135]. The overall ITT response rate was a disappointing 6.9%. There was significant heterogeneity in patient selection, chemotherapy dose and schedule, and response evaluation to explain some of the differences seen.

Cisplatin and gemcitabine are synergistic in the killing of neoplastic cells *in vitro* [136]. It is efficacious for several malignancies including non small cell lung cancer for which it became a standard of care prior to 2008 [137]. In a single institution phase II study from Australia, Byrne and colleagues administered a 6-cycle regimen of cisplatin and gemcitabine to 21 patients with confirmed mesothelioma. Tumour response was assessed by what was to become the modified RECIST criteria. There was an impressive 47.6% response rate that exceeded the results of both drugs as single agents, and a number of patients, including non-responders, found symptom relief [138]. This led to a multicentre phase II study of 53 patients using the same regimen [139]. However, the overall response rate this time was only 33% with a median duration of response of 5.4 months; the overall survival from diagnosis was a median of 17.3 months. In Europe, a phase II trial using a different dosing and scheduling regimen, obtained a response rate of 16% for the 25 patients using the WHO criteria for assessment [140].

In the absence of better phase III results, cisplatin and gemcitabine became widely adopted at the turn of the millenium and was also appropriated into multimodality regimens. In a single institution Swiss trimodality study, neoadjuvant chemotherapy with cisplatin and gemcita‐ bine gave a response rate of 32% without increasing perioperative morbidity or mortality, and the ITT overall survival was 23 months [108]. A similar study from Memorial Sloan-Kettering Cancer Centre with 21 patients with advanced MPM reported a response rate of 26% to neoadjuvant cisplatin and gemcitabine. There were no postoperative mortality despite neoadjuvant treatment. The median survival was 33.5 months for those who completed all three modalities [141].

those who were fully supplemented, the instance of neutropenic sepsis fell from 6.3% to 0.6%,

Malignant Pleural Mesothelioma and the Role of Non–Operative Therapies

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145

The trial found a significantly better response rates, time to progressive disease and survival in the combination therapy arm. The headline response rate was a remarkable 41.3% in the combination arm and 16.7% in the cisplation-only arm (*p*<0.0001), all responses were partial responses. However, true to the difficulty of assessing response, an independent review of imaging by the FDA confirmed only 47 of the 94 reported responses in the combination arm,

In the final analysis, the median survival was 12.8 months in the combination arm versus 9.0 months in the cisplatin-only arm, with a hazard ratio of 0.74 [148]. Importantly, the use of vitamin supplementation did not appear to impact on the response rate or survival outcomes. On the basis of an advantage on survival, and in spite of the discrepant response rate data, pemetrexed became the first agent to be approved by the FDA for the treatment of MPM in patients whose disease is not resectable or who are otherwise not candidates for curative

A validated quality of life instrument (Lung Cancer Symptom Scale – mesothelioma) was also administered to all patients on the trial, and the overall symptom score was significantly in favour of the combination arm. Pain scores had worsened on the cisplatin arm but improved on the combination arm; dyspnoea scores had also worsened on the cisplatin arm but remain unchanged on the combination arm. The authors concluded that combination cisplatin and

The trial was notable for its scale, rigorous execution and striking findings. However, it has also attracted a number of criticisms [151] [152]. The study was single blinded and this may have contributed to the discrepancy in observed response rates between the investigators and the FDA reviewers. There was concern that the control group was not the standard of care, ie. cisplatin doublet, but was instead single agent cisplatin which was not widely used. Further‐ more, the outcome of the cisplatin-alone arm was unusually poor and this may have resulted in the combination arm appearing more efficacious. In fact, the survival benefit only reached borderline significance (p=0.051) suggesting the conclusion would have been very sensitive to small differences in outcome. The low toxicity seen in the vitamin supplemented patients may suggest that the optimal dosage of pemetrexed has not been reached, as the trial dosage was derived from the maximum tolerated dose from phase I studies carried out without supple‐

Whilst the evidence and the FDA approval was for nonsurgical disease, on the basis of the survival benefits of the Vogelzang trial, several phase II studies of trimodality treatment adopted cisplatin and pemetrexed as their neoadjuvant chemotherapy from 2003. Krug and colleagues reported a multicentre phase II trial of 77 patients with cT1-3,N0-2,M0 histologically confirmed MPM undergoing trimodality therapy with this combination [153]. 64 patients (81.3%) were able to complete 4 cycles of chemotherapy. The radiological response rate with this regimen was 32.4%, of which 3 had pathological complete response at extrapleural pneumonectomy. The ITT median survival was 16.8 months, and for the 52% who completed

but there were nevertheless still more responses in the combination arm [147].

vomiting from 34.4% to 10.7% and diarrhoea from 9.4 to 3.6%.

pemetrexed offered both symptomatic and survival benefit [150].

surgery [149].

mentation.

