Category: Prostate Cancer

Cancer is a disease causes due to mutation in cells and damaged the whole immune system. There are a lot of methods and treatments are used to cure it. And one of them is the use of robots to treat the cancerous part. in it, following are used as nanotechnology, prostate treatment, cyber knife robotics etc

Cancer

It is a disease that causes the cells to divide uncontrollably and results into tumors, damaged immune system and other impairment that can be fatal. There are more than 100 types of cancer as skin cancer, prostate cancer, lung cancer, colon cancer. There symptoms vary depending on type.

Causes of Cancer

There are many causes of cancer and here are the following

In addition to smoking, risk factors for cancer include:

• heavy alcohol consumption
• excess body weight
• physical inactivity
• poor nutrition

For example, over 480,000 people die in the U.S. each year from smoking cigarettes, according to data reported in 2014.

Methods of Treatment

There are many types of treatments that are used and it depends upon which type of cancer do you have and how much advance it is.

• Surgery
• Radiation Therapy
• Chemotherapy
• Immunotherapy to Treat Cancer
• Targeted Therapy
• Hormone Therapy
• Stem Cell Transplant
• Precision Medicine
• Robotics Cancer Treatment

Robotics Cancer Treatment

As the title refers that robot is performing the operation but in real it doesn’t like that. Instead it refers to when surgeons direct the robotic tools during the surgery. Robotics surgery system use more than one robotic arm that control remotely by surgeons. One robot arm has a laparoscope. Other arm of the robot hold smaller surgical instrument that can fit into an inch long incision. That robot provides the surgeon three dimensional view of the tumor. Its just like that of the joy stick of the video game controlling each arm which copy the motions of the wrist and hand providing dexterity.

Historical Background

In 1985, the first document featuring robotic assisted surgical procedure was used. When the first puma 560 robotic surgical arm was used in neuro surgical biopsy.

In 2000, the da vinci surgery system becoming the first robotic system approved by FDA for general laparoscopic surgery. This was the first time when the FDA approved a system of surgical instruments and camera utensils. Its predecessors rely on the use of many surgical assistance and endoscopes to perform surgery. The da vincy robotic surgery system allow the surgeon to see the three dimensional view to operate the area with high resolution.

It is so advanced technique that not available in all hospitals of UK.

Prostate Treatment with Robotics

It is a disease in which cancerous cells form in the tissues of prostate. The prostate is a gland in the male reproductive system.

SMART(Samadi Modified Advanced Robotic Technique) is an advanced prostate cancer surgery treatment that quickly reduces blood loss, pain, hospital stay, recovery time and the side effects of other types of prostate cancer treatments. The SMART Technique is also known as bloodless prostate surgery.

As in this technique there is no need to open the endopelvic fascia or cutting the dorsal vein complex. This results in no sutures and less damage to the neurovascular bundle.

The da Vinci robotic prostate cancer surgery system is able to provide superior clinical prostate cancer treatment results when compared to non-robotic traditional and scope-assisted procedures.

As this procedure provides us the following advantages.

• Reduced Risk of Complications With Robotic Prostate Surgery
• Quicker Recovery Period After Robotic Prostate Surgery
• Minimal Scarring After Robotic Prostate Cancer Surgery

Cyberknife Robotics for Cranial Tumors

The CyberKnife is a frameless robotic radiosurgery system used for the treatment of malignant and benign tumours, and other medical conditions.

In this method radio therapy treatement is used with the intention of targeting the cancerous cells more precisely and more accurately than standard radiotherapy.

That cyber knife consists of two elements that are as follows.

1. Accelerator from which radiations are produced
2. Robotic arm which allows the energy to direct it to any part of the body from any direction.

To find the success rate and the complications offered by cyberknife robotic radio surgery a research was planned at department of cyberknife robotic radio surgery at the jinnah post graduate medical center (JPMC) Karachi, which is the only place in the country where it is offered free of cost and also the only place where the facilities are present according to the need.

Results of research

Initially, 260 patients were selected, but 9(3.5%) were lost, and the final sample size was 251(96.5%). There were 128(50.9%) adult males and 108(43%) adult females in addition to 15(5.9%) children. The overall net age was 47±14.5 years (range: 3.5-84 years).

Clinicall successful results were as seen in 225(90%) patients, while 8(3%) showed no radical change in symptoms and 18(7%) patients’ awaited for the results.. Seven (3%) patients died after treatment; 3(1.2%) of them were at risk of high-grade glioma with repetition ot its occurrence and 0.3 % of it was at the risk of metastasis.

Improvement from radiology was noted in 218(87%) patients, stable disease in 138(55%) and 80(32%) cases showed more than 30% lowering in size after 6-12 months of follow-up. Only 5(2%) cases showed increase in size within 3-month interval due to post-radiation oedema. Acute transient post-radiation changes were seen in 25(10%) patients, sub-acute changes in 4(1.59%) and 1(0.3%) patient showed radionecrosis after 9-month interval. Follow-up MRI of 28(11%) patients were treated in the last 3 months of the study was awaited.

Nano robotics

World health organization estimated that cancer is a major cause of death and 7.6 million people died because of it last year, so in order to reduce these numbers scientists are continuously trying to derive new methods for the treatement and one of it is nanorobotics.

Nano robotics is a technique dealing with miniscule things at moleculer level. These are extremely small electrochemical systems that are designed to perform a specific task with great accuracy and precision. This allows the usage of drugs in nano size to minimize its affects on the other body cells and the operation is performed only on the affected cells

Properties of nano robots

1. They respond to acoustic signals and able to two way communication
2. They are treated as cylinders one micrometer in length and 0.5 micrometer in diameter
3. There structure has two spaces one is interior and other is exterior
4. They consist of sensor elements nano chips containers and motors
5. They work in response to environment stimuli

Nano robot architecture

They consist of chemical sensors and by using which they receive response from the body and also respond to the environmental stimuli, similarly they also respond to the change in ph as well. They consist of actuator as electromagnetic, electrostatic and electrothermal as well energy supply as from the series of hot and cold conductors attached with it causes the production of continuous energy for its proper working

ADVANTAGES

• This technique helps the patient to get rid of disease completely.
• Due to its small size it also helps in the easily flow without blocking the capillary flow.
• It is inexpensive.
• As it attack only on the cancerous part so it is a less painful method.
• It is easily disposable.

DISCUSSION

As the development of robotics method provides the human a lot of methods to treat that fatal disease and it also helps in the reduction of the people’s number who got affected by it but still this method is very complicated as the design of the machine is itself very difficult to design. It is also not available even in al hospitals of UK so not every can avail this facility. Also its initial cost is very high and its electrical system can create stray fields whi9ch can affect the human body so with a lot of advantages it has some drawbacks as well.

REFRENCES

1. R.Hariharan, J.Manohar, ”Nanorobotics As Medicament” IEEE 2010
2. M.Venkatesan, B.Jolad “Nanorobots in cancer treatments”IEEE 2010
3. Abhijeet Kapse ”Fight with cancer using nanorobots ”
4. “New paradigm for tumor theranostic methodology using bacteria based microrobots” Nature.com. Nature publishing group, n.b.web.18 feb 2014
5. www.cancerresearch UK.org / about cancer
6. Susan Mayor ”Robotics surgery for prostate cancer” Published on 27 July 2016
7. Brian Davies “Robotics Surgery a personal view of the past, present and future” published in January 1, 2015
8. David Jayne, ALessio Pigazzi, Helen Marshall”Effect of robotic assisted vs conventional laparascopic surgery” published in 24 October 2017

In the National Archaeological Museum of Lisbon, Portugal, a mummified middle-aged male of ancient Egypt is stored. Not long ago, scientists studied this corpse and found that there are many high-density round tumors between the pelvis and the lumbar spine, which is a typical manifestation of prostate cancer. Moreover, his prostate cancer has spread and spread throughout the body.

From ancient Egypt to the present, more than 2,000 years have passed. Today, prostate cancer is already one of the most common cancers in men, and one out of every nine men will develop prostate cancer in their lifetime. However, according to the authoritative report of the American Cancer Society, the mortality rate of prostate cancer patients in 2014 was sharply reduced by 51% compared with 1993. This reflects the tremendous progress of prostate cancer treatment in the past few decades. In today’s article, the WuXi PharmaTech content team will work with readers to revisit the history of prostate cancer in humans.

From the first prostate cancer to two Nobel Prizes

It is hard to imagine that prostate cancer was considered ‘a very rare disease’ when it was first diagnosed in 1853. In the next century, scientists and doctors have made very limited progress. In the 1940s, prostate cancer was synonymous with death. After diagnosis, the patient’s survival time was only 1-2 years.

The transfer occurred in 1941. This year, Professor Charles Huggins of the University of Chicago and his colleagues published several papers revealing the relationship between hormones and the prostate. In theory, the growth and development of the prostate depends on the action of androgens. Therefore prostate cancer may also be associated with androgens. In other words, if it can inhibit the function of androgen, it may inhibit the growth of prostate cancer.

In this series of studies by Professor Huggins, scientists have confirmed that androgen and estrogen will compete and suppress each other. As they have previously envisaged, by injecting estrogen into patients, it can effectively delay the progression of prostate cancer. In addition, they also found that similar results can be achieved by surgical removal of the testes. Therefore, this practice of treating tumors by reducing androgen levels is also referred to as ‘castration treatment.’

Many scientists believe that this is the first time humans have successfully controlled prostate cancer by using certain chemicals. Since the discovery of this hormone therapy, Professor Huggins also won the 1966 Nobel Prize in Physiology or Medicine.

Professor Huggins’s major discovery unveiled the curtain of endocrine therapy for prostate cancer. In the following decades, scientific breakthroughs have emerged, and a variety of drugs that inhibit androgen have also appeared. One of the important drivers came from the team of Professor Andrew Schally. Their research shows that a hypothalamic hormone called luteinizing hormone releasing hormone (LHRH) can ultimately promote testosterone production through a series of biochemical pathways, and testosterone is a major androgen. Based on this discovery, scientists have developed a drug called LHRH analog. In patients, high levels of LHRH analogues can inhibit testosterone production and also have therapeutic effects. As a result of the discovery of LHRH, Professor Sally shared the 1977 Nobel Prize in Physiology or Medicine with two other scientists.

Hormone therapy continues to break through bottlenecks

However, the road is one foot high and the height is one foot. Over time, people gradually discovered that after castration treatment, cancer cells will gradually adapt to this low hormone level environment and continue to grow. At this time, the disease also progressed to ‘castration-resistant prostate cancer’ (CRPC). Because prostate cancer has a long course, it is almost an inevitable stage of all prostate cancer, and the median survival of patients is only 1 to 2 years.

The presence of castration-resistant prostate cancer once puts endocrine therapy that inhibits androgen into a bottleneck, and treatment relies only on extremely limited means such as chemotherapy and radiation therapy. Until the new century, the relevant therapeutic field finally ushered in a new breakthrough.

