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  • Ovarian cancer is a deadly disease that is challenging to diagnose and manage
  • Although it only accounts for 3% of cancers in women, it is the 5th leading cause of cancer death among women
  • If diagnosed and treated early before it spreads the 5-year survival rate is 92%
  • But only 15% of women with ovarian cancer are diagnosed early
  • The disease is hard to diagnose because it is rare, the symptoms are relatively benign, and there is no effective screening
  • Ovarian cancer is not one disease, but a collection of subtypes each demanding specific treatment pathways
  • Gold standard treatment is surgery followed by chemotherapy
  • A large proportion of patients develop resistance to chemotherapy
 
Improving ovarian cancer treatment

Part I
 
Are things beginning to improve for people living with ovarian cancer? When the British advertising magnate Lord Maurice Saatchi’s wife died of ovarian cancer in 2012 he described her treatment as, “degrading, medieval and ineffective” leading “only to death”. Ovarian cancer patients have long had limited treatment options, which have not changed much in the past two decades, but recently things have begun to change.

 
In this Commentary
 
This is the first of a 2-part Commentary on ovarian cancer, which briefly describes the condition, explains the difficulties of diagnosing it early, and discusses some of the challenges of developing effective screening mechanisms for the cancer in pre-symptomatic women. Part 2, which will follow separately next week, reports new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. It also suggests that improvements in ovarian cancer care are both organizational and scientific. Experts believe that they now have a number of treatment options available to them. Utilising and sequencing these appropriately can have a significant impact on the overall survival rates of patients. Multidisciplinary teams, which are not universally available to all ovarian cancer patients, bring together all specialisms involved in the therapeutic pathway to consider and suggest optimal treatment steps for individual patients, and make a significant contribution to improved ovarian cancer care. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.
 
Ovarian cancer: a complex and deadly disease
 
The ovaries are a pair of small organs located low in the stomach that are connected to the womb and store a woman’s supply of eggs. Ovarian cancer is driven by multicellular pathways, and is better understood as a collection of subtypes with changing origins and clinical behaviors, rather than as a single disease. The tumors often have heterogeneous cell populations, which form unique microcellular environments. The prevalence of ovarian cancer among gynecological malignancies is rising, and is one the most deadly and hard to treat malignancies. While the disease only accounts for about 3% of cancers in women, it is one of the most common types of cancer in women, the 5th leading cause of cancer-related death among women, and the deadliest of gynecologic cancers. The risk of ovarian cancer increases with age. It is rare in women younger than 40, most ovarian cancers develop after menopause. 50% of all ovarian cancers are found in women 63 or older. According to the American Cancer Society the five-year survival rate for all ovarian cancers is 45%. Most women are diagnosed with late-stage ovarian disease and, the 5-year survival rates for these patients are roughly 30%. Age adjusted survival rates of ovarian cancer are improving in most developed countries. For instance, between 1970 and 2010, the 10-year survival rates for ovarian cancer in England increased by 16%, and the 5-year survival rates have almost doubled. This is because of the favorable trends in the use of oral contraceptives, which were introduced early in developed countries. Declines in menopausal hormone use may also have had a favorable effect in older women as well as improved diagnosis, management and therapies. According to Public Health England, over the past 20 years the incidence of ovarian cancer in England has remained fairly stable, although it has decreased slightly in the last few years. Between 2008 and 2010 in England, 36% of some 14,000 women diagnosed with ovarian cancer died in the first year, and more than 1,600 died in the first month. There were 7,378 new cases of ovarian cancer in the UK in 2014 and more than 4,000 women died from the disease.
 
Benign symptoms difficult to diagnose

If ovarian cancer is diagnosed and treated early before it spreads from the ovaries to the abdomen, the 5-year relative survival rate is 92%. However, only 15% of all ovarian cancers are found at this early stage.  This is because it is hard to diagnose since the disease is so rare, the symptoms are relatively benign, and there is no effective screening. As a result, the illness tends not to be detected until the latter stages in around 60% of women, when the prognosis is poor. In about 20% of cases the disease is not diagnosed until it is incurable. Feeling bloated most days for three weeks or more is a significant sign of ovarian cancer. Other symptoms include: feeling full quickly, loss of appetite, pelvic or stomach pain, needing to urinate more frequently than normal, changes in bowel habit, feeling very tired, and unexplained weight loss.
 
“Tumors go from the earliest stage 1 directly to stage 3”
In the video below Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit says, “Ovarian cancer is often diagnosed late because in many cases the disease disseminates into the peritoneal cavity almost simultaneously with the primary declaring itself. Unlike other cancers, the notion that ovarian cancer progresses from stage 1 to stage 2, to stage 3 is possibly mythological. The reality is, these cancer cells often commence in the fallopian tube with a very small primary tumor, which disseminates directly into the peritoneal cavity. In other words, the tumors go from the earliest of stage 1 directly to stage 3."
 
 
Ovarian cancer screening and CA-125

For years scientists have been searching for an effective screening test for ovarian cancer in pre-symptomtic women. The 2 most common are transvaginal ultrasound (TVUS) and the CA-125 blood test. The former uses sound waves to examine the uterus, fallopian tubes, and ovaries by putting an ultrasound wand into the vagina. It can help find a tumor in the ovary, but cannot tell if the tumor is cancerous or benign. Most tumors identified by TVUS are not cancerous. So far, the most promising screening method is CA-125, which measures a protein antigen produced by the tumor.
 
CA-125 studies
To-date, 2 large ovarian cancer screening studies have been completed: one in the US, and another in the UK. Both looked at using the CA-125 blood test along with TVUS to detect ovarian cancer. In these studies, more cancers were found in the women who were screened, and some were at an early stage. But the outcomes of the women who were screened were no better than the women who were not screened: the screened women did not live longer and were not less likely to die from ovarian cancer.