#### *8.3.3. The antifolates*

The other class of drugs which showed promise was the antifolate family of antimetabo‐ lites. Antifolates interfere with DNA synthesis through disrupting nucleotide synthesis, a process which requires folate. A trial of 63 patients with unresectable mesothelioma in the 1980s treated with high dose methotrexate found a 37% response rate (albeit with a looser definition of 'response') [142]. Another phase II trial of edatrexate, a drug very similar to methotrexate but for a single carbon to nitrogen substitution and greater potency, showed a response rate of 25% but with significant toxicity (20% early deaths) [143]. This required a protocol amendment with the use of leucovorin rescue. Unfortunately, this alteration also reduced the response rate.

Pemetrexed is a new generation antifolate which inhibits multiple folate-dependent processes including thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase (GARFT), all of which are involved in thymidine and purine nucleotide synthesis. However, folate competes with pemetrexed for cellular uptake. Low folate levels result in higher intracellular accumulation of pemetrexed and thus higher cytotoxicity. Homocysteine levels has been found to be a marker of overall folate status and correlates clinically with pemetrexed toxicity [144]. However, a threshold level below which homocys‐ teine levels could be considered safe could not be established. From 1999, it became a require‐ ment to supplement folic acid and vitamin B12 in studies with pemetrexed, but trials straddling that period would include both non-supplemented and then supplemented patients.

Pemetrexed on its own showed efficacy similar to other single agents. In a multicentre phase II trial, 64 patients with confirmed MPM received pemetrexed [145], the response rate was 14.6%. Therapy was better tolerated by the supplemented patients, who also fared better with a response rate of 16.3% and median survival of 13.0 months. This was in contrast to 9.5% and 8.0 months in the nonsupplemented patients.

A large, international, multicentre, single-blinded phase III study comparing cisplatin and pemetrexed with cisplatin alone was carried out between 1999 and 2001[146]. In this pivotal study, 456 chemonaïve patients with unresectable disease or who were not surgical candidates were randomised to receive cisplatin and pemetrexed or cisplatin alone. Of these, 8 patients were randomised but were not able to receive treatment. At mid-trial, the protocol was modified to include folate and vitamin B12 supplementation to all enrolled patients. Supple‐ mentation greatly reduced toxicity: comparing patients who were never supplemented with those who were fully supplemented, the instance of neutropenic sepsis fell from 6.3% to 0.6%, vomiting from 34.4% to 10.7% and diarrhoea from 9.4 to 3.6%.

In the absence of better phase III results, cisplatin and gemcitabine became widely adopted at the turn of the millenium and was also appropriated into multimodality regimens. In a single institution Swiss trimodality study, neoadjuvant chemotherapy with cisplatin and gemcita‐ bine gave a response rate of 32% without increasing perioperative morbidity or mortality, and the ITT overall survival was 23 months [108]. A similar study from Memorial Sloan-Kettering Cancer Centre with 21 patients with advanced MPM reported a response rate of 26% to neoadjuvant cisplatin and gemcitabine. There were no postoperative mortality despite neoadjuvant treatment. The median survival was 33.5 months for those who completed all

The other class of drugs which showed promise was the antifolate family of antimetabo‐ lites. Antifolates interfere with DNA synthesis through disrupting nucleotide synthesis, a process which requires folate. A trial of 63 patients with unresectable mesothelioma in the 1980s treated with high dose methotrexate found a 37% response rate (albeit with a looser definition of 'response') [142]. Another phase II trial of edatrexate, a drug very similar to methotrexate but for a single carbon to nitrogen substitution and greater potency, showed a response rate of 25% but with significant toxicity (20% early deaths) [143]. This required a protocol amendment with the use of leucovorin rescue. Unfortunately, this alteration also

Pemetrexed is a new generation antifolate which inhibits multiple folate-dependent processes including thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase (GARFT), all of which are involved in thymidine and purine nucleotide synthesis. However, folate competes with pemetrexed for cellular uptake. Low folate levels result in higher intracellular accumulation of pemetrexed and thus higher cytotoxicity. Homocysteine levels has been found to be a marker of overall folate status and correlates clinically with pemetrexed toxicity [144]. However, a threshold level below which homocys‐ teine levels could be considered safe could not be established. From 1999, it became a require‐ ment to supplement folic acid and vitamin B12 in studies with pemetrexed, but trials straddling

that period would include both non-supplemented and then supplemented patients.