One of the breakthroughs is ‘anti-androgen therapy.’ Unlike previous therapies, these therapies act directly on the androgen receptor, inhibiting androgen binding to it, and doing it more thoroughly. In fact, as early as 1989, the first generation of anti-androgen therapy factor was approved by the US FDA. However, early anti-androgens have a low affinity for androgen receptors, thus limiting the use of such therapies.

In 2012, Xtandi (enzalutamide), jointly developed by Medivation (later acquired by Pfizer) and Astellas, was approved for marketing. As a new generation of anti-androgen therapy, it inhibits both androgen binding to its receptors and inhibits androgen receptors from entering the nucleus, preventing it from initiating downstream biochemical pathways. In patients who suffer from castration-resistant prostate cancer and whose condition has metastasized and chemotherapy is powerless, half of the patients can survive for 18.4 months if they receive Xtandi treatment. This number was nearly five months longer than the placebo control group.

In 2018 and 2019, Janssen’s Erleada (apalutamide) and Bayer’s Nubeqa (darolutamide) were also approved by the FDA for listing in the army of castration-resistant prostate cancer.

It is worth mentioning that, just in September this year, Erleada was also approved to treat castration-sensitive prostate cancer, further expanding the number of people who can benefit. In clinical trials, it significantly prolonged the overall survival of patients and reduced the risk of death by 33%. Xtandi also reached the end of the extended overall survival in clinical trials for hormone-sensitive prostate cancer, and is expected to be approved by the end of this year.

At present, China’s second-generation anti-androgen drugs from three pharmaceutical companies have entered Phase III clinical trials, including SHR3680 from Hengrui Medicine, Pukrudamide from Pioneer Pharmaceuticals, and HC-1119 from Sea Cisco.

In addition to the second-generation antiandrogens, there is the new hormonal therapy of Zytiga (abiraterone) approved by the FDA in 2011. Although it can also inhibit androgen, the principle is not to provide a relatively resistant hormone, nor directly against its receptor. Instead, it targets a key enzyme in the androgen synthesis pathway, CYP17.

As a highly potent, selective and irreversible CYP17 enzyme inhibitor, Zytiga blocks the synthesis of androgen in testes, adrenal glands, and prostate cancer tissues, minimizing androgen levels in the body. In a large phase 3 clinical trial involving 1,195 patients, its efficacy was also confirmed.

Expansion of the ‘weapon bank’: diversified treatment methods

Although hormone therapy continues to break through, it has always relied on the inhibition of androgen receptor signaling pathways to curb the proliferation of cancer cells. However, cancer cells eventually develop resistance to hormone therapy in a variety of ways. As a result, researchers are also developing innovative treatments that are not based on androgen signaling pathways, adding a diverse range of weapons to the arsenal of prostate cancer.

One of the innovative therapies is the world’s first ‘therapeutic’ tumor vaccine Provenge (sipuleucel-T). As an individualized therapy, it separates dendritic cells (an antibody-presenting cell) from the patient’s blood and co-cultures with a specific fusion protein. The fusion protein is divided into two parts, one is prostatic acid phosphatase (PAP), which is the main antigen on prostate cancer cells; the other is an immune signaling factor that promotes the maturity of these antibody-presenting cells. Subsequently, these processed cells, which are able to effectively recognize prostate cancer antigens, are returned to the patient and activate immune T cells to find and kill cancer cells that express PAP. Phase 3 clinical trial results also confirmed that it can significantly improve the median survival of patients.

Fortunately, a recent study found that these immune cells activated by tumor vaccines have long-term memory and are expected to have long-term therapeutic effects.

In addition, Merck’s star immunotherapy Keytruda (pembrolizumab) has also achieved positive results in early clinical trials and has added three phase 3 clinical trials. In the future, it is also expected to bring good news to patients with prostate cancer.

In addition to the immunotherapy described above, targeted therapies developed based on the molecular characteristics of cancer have also become the latest trend in cancer treatment. In prostate cancer, the latest breakthrough comes from the use of PARP inhibitors. For example, in August this year, Merck (MSD) and AstraZeneca announced that Lynparza (olaparib) has achieved positive results in a phase III clinical trial of men with metastatic castration-resistant prostate cancer (mCRPC). Homologous recombination repair gene mutation (HRRm) and previous disease progression after hormone anticancer therapy (such as enzalutamide and abiraterone).

Future directions: prevention and new therapies will build a strong line of defense

At the same time that prostate cancer therapy has made a series of breakthroughs, the diagnosis of prostate cancer has also made important breakthroughs. Currently, a protein called prostate specific antigen (PSA) has been validated for decades, and can be used for early screening, adjuvant diagnosis, therapeutic monitoring, and prognosis of prostate cancer. Recently, a 13-year follow-up of the Lancet showed that PSA screening reduced prostate cancer mortality by 21% in men aged 55-69, and compared with 9 and 11 years of follow-up. This benefit is growing. This also confirms the importance of early screening for prostate cancer.

At present, although the incidence of prostate cancer remains high, it also reflects the progress of diagnostic screening technology to a certain extent. Under a range of available therapies, the patient’s disease is well controlled and treated. The diagnosis of prostate cancer is no longer tantamount to leaving the world in the short term.

In the face of these advances, scientists have not stopped the pace of research and development, whether in the early screening of patients or the development of innovative therapies have made positive progress. For example, Bio-Techne’s liquid-based biopsy test based on exosomes has recently received a breakthrough medical device certification from the US FDA. It allows prostate cancer patients to determine the type of prostate cancer without having to undergo an invasive tissue biopsy.

In the development of innovative therapies, Janssen recently announced that the PARP inhibitor nilapali has received FDA breakthrough therapy for the treatment of castration-resistant prostate cancer patients. In May of this year, WuXi PharmaTech partner Arvinas announced that its leading PROTAC protein degradation therapy ARV-110 was awarded the fast track qualification granted by the US FDA. ARV-110 directly degrades androgen receptors, which can be effective in cancer patients who over-express or produce mutations in androgen receptors, thereby benefiting mCRPC patients who are less responsive to second-generation hormone therapy. The therapy has now entered clinical trials and preliminary data is expected to be released later this year.

With the emergence of early screening techniques and innovative therapies, can humans eradicate prostate cancer, a killer that has plagued men for thousands of years? Let us wait and see!

Introduction

This essay will seek to discuss the role of androgen receptor therapy in advanced prostate cancer. Prostate cancer and the androgen receptor (AR) will be discussed, namely the origins of androgen receptor targeted therapy, its development and role in treatment of advanced prostate cancer today, and the future of targeted therapy. Androgen receptor targeted therapy is utilised in advanced prostate cancer to improve morbidity and mortality. The role of AR targeted therapies have evolved over the past 80 years to become more selective, more efficacious and more favourable. As our understanding of the AR itself grows, so too does our ability to modulate it and improve treatments. From the discovery that prostate cancer was androgen-dependent in 1941, to current treatment methods for advanced prostate cancer, the role of the androgen receptor in treating these cancers has evolved significantly. This essay aims to discuss the evolution of targeted therapies for the AR and to give context in the current treatment of advanced prostate cancer today.

The Prostate Gland

The prostate is an exocrine gland of the male reproductive system, located at the base of the bladder surrounding the urethra. The name “prostate” derives from the ancient Greek προστάτης (pro-státēs), which means “one who stands before/guardian” in reference to its location at the base of the bladder. The prostate is primarily involved in production of prostatic fluid, which is one of the main components of semen. Prostate specific antigen (PSA) is released by prostatic epithelial cells. It is involved in liquefying semen facilitating the motility of sperm. PSA is also an important biomarker of prostate cancer, and is used in screening programmes. Measuring the PSA level in prostate cancer is important, as high serum PSA levels correlate with poorer outcomes. Low serum PSA levels have been shown to generally correlate with more positive outcomes .

Prostate cancer *A lot more detail here – mention CRPC, the Ahmed paper was succinct*, also mention androgen sensitive and androgen-independent cancers.

Prostate cancer is a life-threatening disease. Worldwide, prostate cancer has the second highest incidence of cancer in males at a rate of 31.1 per 100,000 . In the EU in 2012, there were 345,000 new cases of prostate cancer, which accounted for 24% of all newly diagnosed cancers. It also resulted in 72,000 deaths, 10% of all cancer deaths that year . Thus, prostate cancer poses a significant threat to public health. Prostate cancer often remains clinically silent until later stages of the disease, when rates of survival are often lower. Traditionally, the term ‘advanced prostate cancer’ was used to describe cancer which had metastasized into surrounding tissues, pelvic lymph nodes, and bone. However, it is now more accurately characterised as cancer which has spread beyond the capsule of the prostate, with stages as low as T3/N0/M0 to reflect the significant risks of progression and death . Diagnosis of prostate cancer usually occurs following abnormal results of a PSA screening test or digital rectal exam (DRE). A biopsy is then taken, and if cancer is present, it can be given a Gleason grade to assess tumour size, margin status and pathologic stage . Prostate cancers metastasize most commonly to surrounding lymph nodes, bone, the lungs, and the liver . While prostate cancers can initially be treated with androgen deprivation therapy (ADT), all cancers will eventually become resistant, and are then dubbed castration-resistant prostate cancers (CRPC). This process will be discussed in the context of the AR itself later in this essay.

Ligands for the AR

Understanding the ligands for the AR gives a Testosterone and 5-dihydrotestosterone (DHT) are the main androgens activating the AR, and they are synthesised in the adrenal glands and the testes. Androgen synthesis is regulated by Gonadotropin-releasing hormone (GnRH) (also known as luteinizing hormone releasing hormone (LHRH)). GnRH is released by the hypothalamus and travels to the anterior pituitary gland via the hypophyseal portal system. This results in production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the anterior pituitary, which enter the bloodstream. Upon reaching the testes, LH targets Leydig cells in the interstitial space, stimulating testosterone release. GnRH release from the hypothalamus also stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary, which causes the adrenal glands to synthesise and release testosterone. Testosterone displays a negative feedback loop of GnRH and LH release from the hypothalamus and pituitary gland. Several hormonal therapy treatments in advanced prostate cancer target this pathway.

Approximately 90% of testosterone is produced by the testes, and between 5-10% is produced by the adrenal glands. A portion of free testosterone is converted to DHT in prostate cells via the action of 5-alpha-reductase. DHT is a more potent form of the hormone, and has a higher affinity for the AR.

The androgen receptor

The AR is a ligand-dependent nuclear transcription factor, and is a member of the nuclear receptor family. The AR gene is located on the X-chromosome, meaning there is only one copy in males. It has displayed more mutations than any other gene, it is suggested that this is because mutation in the AR is not incompatible with life . Structurally, the AR has 4 regions: an NH2 transactivation domain (NTD) a DNA-binding domain (DBD), a ligand-binding domain (LBD), and a hinge region which connects the LBD and DBD . The ligands which act on the AR are testosterone and 5-dihydrotestosterone (DHT). They bind to the LBD of the AR in the cytosol, which causes a conformational change of the receptor, releasing the heat shock proteins which were acting as chaperone molecules, and allows translocation of the AR to the nucleolus . In the nucleus, the androgen/AR complex dimerises and the DBD binds to androgen receptor elements (AREs) via two zinc fingers, allowing the regulation of gene transcription pathways . These pathways include those responsible for cell proliferation, differentiation and anti-apoptotic pathways.