Pemetrexed on its own showed efficacy similar to other single agents. In a multicentre phase II trial, 64 patients with confirmed MPM received pemetrexed [145], the response rate was 14.6%. Therapy was better tolerated by the supplemented patients, who also fared better with a response rate of 16.3% and median survival of 13.0 months. This was in contrast to 9.5% and

A large, international, multicentre, single-blinded phase III study comparing cisplatin and pemetrexed with cisplatin alone was carried out between 1999 and 2001[146]. In this pivotal study, 456 chemonaïve patients with unresectable disease or who were not surgical candidates were randomised to receive cisplatin and pemetrexed or cisplatin alone. Of these, 8 patients were randomised but were not able to receive treatment. At mid-trial, the protocol was modified to include folate and vitamin B12 supplementation to all enrolled patients. Supple‐ mentation greatly reduced toxicity: comparing patients who were never supplemented with

three modalities [141].

144 Principles and Practice of Cardiothoracic Surgery

reduced the response rate.

8.0 months in the nonsupplemented patients.

*8.3.3. The antifolates*

The trial found a significantly better response rates, time to progressive disease and survival in the combination therapy arm. The headline response rate was a remarkable 41.3% in the combination arm and 16.7% in the cisplation-only arm (*p*<0.0001), all responses were partial responses. However, true to the difficulty of assessing response, an independent review of imaging by the FDA confirmed only 47 of the 94 reported responses in the combination arm, but there were nevertheless still more responses in the combination arm [147].

In the final analysis, the median survival was 12.8 months in the combination arm versus 9.0 months in the cisplatin-only arm, with a hazard ratio of 0.74 [148]. Importantly, the use of vitamin supplementation did not appear to impact on the response rate or survival outcomes. On the basis of an advantage on survival, and in spite of the discrepant response rate data, pemetrexed became the first agent to be approved by the FDA for the treatment of MPM in patients whose disease is not resectable or who are otherwise not candidates for curative surgery [149].

A validated quality of life instrument (Lung Cancer Symptom Scale – mesothelioma) was also administered to all patients on the trial, and the overall symptom score was significantly in favour of the combination arm. Pain scores had worsened on the cisplatin arm but improved on the combination arm; dyspnoea scores had also worsened on the cisplatin arm but remain unchanged on the combination arm. The authors concluded that combination cisplatin and pemetrexed offered both symptomatic and survival benefit [150].

The trial was notable for its scale, rigorous execution and striking findings. However, it has also attracted a number of criticisms [151] [152]. The study was single blinded and this may have contributed to the discrepancy in observed response rates between the investigators and the FDA reviewers. There was concern that the control group was not the standard of care, ie. cisplatin doublet, but was instead single agent cisplatin which was not widely used. Further‐ more, the outcome of the cisplatin-alone arm was unusually poor and this may have resulted in the combination arm appearing more efficacious. In fact, the survival benefit only reached borderline significance (p=0.051) suggesting the conclusion would have been very sensitive to small differences in outcome. The low toxicity seen in the vitamin supplemented patients may suggest that the optimal dosage of pemetrexed has not been reached, as the trial dosage was derived from the maximum tolerated dose from phase I studies carried out without supple‐ mentation.

Whilst the evidence and the FDA approval was for nonsurgical disease, on the basis of the survival benefits of the Vogelzang trial, several phase II studies of trimodality treatment adopted cisplatin and pemetrexed as their neoadjuvant chemotherapy from 2003. Krug and colleagues reported a multicentre phase II trial of 77 patients with cT1-3,N0-2,M0 histologically confirmed MPM undergoing trimodality therapy with this combination [153]. 64 patients (81.3%) were able to complete 4 cycles of chemotherapy. The radiological response rate with this regimen was 32.4%, of which 3 had pathological complete response at extrapleural pneumonectomy. The ITT median survival was 16.8 months, and for the 52% who completed all three modalities, the median survival was 29.1 months. In a similar vein, a multicentre European Organisation for Research and Treatment of Cancer (EORTC) trial in 2005-2007 recruited 58 patients with earlier stage (cT1-3,N0-1,M0) histologically-confirmed MPM for 3 cycles of cisplatin and pemetrexed followed by EPP and radical radiotherapy [154]. The radiological response after chemotherapy was a remarkable 43.9% (24.6% complete response and 19.3% partial response). The ITT median survival was 18.4 months. 37 patients completed all 3 modalities and their median survival was about estimated at 33 months, although the median was barely reached within the follow-up period and so does not allow a confident estimate.

as patients who were older, have poorer performance status were more likely to receive only single agent therapy. They were also more likely to receive fewer chemotherapy cycles.

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147

A multicentre phase III randomised trial also addressed the benefits of pemetrexed alone as second line chemotherapy versus best supportive care in pemetrexed-naïve patients. 243 patients were randomised, but 60% patients died or progressed on the trial treatment. The response rate was 18.7% with pemetrexed and 1.7% without, and progression free survival and time to progression were all in favour of pemetrexed. However, there was no difference in overall survival observed which may relate the large number of patients on the best supportive care arm who went onto receive early post-discontinuation therapy including pemetrexed. Quality of life was difficult to assess because of the rapid rate of attrition of these

For pemetrexed-pretreated patients, both pemetrexed-containing and non-pemetrexedcontaining regimens have been reported in noncomparative studies. For non-pemetrexed containing regimens, the response rates were reported as <10% and the time to progression was 2-3 months [159] [160]. Pemetrexed retreatment have also been investigated in pretreated patients. In one Italian institutional series, 31 pretreated patients were retreated at disease progression. There was a 19% response rate and a progression free survival of 3.8 months. They also noted that patients who had a longer progression free survival after first line chemotherapy also derived a longer progression free survival after second line retreatment [161], so that the ability to respond to the drug is not lost after first line treatment. In a larger multicentre retrospective observational study, the same authors reviewed 120 pemetrexed pretreated patients of which 42 were retreated with a pemetrexed regimen and 78 with a nonpemetrexed regimen. Those who received the pemetrexed regimen had a higher diseasecontrol rate, and those rechallenged with platinum/pemetrexed combination therapy had a significantly longer progression free and overall survival than those receiving monotherapy

However, the results of second line therapy remain poor and there is no standard therapy, this has made it a platform to test new agents. Many of the new targeted therapy drugs have been investigated as part of second line therapy, but this stage of the disease also places extraordi‐ nary demands on a new agent to prove a therapeutic value, and a negative trial on this platform

In addition to the classical and largely indiscriminant cytotoxic chemotherapy, the landscape of oncology has recently been transformed with the arrival of targeted agents which target the many molecular alterations identified on the malignant cells. The successes of these agents in other malignancies have also led to them being tested in mesothelioma. There are many such agents, some of which have been or are investigated for mesothelioma. In this section we will outline the main targets, but the list is by no means exhaustive. The prevailing theme, never‐

theless, is that the agents tested to date have not been successful.

patients.

(HR 0.11) [162].

risks writing off an effective agent.

**8.4. Targeted therapy**

Another new generation antifolate which has been tested in a randomised phase III setting in MPM is raltitrexed. Unlike pemetrexed, raltitrexed is a selective inhibitor of only one folic enzyme - thymidylate synthase. In a phase II study, single agent raltitrexed gave a response rate of 20.8% with only mild toxicity, without requiring vitamin supplementation [155]. This led to a multicentre randomised phase III study of cisplatin/ raltitrexed against cisplatin alone in patients with MPM not amenable to surgical resection [156]. 250 patients were randomised between the two groups. The radiological response rates were 14% for the cisplatin-only group and 24% for combination cisplatin-raltitrexed. There was a borderline significant increase in median survival for the combination chemotherapy arm (8.8 months vs 11.4 months, *p*=0.048). The study also assessed quality-of-life but did not find difference in the measures between the two arms.