In the healthy prostate, epithelial AR supplies secretory proteins to the prostate gland, such as prostate-specific antigen (PSA). Stromal AR plays a role in the growth of the prostate.

In prostate cancer, upregulation of transcription factors leads to increased action of the AR. This leads to the promotion of growth, explaining the increased size of the prostate on DRE. It also accounts for the increased level of PSA found in the blood, allowing for its use as a biomarker of prostate cancer.

Initiation of prostate cancer can occur due to dysregulation of several pathways. These include RAS/RAF and PI3K pathways, and upregulation of the ETS family of transcription factors. The expression of the tumour suppressor PTEN is commonly lost in prostate cancer. The upregulation of ETS factors may prime the prostate epithelium to respond to upstream signals such as PTEN loss. Abnormal AR signalling promotes neoplastic growth as the balance between cell proliferation and apoptosis is lost.

A historical perspective of androgen receptor targeted therapy

The fundamental concept that prostate cancer is androgen sensitive was established by Huggins and Hodges in 1941. They established that androgen deprivation had a beneficial impact on metastatic prostate cancer outcomes. Huggins was awarded the 1966 Nobel prize in physiology or medicine for ”his discoveries concerning hormonal treatment of prostatic cancer” . Their results set the standards of care for prostate cancer: bilateral orchiectomy or administration of oestrogen.

In 1967, the Veterans Administration Cooperative Urological Research Group (VACURG) showed that orchiectomy and administration of the synthetic oestrogen diethylstilboestrol (DES) were equally efficacious in treating prostate cancer. However, DES was later associated with an increased risk of cardiovascular disease and thromboembolic events, leading to a decrease in its use .

In 1971, Schally explained the structure of GnRH and began researching synthetic agents which could act as agonists of the hormone. Increased levels of GnRH agonists lead to decreased pituitary receptors for the hormone, leading to suppression of FSH and LH. This process leads to a decrease in testosterone levels to castration-equivalent levels . Leuprolide is an example of a GnRH agonist.

Antiandrogens

Antiandrogens are a type of androgen receptor therapy. They are also known as androgen antagonists as they prevent the androgens from exerting their effects on the AR. Antiandrogens are mainly used to counteract androgens made locally in the prostate that are of adrenal origin, as testicular androgens are easily depleted by medical or surgical castration

Steroidal antiandrogens were developed before their non-steroidal counterparts. Cyproterone (CPA) was the first steroidal antiandrogen, and was used in advanced prostate cancer. It acts on the AR by competitively blocking DHT and testosterone from binding. CPA was as effective in treating advanced prostate cancer as orchiectomy and DES . Steroidal antiandrogens also displayed many unwanted side effects; mainly due to the lowering of testosterone levels which resulted in a decrease in libido and impotence. As a result of these unwanted effects, development of non-steroidal antiandrogens began.

Non-steroidal antiandrogens target the AR alone and do not display the side effects shown by CPA. First generation antiandrogens were the first to be developed. This essay will look at Flutamide was initially indicated as a bacteriostatic drug, but later trials demonstrated its antiandrogenic effects . It was first nonsteroidal antiandrogen to be approved in the United States by the FDA in 1989 for prostate cancer. Its use was combined with either chemical or surgical castration. A trial in the US administering daily flutamide along with leuprolide (GnRH agonist) to patients with newly diagnosed advanced prostate cancer resulted in a median survival increase of 36 months versus 28 months in patients treated with leuprolide alone . Side effects of flutamide include diarrhoea and anaemia, and the FDA mandated that liver enzymes be measured due to hepatotoxicity seen in some patients.

Nilutamide was shown to improve outcomes in advanced prostate cancer when used in combination with orchiectomy versus orchiectomy alone . This led to the approval of nilutamide in combination with orchiectomy or co-administration of a GnRH agonist by the FDA in 1996.

Bicalutamide is another first generation nonsteroidal antiandrogen and was first approved in the treatment of prostate cancer in 1995 which also inhibits the AR selectively. Bicalutamide has a longer half-life than the other agents, 7 days versus 6-8 hours for flutamide. Due to the increase in testosterone and oestrogen levels in bicalutamide treatment, it is associated with gynaecomastia, breast pain, impotence, and hot flashes.

With continued treatment of first generation antiandrogens in advanced prostate cancer, resistance can occur. It has been suggested that this resistance may be due to AR overexpression, or due to mutations in the LBD of the AR which can alter the response of the receptor and cause the first generation antiandrogens to act as partial agonists. As a result of these limitations, research on the second generation agents began.

Enzalutamide is an example of a second generation nonsteroidal antiandrogen. It is a selective agonist of the AR with a high affinity for the LBD. It was developed following research into antiandrogens which could still function when the AR is overexpressed, one mechanism of CRPC. When enzalutamide binds to the AR, it inhibits translocation of the receptor to the cell nucleus. This prevents the recruitment of cofactors in the AR and prevents the AR binding to DNA. It displays a 5-8 times greater affinity for the AR compared to bicalutamide, and also induced tumour shrinkage and bicalutamide only slowed tumour growth . Enzalutamide has been shown to be efficacious in treatment of advanced CRPC. The PREVAIL study found that disease progression was reduced by 81% in the enzalutamide group compared to the placebo group. When the study finished, 72% of the enzalutamide group were alive compared to 63% of the placebo group; equating to a 29% reduction in risk of death for the group size . The adverse effects seen in enzalutamide therapy include back pain, hot flushes, and most commonly, fatigue.

Introduction

Drug discovery and development involve a number of stages to develop a novel drug, therefore a reduction in time frame new approach is developed which is repurposing of existing drugs. Till to date, the importance of drug repurposing is significantly increased to identify new use of the pre-existing drug. Repurposed of the drug can be achieved by two methods, one is unintentionally and another by systemically (Parvathaneni, Kulkarni, Muth and Gupta, 2019). Drug repurposing is one type of drug recycling, to treat except the original one. For the new drug approximately 15 years can be taken place to bring it in the market as compared to repurposed drug takes only 3 to 12 years (Dey, 2019). This literature review is about drug repurposing with its development, opportunities and challenges. There are a number of methods are developed to identify and validate target of drug repurposing such as, computational and experimental. Both methods are different in lots of way except proteomics and genomics because these two entities make cells and tissues. These Omics are good biomarkers for the accurate treatment of disease. (Talevi, 2018). There are a number of the opportunities of drug repurposing such as, when economic conditions are not good, unclear pathophysiology of rare disease, repurposing method is quick way to identify genetic variation, responsible factors of the disease and identified protein target (Pushpakom et al., 2018). There is low risk of adverse drug reaction and toxicity. Drug repurposing has high success rate i.e. 1/10 as compared to novel drug discovery i.e.1/10000. In the drawback, impairment in patenting new use of existing medicine, sometimes chances of the rejection because of previous toxic, adverse reaction and safety history. There are some strategies to accelerate drug repurposing such as, in silico models, target docking, artificial intelligence (AI). For the promotion of drug repurposing collaboration for bringing new ideas and approaches, corporate social responsibility, social media is also helpful to promote the awareness of drug repurposing (Dey, 2019). The main aim and objective of this literature review is, to review repurposed drugs with their potential as repurposed use including advances and challenges.

Discussion

This literature review includes discussion about the Statins, Digoxin, Exenatide and Itraconazole with their history of link between traditional use and repurposed use, how they act potentially on target as a repurposed drug with their challenges.

Repurposed drugs:

Statins:

Statins are repurposed as an anti-cancer drug because; there is a common link between cardiovascular disease and cancer such as, aging-related, epidemiology and pathophysiology. Both are overlapping on each other in case of biology. Both have similar risk factors for instance, hypertension, obesity, smoke, and type 2 diabetes mellitus. Tissue inflammation is a common reason for the progression of cancer and CVD. Moreover, clonal hematopoiesis is one of the links between both diseases. Before repurposing statin as an anti-cancer drug, it is approved for the treatment of hypercholesterolemia and atherosclerosis by FDA. Statins reduced the production of farnesyl pyrophosphate and geranyl-geranyl phosphate by inhibiting HMG-CoA reductase in the mevalonate synthesis pathway. These both are important for activation of protein G which regulates proliferation, migration, and death of cell. Higher dose of statins shows apoptosis by decreasing the level of anti-apoptotic proteins such as, Bcl-2 and Bcl-xL and inhibition of cancerous cell growth by blocking G beta and gamma dimer in the plasma membrane. Statins shows major benefit in breast and liver cancer. Few investigations done in the use of Statins with combination therapy such as, simvastins combined with irinotecan, 5-flurouracil and leucovorin showed good anticancer activity during phase 2 studies (Gelosa, Castiglioni, Camera and Sironi, 2020). Particularly simvastatins gives adorable result in the case of solid tumor, shown during clinical trial. In the case study of simvastatin shows that , ≥40 mg/day for 2-5 years reduced colorectal cancer. These studies show the potential of Statins as an anti-cancer drug (Kale et al., 2020). Statins shows anti-cancer activity in glioma proven by pre-clinical studies. The activation of ERK and AKT in rat C6 glioma cells is block by mevastatins and simvastatins. In mice, simvastatines caused autophagy and inhibit TGF-β signaling and give relief in glioma, however during a control case study at two centre, Columbia University Medical Center and the University of California San Francisco showed inverse effect with simvastatins with long duration use but there were no risk with rosuvasttin and atorvastatin. More lipophilic statins show best risk reduction. Therefore, it is major challenge in glioma only risk reduction achieved by use of only lipophilic statins (Siegelin et al., 2019).

Digoxin:

Digoxin has the property of cardiac glycoside obtained from foxglove. It is mainly used in the treatment of heart failure and arrhythmia by act as inhibitor of Na+/K+-ATPase pump in cell membrane, thereby increase concentration of ca+2 in Myocardiocytes and pacemaker cells to longer action potential. During the statistic group studies, digoxin shows decreased in the recurrence and aggressiveness of the breast cancer in early 1980s. It act by interfering with signaling of estrogen receptor in cancer cells and suppress the growth of breast cancer. However, after two decades it shows inverse result, the population who were taken a digitoxin had more risk of breast cancer as compared to control group showed by Haux et al. it increases the incident of ER-positive breast cancer rather than ER-negative. In the recent advances, digoxin identified as most potent drug in prostate cancer. It reduces approximately 25% incidence of prostate cancer. It shows 46% reduction in the incidence of prostate cancer after used it for more than 10 year. It acts by inhibiting the secretion of prostate specific antigen in androgen receptor. Most challenging is narrow therapeutic index of digoxin, therefore therapeutic serum level of digoxin is unclear for inhibiting prostate cancer. Recently there are number of the trails ongoing for treatment of the cancer as monotherapy or combination therapy of digoxin (Shim and Liu, 2014).