Aside from the scale of the trials, the magnitude of benefits seen in the pemetrexed and raltitrexed randomised trials were very similar. An economic analysis recently found ralti‐ trexed/cisplatin to be much more cost effective than pemetrexed/cisplatin combination chemotherapy [157]. Raltitrexed however, is not available in the US, and so the standard of care there remains cisplatin with pemetrexed or gemcitabine [124].

#### *8.3.4. Second-line chemotherapy*

The response rate for existing chemotherapy is poor and many patients have disease progres‐ sion during first line therapy. Even for those who respond, the improvement is not durable. This relentless progression inevitably leads to a question of second line chemotherapy. The evidence for second-line therapy is however, limited, and many studies are confounded by rampant immortal time bias – that only patients who can survive to and are fit enough to receive second-line chemotherapy will receive it, so that treatment benefits will be arbitrarily overestimated.

For pemetrexed-naïve patients, both pemetrexed and non-pemetrexed-containing regimens have been used. There is little difference between the two and the outcomes were generally poor with a median time to progression of several months. Janne et al. reported on the outcomes of the extended access program for pemetrexed on 153 pemetrexed-naïve patients [158]. Some patients received single-agent pemetrexed, and others combination cisplatin and pemetrexed. The response rate and median survival was 32.5% and 7.6 months for combination therapy and 5.5% and 4.1 months for single agent therapy. There is an element of selection bias as patients who were older, have poorer performance status were more likely to receive only single agent therapy. They were also more likely to receive fewer chemotherapy cycles.

A multicentre phase III randomised trial also addressed the benefits of pemetrexed alone as second line chemotherapy versus best supportive care in pemetrexed-naïve patients. 243 patients were randomised, but 60% patients died or progressed on the trial treatment. The response rate was 18.7% with pemetrexed and 1.7% without, and progression free survival and time to progression were all in favour of pemetrexed. However, there was no difference in overall survival observed which may relate the large number of patients on the best supportive care arm who went onto receive early post-discontinuation therapy including pemetrexed. Quality of life was difficult to assess because of the rapid rate of attrition of these patients.

For pemetrexed-pretreated patients, both pemetrexed-containing and non-pemetrexedcontaining regimens have been reported in noncomparative studies. For non-pemetrexed containing regimens, the response rates were reported as <10% and the time to progression was 2-3 months [159] [160]. Pemetrexed retreatment have also been investigated in pretreated patients. In one Italian institutional series, 31 pretreated patients were retreated at disease progression. There was a 19% response rate and a progression free survival of 3.8 months. They also noted that patients who had a longer progression free survival after first line chemotherapy also derived a longer progression free survival after second line retreatment [161], so that the ability to respond to the drug is not lost after first line treatment. In a larger multicentre retrospective observational study, the same authors reviewed 120 pemetrexed pretreated patients of which 42 were retreated with a pemetrexed regimen and 78 with a nonpemetrexed regimen. Those who received the pemetrexed regimen had a higher diseasecontrol rate, and those rechallenged with platinum/pemetrexed combination therapy had a significantly longer progression free and overall survival than those receiving monotherapy (HR 0.11) [162].

However, the results of second line therapy remain poor and there is no standard therapy, this has made it a platform to test new agents. Many of the new targeted therapy drugs have been investigated as part of second line therapy, but this stage of the disease also places extraordi‐ nary demands on a new agent to prove a therapeutic value, and a negative trial on this platform risks writing off an effective agent.

#### **8.4. Targeted therapy**

all three modalities, the median survival was 29.1 months. In a similar vein, a multicentre European Organisation for Research and Treatment of Cancer (EORTC) trial in 2005-2007 recruited 58 patients with earlier stage (cT1-3,N0-1,M0) histologically-confirmed MPM for 3 cycles of cisplatin and pemetrexed followed by EPP and radical radiotherapy [154]. The radiological response after chemotherapy was a remarkable 43.9% (24.6% complete response and 19.3% partial response). The ITT median survival was 18.4 months. 37 patients completed all 3 modalities and their median survival was about estimated at 33 months, although the median was barely reached within the follow-up period and so does not allow a confident

Another new generation antifolate which has been tested in a randomised phase III setting in MPM is raltitrexed. Unlike pemetrexed, raltitrexed is a selective inhibitor of only one folic enzyme - thymidylate synthase. In a phase II study, single agent raltitrexed gave a response rate of 20.8% with only mild toxicity, without requiring vitamin supplementation [155]. This led to a multicentre randomised phase III study of cisplatin/ raltitrexed against cisplatin alone in patients with MPM not amenable to surgical resection [156]. 250 patients were randomised between the two groups. The radiological response rates were 14% for the cisplatin-only group and 24% for combination cisplatin-raltitrexed. There was a borderline significant increase in median survival for the combination chemotherapy arm (8.8 months vs 11.4 months, *p*=0.048). The study also assessed quality-of-life but did not find difference in the measures between the

Aside from the scale of the trials, the magnitude of benefits seen in the pemetrexed and raltitrexed randomised trials were very similar. An economic analysis recently found ralti‐ trexed/cisplatin to be much more cost effective than pemetrexed/cisplatin combination chemotherapy [157]. Raltitrexed however, is not available in the US, and so the standard of

The response rate for existing chemotherapy is poor and many patients have disease progres‐ sion during first line therapy. Even for those who respond, the improvement is not durable. This relentless progression inevitably leads to a question of second line chemotherapy. The evidence for second-line therapy is however, limited, and many studies are confounded by rampant immortal time bias – that only patients who can survive to and are fit enough to receive second-line chemotherapy will receive it, so that treatment benefits will be arbitrarily

For pemetrexed-naïve patients, both pemetrexed and non-pemetrexed-containing regimens have been used. There is little difference between the two and the outcomes were generally poor with a median time to progression of several months. Janne et al. reported on the outcomes of the extended access program for pemetrexed on 153 pemetrexed-naïve patients [158]. Some patients received single-agent pemetrexed, and others combination cisplatin and pemetrexed. The response rate and median survival was 32.5% and 7.6 months for combination therapy and 5.5% and 4.1 months for single agent therapy. There is an element of selection bias

care there remains cisplatin with pemetrexed or gemcitabine [124].

estimate.

146 Principles and Practice of Cardiothoracic Surgery

two arms.

overestimated.

*8.3.4. Second-line chemotherapy*

In addition to the classical and largely indiscriminant cytotoxic chemotherapy, the landscape of oncology has recently been transformed with the arrival of targeted agents which target the many molecular alterations identified on the malignant cells. The successes of these agents in other malignancies have also led to them being tested in mesothelioma. There are many such agents, some of which have been or are investigated for mesothelioma. In this section we will outline the main targets, but the list is by no means exhaustive. The prevailing theme, never‐ theless, is that the agents tested to date have not been successful.

### *8.4.1. Vascular Endothelial Growth Factor (VEGF)*

Angiogenesis is crucial for tumour growth and mesothelioma is no exception. Indeed, angiogenesis is itself a poor prognostic factor for mesothelioma [163]. VEGF is not only a paracrine growth factor for blood vessels but also an autocrine signal for mesothelioma cells which expresses the VEGF receptors (VEGFR) -1, -2 and -3 [164]. A number of angiogenesis inhibitors are now available, and some has demonstrated effectiveness against malignancies such as colorectal cancer, non-small cell lung cancer (NSCLC) and multiple myeloma.

*8.4.4. NF-κB pathway*

**9. Radiotherapy**

**9.1. Prophylactic irradiation**

subgroup analysis of the pretreated subgroup [179].

we will focus our discussion here on the other two roles.

guidelines [182] [183] and clinical practice [184] [185].

confirmation of subcutaneous nodules obtained.

The NF-κB pathway is important in the pathogenesis of mesothelioma. Two agents that target the pathway have been investigated in mesothelioma. Bortezomib, a proteasome inhibitor which induces apoptosis in mesothelioma cells is currently studied in several trials [176]. In a phase II trial of monotherapy bortezomib, the response rate was 4.8%, and the majority of patients had disease progression on treatment within the first two cycles [177]. Ranpirnase is a ribonuclease found in the Northern Leopard Frog oocyte. It is a tRNase that also prevents NF-κB nuclear translocation. In a large phase II study of single-agent ranpirnase which included patients who previously did not respond to chemotherapy, the response rate was 5% and the ITT median survival was 6 months [178]. In a phase III randomised trial of doxorubicin with or without ranpirnase for both chemonaïve and pretreated patients, there was no difference in ITT overall survival. However, a survival benefit could be seen in the preplanned