Digoxin also inhibit the factor-kappaB and DNA topoisimerase 2, thereby induced apoptosis and act as anti-tumor agent. Another mechanism of digoxin is inhibition of protein suppression, altering signaling pathway of interferon, disruption of mitochondrial activity and calcium based signals. Digitalis is fully evaluated as therapeutic agent and recently, 8 trail are completed, 2 active and 4 are recruiting trails are registered (Kirtonia et al., 2020). Though digoxin reported for an inhibitor of heavily implicated factor in promoting tumor growth- HIF-1 such as, VEGF, GLUT1, HK1 and HK2 for prostate cancer, it shows inversely effect on HIF-1 at therapeutic level in mice as relevant in humans. It shows significant inhibiting effect on prostate cancer (Turanli et al., 2018).

Exenatide:

Exenatide is an agonist of GLP-1(Glucagon-like peptide 1 receptor) approved by FDA for the treatment of the diabetes mellitus.GLP-1 is secreted in the response of the food intake by small intestine and readily metabolized so it is not feasible for outside treatment. Exenatide is long acting analogue of GLP-1. Main expression of glp-1 is in the pancreases, however it also present in brain and its analogues are demonstrated for neuroprotective effect such as, decreases in neuroinflammation as well as increases neurotrophic and neurogenicity. It shows decrease in the loss of SN cell and activity, in addition it also store the striatal dopamine in mice treated with MPTP. Exenatide inhibit neuronal toxicity and prevent the formation of p-tau. According to preclinical study, clinical study is conducted with single blind, in which 45PD patient randomly assigned with exenatide treatment and no exenatide for 12 months. Result comes in the favor of exenatide. Successful single blind study lead to double blind study which shows improvement in motor activity with the group of exenatide. In the challenge of exenatide, it provide only symptomatic relief not disease modifying treatment. Moreover, there is no major outcome in daily routine activity and mood of patient. However, new generation of GLP-1 shows neuroprotective effect in mice. Recently, exenatide effect is assessed in biomarker of progression PD (Guttuso, Andrzejewski, Lichter and Andersen, 2019). Exenatide can cross blood brain barrier and affect pathway of central nervous system such as, neuroinflamation, oxidativestress, neuronal growth and proliferation. Exenatide activate GLP-1 receptor and GLP-1 lead to activation of cyclic adenosine monophosphate thereby it activate protein kinase A and phosphoinoside-3 kinase these all stabilized dendritic spines and promote neuronal survival. (Kakkar, Singh and Medhi, 2018). Exenatide increases anti-inflammatory effect as well as decreses in pro-inflammatory mediators. PT302 is modified formulation of exetanide created by peptron the south corean company. It is slow release formulation by use of the D, L-Lactideco-glycolide. Exenatide micropaticles coated with L-lysine for suppression of burst in injection. In addition, PT302 explore disease modifying effect on Parkinson’s disease. (Foltynie and Athauda, 2020).

Itraconazole:

Itraconazole was anti-fungal agent belongs to the triazole family. It act on cytochrome p450-dependent lanosterol 14-α demethylase, which is paramount in the ergosterol synthesis. Itraconazole act by destructing fungal cell membrane and truncated synthesis of ergosterol. Albeit itraconazole is not more efficacious as anti- fungal, it has potential anti-cancer activity by inverting the p-glycoprotein chemoresistance and adjusting hedgehog and b-catenin pathway of signal transduction. In additament it withal inhibit angiogenesis. Itraconazole shows better result when it coalesces with other chemotherapy for the utilization in pancreatic, ovarian, and breast cancer by truncating endothelial cell proliferation and migration. (Tsubamoto et al., 2017). In the case of itraconazole, it is expeditious for clinical tribulation implementation in sarcomas such as, in osteosarcome by act on hedgehog pathway. Itraconazole damage cholesterol trafficking and inhibits the mTOR and VEGFR2 signaling pathways in endothelial cells suggested by Xu et al. (2010) (Xu et al., 2010). After that, oral itraconazole is evaluated for anti-tumor efficacy for treatment of metastatics CRPC during phase 2 tribulation and suggested that high dose(600 mg/day) has highest anti-cancer activity by suppressed Hedgehog pathway (Antonarakis et al., 2013).

Nilotinib:

Nilotinib used in chronic myeloid leukemia by inhibiting Bcr-Abl tyrosine-kinase fusion. It is 30 times more potent than imatinib. Recently, approved for Philadelphia chromosome CML patient because of the intolerance of the imatinib. In the neurodegenerative disease Abelson non-receptor tyrosine kinase play important role and it can be activated by oxidative process. After the activation of c-Abl it caused accumulation of parkin interacting substrate, thereby produced downregulation of peroxisome proliferator receptor, mitochondrial dysfunction and loss of dopaminergic neurons. Activate c-Abl converte α-synuclein in to the lewy bodies by the phosphorylation (Lindholm et al., 2016). Nilotinib is tested for the treatment on the α-synuclein in rodent and it shown reduction in Abl activity with autophagic α-synuclein clearance. It also improved in dopamine level and motor function (Hebron et al., 2013). Currently nilotibin tested for phase-1 study with PD patient with different doses and it proven safe. Though there are benefit of Nilotinib as repurposed drug, it also has risk of adverse drug reaction and issue of tolerability as challenge. Recently, nilotinib is tested for phase-2 study for further investigation of its treatment in PD. Nilotinib proven as safe in randomized, double blind and placebo control study in the aspect of pharmacokinetics. Therefore, it is an alluring opening to developed repurposed drug for the PD treatment. (Kakkar, Singh and Medhi, 2018)

Conclusion

Drug repositioning is advantageous process as compared to discovery of novel drug. Pharmaceutical and biotech companies indentified knowledge of drug repurposing and there are so many drugs are approved by FDA as repurposing use. Drug repurposing is cost effective, less time consuming, successful method as compared to novel drug discovery process. High success rate as compared to De novo drug. According to discussion of this review it is concluded that, there are significant achievement of the repurposed drug in the anti-cancer therapy such as, Statins which shows good potential as monotherapy as well as combination therapy, Digoxin shows significant result specially in prostate cancer as compared to breast cancer and still trails are ongoing for its combination therapy studies, Itraconazole proven potential in sarcomas. Repurposed drug in Parkinson’s disease such as, Exenatide passes single and double blind trial. Moreover its modified formulation PT302 proven for disease modifying effect, Nilotinib successfully passes phase-1 and phase-2 trail and attributing new opportunity for the treatment of the Parkinson’s disease.

Reference:

1. Kaitin, K., 2012. Translational Research and the Evolving Landscape for Biomedical Innovation. Journal of Investigative Medicine, 60(7), pp.995-998.
2. Collins, F., 2016.Seeking a Cure for One of the Rarest Diseases: Progeria. Circulation, 134(2), pp.126-129
3. Allison, M., 2012. NCATS launches drug repurposing program. Nature Biotechnology, 30(7), pp.571-572.
4. Talevi, A., 2018. Drug repositioning: current approaches and their implications in the precision medicine era. Expert Review of Precision Medicine and Drug Development, 3(1), pp.49-61.
5. Pushpakom, S., Iorio, F., Eyers, P., Escott, K., Hopper, S., Wells, A., Doig, A., Guilliams, T., Latimer, J., McNamee, C., Norris, A., Sanseau, P., Cavalla, D. and Pirmohamed, M., 2018. Drug repurposing: progress, challenges and recommendations. Nature Reviews Drug Discovery, 18(1), pp.41-58.
6. Xu, Y., Fang, F., Sun, Y., St. Clair, D. and St. Clair, W., 2010. RelB-Dependent Differential Radiosensitization Effect of STI571 on Prostate Cancer Cells. Molecular Cancer Therapeutics, 9(4), pp.803-812.
7. Gelosa, P., Castiglioni, L., Camera, M. and Sironi, L., 2020. Repurposing of drugs approved for cardiovascular diseases: Opportunity or mirage?. Biochemical Pharmacology, p.113895.
8. Kale, V., Habib, H., Chitren, R., Patel, M., Pramanik, K., Jonnalagadda, S., Challagundla, K. and Pandey, M., 2020. Old drugs, new uses: Drug repurposing in hematological malignancies. Seminars in Cancer Biology,.
9. Siegelin, M., Schneider, E., Westhoff, M., Wirtz, C. and Karpel-Massler, G., 2019. Current state and future perspective of drug repurposing in malignant glioma. Seminars in Cancer Biology,.
10. Shim, J. and Liu, J., 2014. Recent Advances in Drug Repositioning for the Discovery of New Anticancer Drugs. International Journal of Biological Sciences, 10(7), pp.654-663.
11. Kirtonia, A., Gala, K., Fernandes, S., Pandya, G., Pandey, A., Sethi, G., Khattar, E. and Garg, M., 2020. Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics. Seminars in Cancer Biology,.
12. Turanli, B., Grøtli, M., Boren, J., Nielsen, J., Uhlen, M., Arga, K. and Mardinoglu, A., 2018. Drug Repositioning for Effective Prostate Cancer Treatment. Frontiers in Physiology, 9.
13. Guttuso, T., Andrzejewski, K., Lichter, D. and Andersen, J., 2019. Targeting kinases in Parkinson’s disease: A mechanism shared by LRRK2, neurotrophins, exenatide, urate, nilotinib and lithium. Journal of the Neurological Sciences, 402, pp.121-130.
14. Kakkar, A., Singh, H. and Medhi, B., 2018. Old wines in new bottles: Repurposing opportunities for Parkinson’s disease. European Journal of Pharmacology, 830, pp.115-127.
15. Foltynie, T. and Athauda, D., 2020. Repurposing anti-diabetic drugs for the treatment of Parkinson’s disease: Rationale and clinical experience. Progress in Brain Research, pp.493-523.
16. Dey, G., 2019. An Overview of Drug Repurposing: Review Article. Journal of Medical Science And clinical Research, 7(2).
17. Lindholm, D., Pham, D., Cascone, A., Eriksson, O., Wennerberg, K. and Saarma, M., 2016. c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease. Frontiers in Aging Neuroscience, 8.
18. Hebron, M., Lonskaya, I. and Moussa, C., 2013. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of -synuclein in Parkinson’s disease models. Human Molecular Genetics, 22(16), pp.3315-3328.
19. Tsubamoto, H., Ueda, T., Inoue, K., Sakata, K., Shibahara, H. and Sonoda, T., 2017. Repurposing itraconazole as an anticancer agent. Oncology Letters, 14(2), pp.1240-1246.
20. Antonarakis, E., Heath, E., Smith, D., Rathkopf, D., Blackford, A., Danila, D., King, S., Frost, A., Ajiboye, A., Zhao, M., Mendonca, J., Kachhap, S., Rudek, M. and Carducci, M., 2013. Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration‐Resistant Prostate Cancer. The Oncologist, 18(2), pp.163-173.

Introduction

Prostate cancer is the second most frequently diagnosed cancer in the world.1 Androgen deprivation therapy is the main treatment for advanced disease. Androgen deprivation therapy (ADT) is a temporary measure but can accelerate osteoporosis, and bone metastases are common in advanced prostate cancer and are associated with significant morbidity, including pain. All patients eventually develop castration-resistant prostate cancer (CRPC). CRPC patients had a poor prognosis, with a median survival of about 18 months.2 Clearly, new drugs are needed to treat CRPC to slow disease progression and improve quality of life.