Malignant Pleural Mesothelioma and the Role of Non–Operative Therapies

http://dx.doi.org/10.5772/55722

149

Radiotherapy has been studied in three roles for the management of mesothelioma: the palliation of symptoms, prevention of tract site metastases and with radical intent to improve survival alone or as part of multimodality treatment. The first of these was covered earlier and

Mesothelioma has been known to seed along interventional tracts to form painful subcutane‐ ous nodules and radiotherapy is commonly used in the prevention of such metastases. In general, the more invasive the procedure, the higher the likelihood is of getting tract metastases [180]. The carte blanche to give prophylactic irradiation came from a randomised trial in 1995 [181]. Boutin et al. randomised 40 patients following thoracoscopy to local irradiation with 21Gy of 12.5-15 MeV electrons in 3 fractions within 15 days of the procedure. They found an incidence of subcutaneous nodules of 40% in the untreated patients and 0% in the irradiated patients. Since then, prophylactic irradiation of intervention sites has become entrenched in

Two subsequent randomised trials found an incidence of subcutaneous nodules of only about 10% of patients, and that prophylactic irradiation offered no protection against the develop‐ ment of these nodules [186] [187]. The interpretation of these results was confounded by different radiotherapy techniques in these trials [188]. Bydder et al. employed a single fraction of 10Gy of 9MeV electrons delivered up to 15 days following intervention, and O'Rourke employed 21Gy in 3 fractions of 9-12 MeV electrons up to 21 days following intervention. Furthermore, all three trials were underpowered, and in none of them was histological

Further questions which confuse the issue for prophylactic irradiation included the degree to which these nodules are symptomatic - reports varied between 25% and 75% [187] [189],

A number of anti-VEGF agents have been tested in mesothelioma but the results have been disappointing. Bevacizumab (Avastin) is a humanised anti-VEGF-A antibody which has showed effectiveness in metastatic colorectal cancer and NSCLC. In a phase II trial of patients with mesothelioma not amenable to curative intent surgery, they were randomised to cisplatin/ gemcitabine with either bevazicumab or placebo. There was no difference in progression free or overall survival [165]. In a similar vein, the addition of bevazicumab to cisplatin and pemetrexed in a noncomparative trial did not result in improvements in response rates or survival compared to historical results [166]. A randomised trial of pemetrexed-cisplatin with or without bevacizumab is currently ongoing in Europe (MAPS trial).

Thalidomide has been resurrected in the 1990s when it was shown to be a powerful antian‐ giogenic agent. Clinically, it has showed effectiveness in multiple myeloma. In a dose escala‐ tion study, it was given to 40 patients with MPM irrespective of previous treatment [167]. Response was not formally reported, but only 27.5% patients were free from progression at 6 months.

Many other agents targeting the angiogenesis pathways such as sunitinib, vatalanib, sorafenib and NGR-hTNF have been tested in MPM alone or in addition to a cisplatin doublet, however, they mostly showed no or only very modest activity against MPM [168] [169] [170] [171].

#### *8.4.2. Epidermal Growth Factor Signalling*

EGF receptors (EGFR) is overexpressed in MPM. The tyrosine kinase inhibitors targeting EGFR, such as erlotinib and gefitinib, have been so successful in various types of cancer they too have been tested in MPM. Unfortunately, in phase II trials, these two agents did not show any significant activity against MPM: in both erlotonib trials, no objective response was observed [172] [173] whilst the gefitinib trial only showed a 4% response rate [174].

#### *8.4.3. Histone deactylase inhibitors*

Acetylation of histones is an important mechanism of epigenetic regulation of gene expression: acetylation frees the DNA from histones and increases gene expression, at the same time promoting cell cycle arrest or apoptosis. Histone deacetylase (HDAC) inhibitors have been developed and investigated in MPM. In the largest randomised trial in MPM to date, 660 patients pretreated were randomised to vorinostat, (a HDAC inhibitor) or placebo. The results were reported at the European Multidisciplinary Cancer Congress in September 2011. The triallists reported that vorinostat did not improve the response rate or overall survival compared to placebo [175].

#### *8.4.4. NF-κB pathway*

*8.4.1. Vascular Endothelial Growth Factor (VEGF)*

148 Principles and Practice of Cardiothoracic Surgery

months.

*8.4.2. Epidermal Growth Factor Signalling*

*8.4.3. Histone deactylase inhibitors*

compared to placebo [175].

Angiogenesis is crucial for tumour growth and mesothelioma is no exception. Indeed, angiogenesis is itself a poor prognostic factor for mesothelioma [163]. VEGF is not only a paracrine growth factor for blood vessels but also an autocrine signal for mesothelioma cells which expresses the VEGF receptors (VEGFR) -1, -2 and -3 [164]. A number of angiogenesis inhibitors are now available, and some has demonstrated effectiveness against malignancies such as colorectal cancer, non-small cell lung cancer (NSCLC) and multiple myeloma.

A number of anti-VEGF agents have been tested in mesothelioma but the results have been disappointing. Bevacizumab (Avastin) is a humanised anti-VEGF-A antibody which has showed effectiveness in metastatic colorectal cancer and NSCLC. In a phase II trial of patients with mesothelioma not amenable to curative intent surgery, they were randomised to cisplatin/ gemcitabine with either bevazicumab or placebo. There was no difference in progression free or overall survival [165]. In a similar vein, the addition of bevazicumab to cisplatin and pemetrexed in a noncomparative trial did not result in improvements in response rates or survival compared to historical results [166]. A randomised trial of pemetrexed-cisplatin with

Thalidomide has been resurrected in the 1990s when it was shown to be a powerful antian‐ giogenic agent. Clinically, it has showed effectiveness in multiple myeloma. In a dose escala‐ tion study, it was given to 40 patients with MPM irrespective of previous treatment [167]. Response was not formally reported, but only 27.5% patients were free from progression at 6

Many other agents targeting the angiogenesis pathways such as sunitinib, vatalanib, sorafenib and NGR-hTNF have been tested in MPM alone or in addition to a cisplatin doublet, however, they mostly showed no or only very modest activity against MPM [168] [169] [170] [171].

EGF receptors (EGFR) is overexpressed in MPM. The tyrosine kinase inhibitors targeting EGFR, such as erlotinib and gefitinib, have been so successful in various types of cancer they too have been tested in MPM. Unfortunately, in phase II trials, these two agents did not show any significant activity against MPM: in both erlotonib trials, no objective response was

Acetylation of histones is an important mechanism of epigenetic regulation of gene expression: acetylation frees the DNA from histones and increases gene expression, at the same time promoting cell cycle arrest or apoptosis. Histone deacetylase (HDAC) inhibitors have been developed and investigated in MPM. In the largest randomised trial in MPM to date, 660 patients pretreated were randomised to vorinostat, (a HDAC inhibitor) or placebo. The results were reported at the European Multidisciplinary Cancer Congress in September 2011. The triallists reported that vorinostat did not improve the response rate or overall survival

observed [172] [173] whilst the gefitinib trial only showed a 4% response rate [174].

or without bevacizumab is currently ongoing in Europe (MAPS trial).

The NF-κB pathway is important in the pathogenesis of mesothelioma. Two agents that target the pathway have been investigated in mesothelioma. Bortezomib, a proteasome inhibitor which induces apoptosis in mesothelioma cells is currently studied in several trials [176]. In a phase II trial of monotherapy bortezomib, the response rate was 4.8%, and the majority of patients had disease progression on treatment within the first two cycles [177]. Ranpirnase is a ribonuclease found in the Northern Leopard Frog oocyte. It is a tRNase that also prevents NF-κB nuclear translocation. In a large phase II study of single-agent ranpirnase which included patients who previously did not respond to chemotherapy, the response rate was 5% and the ITT median survival was 6 months [178]. In a phase III randomised trial of doxorubicin with or without ranpirnase for both chemonaïve and pretreated patients, there was no difference in ITT overall survival. However, a survival benefit could be seen in the preplanned subgroup analysis of the pretreated subgroup [179].


**10. Performance evolution**

We will utilize Classification Accuracy, Confusion Matrix, and ROC curve to assess the effectiveness of our systems.

Classification Precision It is a model classification metric in which the number of right predictions is compared to the total number of predictions produced by each model. Matrix of Confusion is one of the evaluation techniques that use the model's output and four categories: True positives are values that are supposed to be positive, whereas false positives are values that are expected to be positive but turned out negatively, making them fake. True negative values are those that are predicted to be negative and hence are true. False negative denotes Values that are predicted to be negative but are positive, hence they are false [13, 14].