Endothelin, especially endothelin-1 (ET-1), plays a regulatory role in tumor growth and proliferation. ET-1 is produced by tumor cells and ACTS primarily by binding to cell surface endothelin A receptors (ETA) and B receptors (ETB) and altering the effects of other growth factors. Activation of ETA promotes cell growth, while activation of ETB induces cell death through apoptosis. In addition, the combination of ET-1 with ETB can cause ET-1 to be removed from the loop. Moreover, activation of ETA induces expression and activation of tumor proteases and promotes tumor proliferation and metastasis. In addition, activation of ETA leads to osteoblastic proliferation, bone remodeling, and growth factor release, and stimulates the survival and growth of metastatic prostate cancer cells in bone. Specific blocking of ETA provides an effective cancer treatment. On the contrary, antagonistic ETB may lead to adverse effects such as inhibition of apoptosis and reduction of ET-1 clearance rate. Therefore, a drug that is active only against ETA (that is, a specific ETA antagonist) is desirable.3

Figure 1 The effect of endothelin on cells

Pre-clinical development and pre-clinical

Zibotentan (ZD4054), an oral specific ETA receptor antagonist.

Chemical name and structure

N- (3-Methoxy-5-methylpyrazine-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyridine-3-sulfonamide

Figure 2 Zibotentan (ZD4054) structure

Synthesis

In order to study the drug metabolism and pharmacokinetics of ZD4054, the synthesis of ZD4054 was labeled with isotopes.

Figure 3 [oxadiazol-5-14C]

Figure 4 [pyridyl-2,6-14C]

Figure 5 [phenyl-2,3,5,6-2H4]

Three different synthetic routes successfully inserted isotopic markers into 1,3, 4-oxadiazole, pyridine and phenyl rings in ZD4054.4

Receptor interaction/specificity

ZD4054 is an ETA receptor antagonist. Among the available endothelin receptor antagonists for oral administration, ZD4054 can bind ETA more selectively than ETB. In-vitro multi-receptor binding tests, ZD4054 has been shown to specifically and competitively bind to 125I-ET-1 and compete with the ETA receptor of cloned human cells, with an IC50 value of 21 nmol/L. ZD4054 did not bind to the ETB receptor when the concentration reached 100 mmol/ L.5

Clinical trials

Phase I

Treatment plan

The Zibotentan pill is taken orally once a day.In the first group (phase 1), Zibotentan started at 10 mg per day and gradually increased in the three-patient cohort (15 mg, 22.5 mg, 32.5 mg, and 50 mg), with an initial planned maximum of 200 mg per day.Patients who have evidence of clinical benefit and do not meet any exit criteria are allowed to receive Zibotentan at their current dose level until they are no longer receiving clinical benefit.6

Pharmacokinetic evaluation

During the treatment period, a maximum of 21 blood samples will be obtained from each patient, and 1 dose be given at the following times per infusion: 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 12 hours, 18 hours, 24 hours, 30 hours, 36 hours and 48 hours. Groove samples were collected on day 8 and day 15 before the next dose of Zibotentan. Steady-state plasma concentration-time distributions were obtained from blood samples taken immediately before cibotan administration on day 29, at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, and 24 hours after the day 29 dose.The single-dose PK( pharmacokinetics) study of Zibotentan was performed in all 16 patients(Figure 6 and 7).6 Single-dose PK data showed a low apparent clearance rate and distribution volume, with an average final half-life between 7.0 and 9.2h. Minimum concentration accumulation of Zibotentan was observed after repeated administration, and steady-state concentration was reached at least 8 days after treatment (5 days per day). No change in time of Zibotentan PK was observed after repeated administration.

Figure 6 zibotentan plasma concentration-time curves

Figure 7 Single-dose PK of zibotentan

Dose toxicity

No DLTs (dose-limiting toxicity) were observed in patients who received an initial dose of 10 mg or 15 mg.Four patients were at the dose level of 22.5mg, and two of them experienced DLT. One patient received a 22.5mg dose, which was later reduced to 15 mg(Figure 8)6

Figure 8 Adverse events occurring in two or more patients overall

Phase 2

The study recruited men 18 years of age ≤HRPC and with bone metastases who had no pain or mild pain symptoms (no opioid analgesia required) and who had not received chemotherapy. The patient had prostatic adenocarcinoma confirmed histologically or cytologically, with evidence of bone metastasis.7

Treatment plan

Patients were randomly assigned a daily oral dose of ZD405410 mg or ZD405415 mg or placebo at a ratio of 1:1:1:1. Physically identical tablets and packages are used to ensure that patients and investigators are blinded. Patients were instructed to take a pill with a glass of water every morning.All patients received ZD4054 or placebo in the context of supportive care based on local practice.5

Study population

A total of 312 patients were randomly assigned to three treatment groups.(Figure 9)6

Figure 9 Trial profile(phase 2)

Efficacy

In the first data, 209 progress events occurred. No significant difference was observed between the ZD4054 treatment group and placebo group. Overall survival improved, although only 40 deaths occurred at this time. Taking into account the overall survival observed, a second analysis is planned when approximately 110 deaths occur. In the second data, 118 patients died and 167 (86%) of the remaining 194 patients were identified as having a survival status. The results of the second analysis confirm the results of the first analysis. There was no significant difference in progression time between the groups, but the results showed that overall survival was improved in the ZD4054 group compared to the placebo group. After discontinuation of the treatment, the treatment group was generally similar in the use of systemic anticancer therapies, particularly taxanes.6

Figure 10 First data for time to progression and overall survival

Figure 11 Second date for time to progression and overall survival

The study found no significant difference between ZD4054 and placebo for the primary end point of time to progression. However, compared with placebo, both doses of ZD4054 showed promise for prolonging patient overall survival. This information was evident in the first data after 40 deaths and was still present in the second data after 118 deaths.6

Phase 3

Treatment plan

Patients were randomized 1:1 to take Zibotentan10 mg daily or placebo. Patients receive standard support or treatment: chemotherapy. Other experiments agent is not allowed. Patients continued to be randomized until they met the withdrawal criteria.(Figure 12)8

Figure 12 Treatment plan flowchart

Efficacy

No statistically significant improvement was observed in overall survival(Figure 13). Overall survival results consistent with the prognosis and assessment of geographic subgroups, including age, PSA, and bisphosphonate use bone metastases(Figure 14).8

Figure 13 overall survival curve

Figure 14 overall survival for subgroup

No statistically significant differences were observed between treatments for pain progression time, chemotherapy use time, new bone metastasis time, and progression-free survival (PFS).At the time the data were obtained, the proportion of patients who received chemotherapy after randomization was the same in both groups(Figure 15).8

Figure 15 Secondary Efficacy Endpoint

Conclusions

ET receptor antagonistic drugs in the treatment of prostate cancer model is scientific and compelling. ET receptor antagonists can provide direct antitumor effects and affect the tumor environment by inhibiting osteoblasts proliferation, bone remodeling, and release of growth factors that may aid the spread of metastatic tumors in bone. Abt-627 (Abbott Laboratories) is a selective ET receptor antagonist that is also currently under clinical development. Previous studies have shown that atrasentan improves pain and has a tendency to improve progression time (compared to placebo), and clinical trials of the drug are ongoing.9,10

Zibotentan is a specific ETA receptor antagonist. By inhibiting ETA receptors only, the beneficial effects of ETB activation on apoptosis and harm-resistant perception should be preserved. In phase I trials, this phase I dose-escalation study of the specific ETA receptor antagonist Zibotentan in men with metastatic CRPC showed that continuous oral administration of 10 and 15 mg per day was well tolerated. The MWTD(maximum well-tolerated dose) was identified as 15 mg daily.

In the phase 2 trial, although the primary endpoint of progression was not achieved, the overall survival of patients with ZD4054 and asymptomatic or mildly symptomatic metastatic HRPC was expected to improve.The results of this study support ETAR-targeted prostate cancer treatment strategies and support the phase 3 clinical trial study of ZD4054.

In the phase 3 trial, optimal support of zibotentan 10mg daily did not lead to a significant improvement in overall survival in patients with CRPC and bone metastases who were pain-free or mildly symptomatic for pain. There are four possible reasons for this. (1) The primary endpoint in the phase 2 study was time to progress, not over survival.11(2)The placebo group in the phase 3 study survived longer than expected.12(3)Average drug exposure in the phase 2 study is shorter and data for the follow-up system against cancer treatment using less than half of the patients.11,13(4)There are demographic differences between the studies. The phase III trial, which included East Asian patients (from China, Hong Kong, Japan, Singapore, South Korea and Taiwan) and a pre-assigned subgroup analysis of overall survival, showed poorer outcomes for the Asian population compared with patients from other ethnic (mainly white) backgrounds.14,15

Although there was a significant effect on cancerbone interaction in preclinical models, ETA receptor antagonists showed disappointing results in phase 3 in patients with CRPC.16 For patients with CRPC and bone metastasis, with no pain or mild pain symptoms and without chemotherapy for metastatic disease, zibotentan 10mg daily plus standard treatment did not lead to significant OS improvement. As a result, zibotentan is no longer being studied as a potential treatment for prostate cancer patients.But other clinical trials of zibotentan as an ETA receptor antagonist for cancer drugs are still underway.

References and Formatting

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011, 61, 69-90.
2. Kasper S, Cookson MS. Mechanisms leading to the development of hormone-resistant prostate cancer. Urol Clin North Am. 2006, 33, 201-210.
3. Morris. C D, Rose. A, Curwen. J, Hughes. A M, Wilson. D J and Webb. D J, British Journal of Cancer, 2005, DOI: 10.1038/sj.bjc.6602676.
4. Julie A. Bergin, Helen Booth, Ryan A. Bragg, Nick Bushby, John R. Harding, Angela Jordan and Clare D. King, Journal of Labelled Compounds and Radiopharmaceuticals, 2007, DOI: 10.1002/jlcr.1177.
5. Morris CD, Rose A, Curwen J, Hughes AM, Wilson DJ and Webb DJ, Br J Cancer 2005, 92, 2148–2152.
6. William R. Schelman, Glenn Liu, George Wilding, Thomas Morris, De Phung and Robert Dreicer, Investigational New Drugs, 2011, DOI: 10.1007/s10637-009-9318-5.
7. Nicholas D. James, Armelle Caty, Michael Borre, Bernard A. Zonnenberg, Philippe Beuzeboc, Thomas Morris; De Phung and Nancy A. Dawson, European Urology, 2009, DOI: 10.1016/j.eururo.2008.11.002.
8. Joel B. Nelson, Karim Fizazi, Kurt Miller, Celestia Higano, Judd W. Moul, Hideyuki Akaza, Thomas Morrism Stuart McIntoshm Kristine Pemberton and Martin Gleave, Cancer, 2012, DOI: 10.1002/cncr.27674.
9. Carducci MA, Padley RJ, Breul J, Vogelzang NJ, Zonnenberg BA, Daliani DD, Schulman CC, Nabulsi AA, Humerickhouse RA, Weinberg MA and Schmitt JL, J Clin Oncol, 2003, 21, 679–689
10. Carducci MA, Saad F, Abrahamsson PA, Dearnaley DP, Schulman CC, North SA, Sleep DJ and Isaacson JD, Cancer, 2007, 110, 1959-1966.
11. James ND, Caty A, Borre M and et al, Eur Urol, 2009, 55, 1112-1123.
12. Tannock IF, de Wit R, Berry WR, et al. N Engl J Med, 2004, 351, 1502-1512.
13. James ND, Caty A, Payne H and et al, BJU Int, 2010, 106, 966-973.
14. Robbins AS, Koppie TM, Gomez SL, Parikh-Patel A and Mills PK, Cancer, 2007, 110, 1255-1263.
15. Fujimoto H, Nakanishi H, Miki T and et al, Int J Urol, 2011, 18, 876-881.
16. Yin JJ, Mohammad KS, Kakonen SM and et al. Proc Natl Acad Sci USA, 2003, 100, 10954-10959.

Introduction:

[bookmark: _Hlk3485638]Imaging modality plays a great role in treatment planning. Positron emission tomography PET has been used in treatment planning in the delineation of Gross target volume GTV which is considered as the most important component in treatment planning. Also, PET Accuracy in the delineation of GTV impact on dose delivery to tumor tissue while delivering a low dose rate to healthy tissue or critical structure surrounding the tumor. PET has great sensitivity and specificity in the delineation of Gross target volume more than other imaging modality that has been used in treatment planning. because PET uses FDG and these an advantage that reduces the uncertainty in defining tumor margin in radiotherapy treatment planning. [1]

PET-based treatment planning:

Recently PET imaging or molecular imaging has been used in treatment planning for cancer patients. By using PET radiotracer 18F-FDG which allow viewing the molecular pathways for the target (tumor), metabolism, proliferation, oxygen delivery, and consumption many receptors or gene expression. Using PET images in treatment planning can give us information about tumor response to radiotherapy, can localize the reoccurring tumors in an early stage. The most important function of PET imaging in treatment planning is Delineation of tumor or target and organ at risk OAR. [9] Positron emission tomography PET, has an advantage in cancer patient management by using 18F-FDG as a tracer helps in the delineation of the target volume in non-small cell lung cancer NSCLC patients, head and neck squamous cell carcinoma HNSCC, and rectal carcinomas.[9] There is another PET radiotracers differ in their sensitivity and specificity which impact the image and the treatment planning. FDG it has non-specific uptake in tumor and high uptake in other areas such as infection or inflammation sites.[9][10] hypoxia imaging with PET a useful tool to know tumor response during radiotherapy treatment or identify the resistant tumor cells, and to deliver the higher radiation dose to the parts that radio-resistant which have a higher chance of tumor reoccurrence. [4] the best PET tracer should have these properties high uptake values in the tumor, high sensitivity and specificity in tumor site, low production cost, and availability.[5]

Why PET used in treatment planning:

• Provide molecular information about the tumor.
• Higher sensitivity, specificity, and accuracy due to PET tracers.
• Provides accurate information about tumor stage.
• Give information about tumor response and resistant to radiotherapy.
• Accurate delineation of GTV.
• Dose painting with hypoxia tracers (FMISO, FAZA, CU-ATSM) and FLT.
• dose painting by numbers DPBN, shape the dose depending on the voxel intensity.
• Accurate diagnosis of NSCLC and high contrast images.
• Enhance the main aim of radiotherapy treatment by concentrated the radiation dose to the target and lower dose for surrounding tissue or OAR. [5][12][7]

PET Tracers (agents):

· FDG

The first use of PET-FDG was with non-small cancer lung cells NSCLC by accurate delineation for nodal and distant metastases. FDG-PET has been used with CT images due to the poor spatial resolution of FDG-PET.[9] FDG-PET more accurate than CT in localizing mediastinal nodal in SCLC, also FDG-PET helps to reduce the isolated nodal failures outside the clinical target volume CTV.[9] The resolution limits for PET 5-7mm, any object lower than this limit will have a weak signal which affects the resulting image.[9] Due to this limitation, there is the uncertainty of estimating the real tumor size. PET images may contain a signal noise. [12] FDG used as a guide through the segmentation process, then these segments combined to form the large target region. The main objective of segmentation to determine which part of the target will receive the primary dose and which one will have the higher dose GTV.[10] PET-avid delivery of a nonhomogeneous dose of FDG-PET to the target region, by concerted the higher dose to the avid region and lower dose to the OAR or keep the dose below the threshold of deterministic effects.[10] the disadvantage of FDG is non-specific uptakes values for tumor due to the high activity of glucose. [5]

· 18F-FDG PET/CT:

[bookmark: _Hlk3558885][bookmark: _Hlk3558888]Using FDG-PET with CT handle the limitation of low spatial resolution of PET. [9] Fusing PET images with CT images improve the accuracy of delineation, and high sensitivity, and specificity (96.6%) of tumor detection and contributed in treatment decision based on the changing of GTV. [11] since CT provides electron density data that improve the dose calculation in treatment planning. [12] Using two imaging modalities enhance the detection of reoccurrence tumors especially colorectal cancers.[11] Fusing techniques: (1) Hybrid PET/CT fusing the images in the system by RTP and (2) Fusing PET and CT images separately and two registration methods: (1) rigid and (2) deformable. In PET/CT it is important that the immobilization device fits with PET/CT, immobilization device such as masks and shoulder in head and neck cancer easily fits with PET/CT. PET/CT has been used in gate acquisition of lung and thoracic and excellent bowel preparation of abdominopelvic malignancies. Both PET and CT have artifacts due to patient motion especially respiratory motion which lead to the wrong estimation of SUV and tumor size. Inaccurate SUV due to a mismatch between PET and CT because of the difference in time acquisition. PET has superior sensitivity and specificity over CT in lung cancer helps to improve the therapeutic ratio by increasing the dose in the target site and minimize the dose in OAR and normal tissue. There is two correction techniques of respiratory motion 4D PET/CT, DIBH PET/CT. [12]

The uptake process 18F-FDG PET/CT:

1. Before the examination, the patient had to be fasting for at least 6 hours.
2. Then injects the patient with FDG, the amount of FDG calculated by [w×4+20] MBq.
3. Then after 60 min, the PET and CT images obtained. [9]

· 18F-FLT

18F-fluorothymidine FLT it is cellular proliferation, phosphorylated by thymidine kinase inactive cells and trapped in the cell but does not marker DNA.[9][10] FLT is excellent image for tumor volume changes due to radiotherapy. [13] FLT can give information about the tumor response during the treatment course. After 15 to 18 fractioned doses ( chances in GTV is detectable. The uptake values of FLT decrease due to the reduction of tumor cell density during the treatment and this is impacting on the FLT signal.[14]

The uptake process of FLT-PET/CT:

1. The patient fast for at least 6 hours before the examination.
2. Rest for 15 min before the injection of 300-400MBq of FLT.
3. The images were obtained in 60 min after injection.[13]

Comparison between FLT and FDG PET tracers in treatment planning:

FLT

FDG

esophageal cancer

Has a low dose to the lung and cardiac

Higher dose to lung and cardiac

rectal cancer

The same GTV for both

brain tumors

Superior in defining the target in the brain

Has high uptake value in cortical

reactive lymph nodes

May have some uptake value in reactive lymph nodes which increases the difficulty to distinguish active tumors.

specificity

excellent

Good

accuracy for nodal staging

excellent

Good

Primary tumors

Lower sensitivity to detect primary tumors

higher sensitivity to detect primary tumors

[9][10]

· 11C-methionine

The sensitivity of 11C-methionine PET in brain tumor is higher than FDG-PET due to the high activity of glucose in normal brain tissue. This is making 11C-methionine the best PET tracer for brain tumor delineation. [5] 11C-methionine provides biological information about the tumor and the response to treatment. 11C-methionine helps in diagnosis identify the tumor activity with primary and recurrent gliomas patients.[15] tumor grading may be estimated incorrectly in brain tumor especially gliomas kind because it is formed of heterogeneous and microscopic areas of necrosis. so, the biopsy may represent a small part of the primary tumor and underestimate the tumor grading. 11C-methionine shows that are a useful biomarker in gliomas patients and has a higher sensitivity of detection and delineation of the tumor. In contrast with FDG-PET, 11C-methionine can detect tumors with (hypometabolism or is metabolism). 11C-methionine can be used as guidance during the biopsy process.[16] 11C-methionine shows a high uptake value in the pituitary gland and can distinguish between pituitary adenoma and other normal tissue in the brain. These increasing the reduction of GTV and the radiation dose to the normal tissue and the parotid glands, lacrimal glands and inner ears. The drawback of 11C-methionine it has a shorter half-life 20 min, also there is uptake values in other sites such as lacrimal glands, parotid glands, nasopharynx, bone marrow, and normal pituitary gland. [17]

The uptake process of 11C-methionine:

1. Injection the patient with 11C-methionine 210MBq.
2. After 20 min PET image obtained in 3D for 5min /bed position. [15]

· 11C-Choline

11C-Choline can distinguish between curable diseases from metastatic diseases. [18]11C-Choline has been used for prostate cancer and contributed to choosing the best treatment strategy. 11C-Choline helps to improve the therapeutic ratio by high-precision radiation to the target and minimum dose to the normal tissue. It is not recommended using 11C-Choline in early diagnosis or tumor staging. The advantage of using 11C-Choline with prostate cancer that detects the target that localizes beyond the prostate bed so unnecessary radiation dose for prostate bed will be avoided.[19] 11C-Choline has sensitivity and specificity of 85%and 88% inpatient prostate-specific antigen (PSA). The limitation of 11C-Choline is cannot detect small lesions or low activity lesions. [20] other limitation of 11C-Choline cannot distinguish between tumor and non-tumor tissue in the prostate. [21]

The uptake process of 11C-Choline:

1. The patient fast at least for 6 hours before 11C-Choline PET/CT scan.

2. Then patient drink diluted oral contras 300 mg.

3. A rectal filling negative contract agent 100-200mL.

4. Then injected the patient of 691 ±70MBq of 11C-Choline.

5. Then after 5 min, the PET/CT images were obtained.[22]

· 68Ga-PSMA-PET 21

68Ga-PSMA-PET has high sensitivity and specificity in diagnosing prostate cancer. [23]68Ga-PSMA-PET can diagnosis the reoccurrence primary prostate cancer PCA.[21] 68Ga-PSMA helps to eliminate 35.7% Lymph nodes LNs out of CTV which enhances the therapeutic ratio by minimizing the dose to LNs. [23]

The uptake process of 68Ga-PSMA-PET:

1. Patient fasts for at least 4 hours before injection.
2. Then injected the patient 172±34 MBq of 68Ga-PSMA.
3. Then after one-hour PET scan performed. [21]

· 18F-fluciclovine PET/CT

18F-fluciclovine has been used in postprostatectomy to delineate the volume target (prostate bed) and the changes that may affect the OAR. 18F-fluciclovine a non-physiologic uptake in prostate bed, lymph nodes, or bone. [24]

The uptake process of 18F-fluciclovine:

1. The patient must fast at least for 4 hours.
2. Then the patient injected with (371.6±12.4 MBq) over 2 min.
3. The acquisitions of the pelvis to diaphragm obtained at 5-15.5min and at 16-27.5min. [24]

· Hypoxia Tracers:

Hypoxia traces have a great role in treatment planning provides a lot of information by Identify the resistant cells in the tumor. The target/background activity is less than FDG-PET. [10] Hypoxia traces is a nitroimidazole compound. [25] hypoxia tracer it is common to use in solid tumors such as head and neck squamous cell carcinomas (HNSCC). [26]

1. (18F-MISO) the first hypoxia PET tracer can increase the dose to hypoxic tumor up to 105Gy, can detect different tumor sites in one patient.[26]
2. (18F-FAZA) has the same uptake values and biodistribution as 18F-MISO, but the lower concentration in the tumor, that mean lower sensitivity in detection hypoxic sites.[26]

The importance of hypoxia tracer:

1. Prediction of failure of radiotherapy.
2. Prediction of chemotherapy-resistant (ꜜproliferation ꜜdrugs concentration).[26]

PET tracer

Cancer type

Sensitivity-specificity

In GTV delineation

FDG-PET

· Nonsmall cancer lung cells NSCLC

80-90%

85-100%

· Head and neck

50-96%

88-100%

· Cervical carcinoma

75-91%

92-100%

· Esophageal

30-78%

86-98%

· Prostate cancer

67%

83%

11C-Choline PET

· Prostate cancer

80%

96%

11C-Acetate PET

· Prostate cancer

80%

29%

[25][27]

FDG-PET in brachytherapy:

FDG-PET images have been used in brachytherapy for the cervix cancer patient. FDG-PET give significant information in 3D of the tumor or disease spread. The advantage from use FDG-PET image in treatment planning of cervix cancer patient is to reduce the dose to bladder and rectum due to the accurate dose coverage to the target volume. [28]

New PET tracer 18Ffluoroethyl-L-tyrosine FET:

The new PET tracer FET has used in the detection of glioma and has excellent sensitivity and specificity improving the detection. also, have been used with Highly malignant or high-grade glioma. FET-PET used with MRI-based plans to shows the contrast. A mismatch between FET-PET and MRI-based in target volume contour, which improve treatment planning. Also, FET-FDG shows other sites that CT-based did not cover.[29] FET-PET id better than FDG-PET in the detection of a brain tumor but have the same performance in grade glioma. FET-PET mean, and maximum target/background ratio only can distinguish between tumor tissues and nontumor tissues. FET-PET helps to identify the tumor response to radiotherapy and delineation of target volume before radiotherapy which helps in estimating the effect of radiotherapy and chemotherapy in the tumor.[30]

Nonsmall cancer lung cells NSCLC:

In intensity modulated radiotherapy IMRT PET and CT scan improve the treatment planning for NSCLC patients. [31] 18F-FDG PET/CT has the ability to distinguish between tumor tissues and healthy tissues with 93% sensitivity and 88% specificity. the sensitivity, accuracy, and positive predictive value in the detection of primary lung tumors are 94%,94%, and 100% respectively. 18F-FDG PET/CT contributed to changing the treatment planning during the treatment course.[32]

Bibliography:

1. Salahuddin Ahmad, PET-based GTV definition is the future of radiotherapy treatment planning, Med. Phys. 39 (10), October 2012, [http://dx.doi.org10.1118/1.3694666].
2. Vincent Grégoire, PET-Based Treatment Planning in Radiotherapy: A New Standard? , THE JOURNAL OF NUCLEAR MEDICINE • Vol. 48 • No. 1 (Suppl) • January 2007, J Nucl Med 2007; 48:68S–77S.
3. Christina K. Speirs, PET-Based Radiation Therapy Planning, PET Clin 10 (2015) 27–44, http://dx.doi.org/10.1016/j.cpet.2014.09.003.
4. Alexander Chi, The utility of positron emission tomography in the treatment planning of image-guided radiotherapy for non-small cell lung cancer, October 2014 | Volume 4 | Article 273,doi: 10.3389/fonc.2014.00273.
5. Michael MacManus, Use of PET and PET/CT for Radiation Therapy Planning: IAEA expert report 2006–2007, Radiotherapy and Oncology 91 (2009) 85–94, doi:10.1016/j.radonc.2008.11.008.
6. Daniela Thorwarth, Physical radiotherapy treatment planning based on functional PET/CT data, Radiotherapy and Oncology 96 (2010) 317–324, doi:10.1016/j.radonc.2010.07.012.
7. ALEKSANDAR GRGIC, FDG-PET–Based Radiotherapy Planning in Lung Cancer: Optimum Breathing Protocol and Patient Positioning—An Intraindividual Comparison, Int. J. Radiation Oncology Biol. Phys., Vol. 73, No. 1, pp. 103–111, 2009 ,doi:10.1016/j.ijrobp.2008.03.063.
8. Homer A. Macapinlac, Clinical Applications of Positron Emission Tomography/Computed Tomography Treatment Planning, Nucl Med 38:137-140 © 2008 Elsevier Inc. doi:10.1053/j.semnuclmed.2007.11.005.
9. Judith van Loon,18FDG-PET-based radiation planning of mediastinal lymph nodes in limited disease small-cell lung cancer changes radiotherapy fields: A planning study, Radiotherapy and Oncology 87 (2008) 49–54, doi:10.1016/j.radonc.2008.02.019.
10. Junzo Chino, Positron Emission Tomography in Radiation Treatment Planning The Potential of Metabolic Imaging, Radiol Clin N Am 51 (2013) 913–925, http://dx.doi.org/10.1016/j.rcl.2013.05.007.
11. Vera Artiko, Can 18F-FDG PET/CT scan change treatment planning and be prognostic in recurrent colorectal carcinoma? A prospective and follow-up study, Hell J Nucl Med 2015; 18(1): 35-41.
12. Paola G. Scripts, Technical Aspects of Positron Emission Tomography/Computed Tomography in Radiotherapy Treatment Planning, Nucl Med 42:283-288 © 2012 Elsevier Inc. http://dx.doi.org/10.1053/j.semnuclmed.2012.04.006.
13. Guifang Zhang, Gradient-based delineation of the primary GTV on FLT PET in squamous cell cancer of the thoracic esophagus and impact on radiotherapy planning,Zhang et al. Radiation Oncology (2015) 10:11, DOI 10.1186/s13014-014-0304-5.
14. Esther G.C. Troost ,18F-FLT PET/CT for Early Response Monitoring and Dose Escalation in Oropharyngeal Tumors, J Nucl Med 2010; 51:866–874, DOI: 10.2967/jnumed.109.069310.
15. Matteo Santoni,[11C]-Methionine Positron Emission Tomography in the Postoperative Imaging and Followup of Patients with Primary and Recurrent Gliomas, Volume 2014, Article ID 463152, 6 pages, http://dx.doi.org/10.1155/2014/463152.
16. S. Ceyssens, K. Van Laere,[11C]Methionine PET, Histopathology, and Survival in Primary Brain Tumors and Recurrence, Ceyssens AJNR 27 Aug 2006 www.ajnr.org.
17. Taku N, Koulouri O, Scoffings D, Gurnell M, Burnet N. The use of 11carbon methionine positron emission tomography (PET) imaging to enhance radiotherapy planning in the treatment of a giant, invasive pituitary adenoma. BJR Case Rep 201; 2: 20160098.
18. Francesco Ceci, Evaluation of Prostate Cancer with 11C-Choline PET/CT for Treatment Planning, Response Assessment, and Prognosis, J Nucl Med 2016; 57:49S–54S, DOI: 10.2967/jnumed.115.170126.
19. Barbara Alicja Jereczek-Fossa,[11C]Choline PET/CT Impacts Treatment Decision Making in Patients With Prostate Cancer Referred for Radiotherapy, June 2014Volume 12, Issue 3, Pages 155–159, https://doi.org/10.1016/j.clgc.2013.11.002.
20. Gregor Habl, 68Ga-PSMA-PET for radiation treatment planning in prostate cancer recurrences after surgery: Individualized medicine or new standard in salvage treatment, wileyonlinelibrary.com/journal/pros The Prostate. 2017;77:920–927, DOI 10.1002/pros.23347.
21. Constantinos Zamboglou, MRI versus 68Ga-PSMA PET/CT for gross tumour volume delineation in the radiation treatment planning of primary prostate cancer, Eur J Nucl Med Mol Imaging (2016) 43:889–897, DOI 10.1007/s00259-015-3257-5.
22. Michael Souvatzoglou ,Influence of 11C-choline PET/CT on the treatment planning for salvage radiation therapy in patients with biochemical recurrence of prostate cancer, Radiotherapy and Oncology 99 (2011) 193–200, doi:10.1016/j.radonc.2011.05.005.
23. K. Schiller, Impact of 68Ga-PSMA-PET imaging on target volume definition and guidelines in radiation oncology – patterns of failure analysis in patients with primary diagnosis of prostate cancer, Schiller et al. Radiation Oncology (2018) 13:36 https://doi.org/10.1186/s13014-018-0977-2.
24. Ashesh B. Jani, Impact of 18F-Fluciclovine PET on Target Volume Definition for Postprostatectomy Salvage Radiotherapy: Initial Findings from a Randomized Trial, J Nucl Med 2017; 58:412–418, DOI: 10.2967/jnumed.116.176057.
25. Anca-Ligia Grosu, Positron Emission Tomography for Radiation Treatment Planning, Strahlenther Onkol 2005;181:483–99, DOI 10.1007/s00066-005-1422-7.
26. Marina Hodoli, Hypoxia PET Tracers in EBRT Dose Planning in Head and Neck Cancer, Current Radiopharmaceuticals, 2015, 8, 32-37.
27. Ilaria Grassi, the clinical use of PET with 11C-acetate, Am J Nucl Med Mol Imaging 2012;2(1):33-47, ISSN:2160-8407/ajnmmi1106004.
28. LILIE L. LIN, M.D, ADAPTIVE BRACHYTHERAPY TREATMENT PLANNING FOR CERVICAL CANCER USING FDG-PET, Int. J. Radiation Oncology Biol. Phys., Vol. 67, No. 1, pp. 91–96, 2007, doi:10.1016/j.ijrobp.2006.08.017.
29. Dasantha T Jaymanne, Utilizing 18F-fluoroethyl-L-tyrosine positron emission tomography in high-grade glioma for radiation treatment planning in patients with contraindications to MRI, Journal of Medical Imaging and Radiation Oncology 62 (2018) 122–127, doi:10.1111/1754-9485.12676.
30. Vincent Dunet, Performance of 18F-FET versus 18F-FDG-PET for the diagnosis and grading of brain tumors: systematic review and meta-analysis, Neuro Oncol. 2016 Mar; 18(3): 426–434. Published online 2015 Aug4. DOI: 10.1093/neuonc/nov148.
31. Davina Pawaroo, Non–Small Cell Lung Carcinoma: Accuracy of PET/CT in Determining the Size of T1 and T2 Primary Tumors, American Journal of Roentgenology. 2011;196: 1176-1181.10.2214/AJR.10.4980.
32. Emine Budak, The Contribution of Fluorine 18F-FDG PET/CT to Lung Cancer Diagnosis, Staging and Treatment Planning, Mol Imaging Radionucl Ther 2018;27:73-80 DOI:10.4274/mirt.53315.

1. Introduction.

With cancer affecting 1 in 7 men in South Africa (SA) during their lifetime prostate cancer (PCa) is the no. 1 cancer that affects SA men, It is estimated that 1 in 18 SA men will develop prostate cancer according to the National Cancer Registry of South Africa. (NCR-SA, 2014).⁠ Prostatic adenocarcinoma (typically called “prostate cancer” or “prostate carcinoma”), a malignancy of prostate gland epithelial cells, accounts for all but a tiny fraction of prostatic malignancies. (NCR-SA, 2014) In the passage below prostate gland anatomy, common masses found in the prostate gland, modalities used to diagnose prostate cancer, role, advantages and limitations of each modality will be discussed.

2. The anatomy and physiology of the prostate

The prostate is a single, doughnut-shaped gland about the size of a golf ball. It measures about 4 cm from side to side, about 3 cm (1.2 in.) from top to bottom, and about 2 cm. Prostate is a pelvic secretory organ located under the urinary bladder and in front of the rectum, and secretes a milky, slightly acidic fluid (pH about6.5) that contains several substances. It is combined by glandular and non-glandular composition encircled by one same container. It also consists of contractile organ fibrous tissue, which it is divided into about 50 tubule-alveolar glands, at the lateral and posterior segment of the urethra, which drain to 20–30 small prostatic ductules opening in the prostate, or close to the posterior wall of the prostatic urethra.

3. The common masses found in the prostate

Benign enlargement owes to glandular hyperplasia, mainly in the central area. On the other hand, prostate cancer usually develops in the posterior and peripheral parts. Some prostatic cancers are palpable because of the employment of DRE and are recognizable because they are much firmer than normal prostate.

According to the masses are separated as the following Small-cell Neuroendocrine Carcinoma, Basal Cell/Adenoid Cystic Carcinoma and Primary will be, Primary Squamous Cell Carcinoma, Primary Urothelial Carcinoma and Primary Sarcomatoid Carcinoma

Nuclear changes, these changes are normally in areas of inflammation,basal cell hyperplasia, atrophy, or Paneth cell-like change. Perineural invasion, includes the presence of glands in a perineural location used to be considered as a diagnostic trademark of malignancy. Circumferential growth or intraneural invasion should be regarded as pathognomonic of cancer. Cytoplasmic features in malignancy vary from clear amphophilic to eosinophilic, they are very useful features in differentiation between benign and atypical/cancerous glands. And collagenous micronodules are another recently described histological observation in Prostate cancer, these nodular can be seen microscopically.

Prostatic crystalloids are intraluminal, eosinophilic and refractile structures of varying size and shape, which are closely associated with prostate cancer.

Diagnostic criteria for benign is prostatic intraepithelial neoplasia (PIN), it is characterized by unrepresentative prostatic epithelial cells that contain some of the molecular changes found in prostatic carcinoma. Massive nodular hyperplasia of the prostate, the middle part of the gland protrudes into the bladder. Benign prostatic hyperplasia (BPH), it is the condition causing nodular hyperplasia of the prostate gland and the fibro-muscular supporting tissue around the gland. (

4. Imaging modalities to diagnose prostate.

The prostate gland diseases surveillance is traditionally performed by ultrasound, initially with transabdominal transducers and later superseded by transrectal (TRUS) transducers (Hegde et al., 2013: 1036)⁠

The following can be used to detect and stage Pca TRUS (can be use with or without MRI), CT (can be used with or without MRI), MRI using SPECT and Bone scan 99Tc- MDP bone scan.(Kelloff et al., 2009; Kim et al., 2010)⁠ ⁠

Primarily two main modalities that are recently used to diagnose prostate cancer are ultrasound and Magnetic resonance, these modalities have been improved to transrectal ultrasound (TRUS) and multiparametric mpMRI approach. (Heidenreich et al., 2011)⁠

The is a lot of advancement done in prostate MR imaging that is accepted and now is spreading worldwide. The MRI examination in general is performed as a combination of T1 and T2 Weighted imaging, DWI, and dynamic contrast-enhanced DCE imaging (in coronal, sagittal, and axial planes). The article further argues that MRI with either a 1.5- or 3.0-T magnet and with or without an endorectal coil is now the favored and advisable approach to all men presenting with signs of prostate cancer. (Hegde et al., 2013: 164; Penzkofer & Tempany-Afdhal, 2014: 4)⁠⁠

(PET) is still evolving but is likely to be most important in determining the early spread of disease in patients with aggressive tumors and for monitoring response to therapy in more advanced patients. (Schöder & Larson, 2004: 275)

5. The role of each modality, advantages, and limitations.

5.1. Role of each

The transrectal ultrasound (TRUS) biopsy procedure is highly user-dependent, it is able to distinguish whether a lesion is solid, cystic, or vascular. (Birs et al., 2016: 8)

According to (Schöder & Larson, 2004) Transrectal ultrasound (TRUS) is the most commonly used imaging modality for viewing the prostate. However, only 60% of tumors are visualized by TRUS, and the method often is used simply to localize the prostate, as a guide to biopsy. Nonetheless, it is said that in the hands of experts, TRUS detects extracapsular extension with accuracy between 58% and 86%.

MRI combines both MR parameters for a gross anatomical and functional classification of the prostate gland tissues. Multi-parametric prostate (mpMRI), on the other hand, is able to distinguish between the various anatomical zones of the prostate and has a good visual image of the anterior zone where some cancers may develop. (Birs et al., 2016: 8)⁠⁠

CT is responsible for mathematical measuring of extra-capsular extension to help with the treatment planning and Bone scan can be used to manage metastatic PCa, whoever this modality are not used for diagnosis. (Kelloff et al., 2009: 1456)⁠

PET is useful in evaluating the pelvic lymph nodes was severely limited by bladder activity and streak artifacts. And although the quality of FDG-PET images of the pelvis has improved significantly with the use of iterative reconstruction algorithms

5.2. Advantages

TRUS has the ability to diagnose and detect organs with cancer, Ultrasound imaging modality can provide a tissue diagnosis by fine-needle aspiration (FNA) and deliver therapy (interventional EUS).

While CT with or without MRI is having a ability to outline patient-specific representation of prostate gland location and pure mathematics. CT is not dependent on the bone remodeling by lesion, it shows more lasions. (Kelloff et al., 2009)

(CT) is one of the most frequently used hospital diagnostic tools and also one of the most cost-effective (Kim et al., 2010: 3689)⁠

⁠MRI is mostly desirable due to a higher signal-to-noise ratio (SNR), yielding advantages by contributing to improved structural and functional detail. Current receiver coil technology includes pelvic phased-array coils with or without the add-on of an endorectal coil(Hegde et al., 2013: 1036)⁠

MRI does not impose radiation exposure on the patient. This advantage is important when imaging non-oncological patients or patients with a potentially curable oncological disease. Also multiparametric prostate MRI is used diagnose and investigate the prostate cancer antigen (Pca), whether it be through lesion visualization or by assisting in marked biopsies. (Birs et al., 2016)

⁠It is generally accepted that FDG-PET has very low a sensitiveness to be helpful in the diagnosing of lymph node metastases during direct staging of prostate cancer (Schöder & Larson, 2004: 280)⁠

5.3. Limitations

According to Byrne & Jowell, 2002 ultrasound education in tumor size may be helpful to determine prognosis to some practitioners, but a challenging problem with EUS is that it cannot dependably separate inflammatory tissue from cancer. With EUS it may prove impracticable to advance the EUS investigation through the stenosis, 29 and in this situation some authors have suggested dilatation to allow for EUS evaluation. (Byrne & Jowell, 2002: 134)

Most cancers cannot be seen by current TRUS techniques, while MRI SPECT is proven its ability is limited when it comes to diagnostic accuracy, poor sensitivity and specificity. 99mTc- MDP bone scan is proven to be sensitive but is poor when it comes to the spatial resolution of the visceral disease and limited specificity. (Kelloff et al., 2009: 1456)

⁠MRI is more expensive and is defined by considerably increased examination times. The procedure direction strongly depends on the imaging protocol ( such as the number and type of sequences). (Antoch & Bockisch, 2009: 114)

6. Conclusion.

Studies consulted provide evidence that all mentioned studies are of importance in the clinical environment, however, their use will be determined on what the physician is hoping to find out. For example, ultrasound and Magnetic resonance can be used to localize and stage the organ containing cancer, while the bone scan is used to determine metastatic disease and CT helps with treatment planning. The advancement of modalities help in improving the quality of care but education is always need to be applied in order to be able to utilise this improvement.

7. References.

1. Antioch, G. & Bockisch, A. 2009. Combined PET/MRI: A new dimension in whole-body oncology imaging? European Journal of Nuclear Medicine and Molecular Imaging, 36(SUPPL. 1): 113–120.
2. Birs, A., Joyce, P.H., Pavlovic, Z.J. & Lim, A. 2016. Diagnosis and Monitoring of Prostatic Lesions: A Comparison of Three Modalities: Multiparametric MRI, Fusion MRI/Transrectal Ultrasound (TRUS), and Traditional TRUS. Cureus.
3. Hegde, J. V., Mulkern, R. V., Panych, L.P., Fennessy, F.M., Fedorov, A., Maier, S.E. & Tempany, C.M.C. 2013. Multiparametric MRI of prostate cancer: An update on state-of-the-art techniques and their performance in detecting and localizing prostate cancer. Journal of Magnetic Resonance Imaging.
4. Heidenreich, A., Bolla, M., Joniau, S., Mason, M.D., Matveev, V., Mottet, N., Schmid, H., Kwast, T.H. Van Der, Wiegel, T. & Zattoni, F. 2011. Guidelines on Prostate Cancer. European Association of Urology.
5. Kelloff, G.J., Choyke, P. & Coffey, D.S. 2009. Challenges in clinical prostate cancer: Role of imaging. American Journal of Roentgenology.
6. Kim, D., Jeong, Y.Y. & Jon, S. 2010. A drug-loaded aptamer – Gold nanoparticle bioconjugate for combined ct imaging and therapy of prostate cancer. ACS Nano.
7. National Cancer Registry. 2014. Cancer In South Africa 2014 Full Report. http://www.nicd.ac.za/index.php/centres/national-cancer-registry/# [22 May 2018]
8. Penzkofer, T. & Tempany-Afdhal, C.M. 2014. Prostate cancer detection and diagnosis: The role of MR and its comparison with other diagnostic modalities – a radiologist’s perspective. NMR in Biomedicine.
9. Schöder, H. & Larson, S.M. 2004. Positron emission tomography for prostate, bladder, and renal cancer. Seminars in Nuclear Medicine.