Another study published in 2017 in the Journal of Clinical Oncology screened 4,346 women over 3 years at 42 centers across the UK, undertook follow-up studies 5 years later, and came to similar conclusions as the 2 previous studies. Further, “there are a number of non-ovarian diseases, which can cause elevated CA-125’s. Breast cancer, endometriosis, and irritation of the peritoneal cavity can all cause elevated CA-125,” says Michael Birrer, Director of Medical Gynecologic Oncology at the Massachusetts General Hospital and Professor of Medicine at Harvard University.


Controversial findings
Findings from screening tests using CA-125 can give false positives for ovarian cancer, and this puts pressure on patients to have further, often unnecessary interventions, which sometimes include surgery. Also, the limitations of the CA-125 test mean that many women with early stage ovarian cancer will receive a false negative from testing, and not get further treatment for their condition. Thus, the potential role of CA-125 for the early detection of ovarian cancer is controversial, and therefore it has not been adopted for widespread screening in asymptomatic women.
 
In the video below Birrer explains that, “pre-operatively and during therapy physicians will usually check CA-125 as a measure of the effectiveness of the therapy. At the completion of therapy one would anticipate that the CA-125 would be normal. After that, it is somewhat controversial as to whether follow-up with CA-125 to test for recurring disease is clinically relevant,” says Birrer. Since the discovery of CA-125 in 1981, there has been intense research focus on novel biomarkers for cancer, and significant scientific advances in genomics, proteomic, and epigenomics etc., which have been extensively used in scientific discovery, but as yet no new major cancer biomarkers have been introduced to practicing oncologists. 

 
Limited treatment options

As most ovarian cancer patients are diagnosed late when the disease has already spread, treatment options are limited. The first line treatment is surgery called debulking, (also known as cytoreduction or cytoreductive surgery), which is the reduction of as much of the volume (bulk) of a tumor as possible. 
 
Be prepared for extensive surgery
Whether a patient is a candidate for surgery depends on a number of factors including the type, size, location, grade and stage of the tumor, pre-existing medical conditions, and in the case of a recurrence, when the last cancer treatment was performed, as well as general health factors such as age, physical fitness and other medical comorbidities. People diagnosed with ovarian cancer, “need to be prepared to have extensive surgery because the real extent of the tumor dissemination cannot be detected by conventional imagining pre-operatively,” says Professor Christina Fotopoulou, consultant gynaecological oncologist at Queen Charlotte's & Chelsea Hospital, London: see video below. 
 
 
Platinum resistance

Surgery is usually followed by chemotherapy. There are more than 100 chemotherapy agents used to treat cancer either alone or in combination. Chemotherapy drugs target cells at different phases of the process of forming new cells, called the cell cycle. Understanding how these drugs work helps oncologists predict, which drugs are likely to work well together. Clinicians can also plan how often doses of each drug should be given based on the timing of the cell phases. Chemotherapy drugs can be grouped by their chemical composition, their relationship with other drugs, their utility in treating specific forms of cancer, and their side effects.  
 
You can reduce chemotherapy resistance by using a combination of drugs that target different processes in the cancer so that the probability that the cancer will simultaneously become resistant to both drugs is much lower than if you use one drug at a time, ” says David Bowtell,  Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia: see video:
 
 
Improving the chemotherapy agent cisplatin
The standard chemotherapy treatment for ovarian cancer is a combination of a platinum compound, such as cisplatin or carboplatin, and a taxane, which represents a class of drug originally identified from plants. Since cisplatin’s discovery in 1965 and its FDA approval in 1978, it has been used continuously in treatments for several types of cancer, and is best known as a cure for testicular cancer. Scientists have searched for ways to improve the anti-tumor efficacy of platinum based drugs, reducing their toxicity, strengthening them against resistance by expanding the class to include several new analogues of cisplatin, and putting these through clinical studies to broaden the different types of cancers against which they can be safely used.
 
Slow progress transitioning research into clinical practice
Despite these endeavors, platinum resistance remains a significant clinical challenge. Between 55 and 75% of women with ovarian cancer develop resistance to platinum based chemotherapy treatments. Significant research efforts have been dedicated to understanding this, but there has been relatively slow progress transitioning the research into effective clinical applications. According to Birrer, “the mechanism of platinum resistance from a molecular standpoint has not been well defined. It is likely to be heterogeneous, which means that each patient’s tumor may be slightly different. The hope is for targeted therapies and personalised medicine to have a chance of overcoming this, in that we could characterize the mechanism of the platinum resistance and apply and target therapy.”
 
2 theories of platinum resistance
In the video below, Birrer posits 2 theories to explain platinum resistance. “One suggests that under the influence of platinum the tumor changes and becomes resistant. Another suggests that there are 2 groups of cells to begin with. The vast majority of the tumor is sensitive, but there are small clusters of resistant cells. Once you kill the sensitive cells you have only the resistant cells left. Although these 2 theories have been around for about 25 years, there are no definitive data to suggest which theory is right. I have a personal scientific bias to think that the resistant cells are present at the time that we start the therapy. Being able to identify and characterize these cells upfront would be a radical breakthrough because then we would be able to target them at a time when they are only a small portion of the tumor,” says Birrer.
 
 
Takeaways

Saatchi is right; for decades ovarian cancer treatment has been wanting, but studies we describe in part-2 of this Commentary suggest that the tide might be turning for people living with ovarian cancer. So don't miss part-2 next week!
 
 
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  • The clandestine status of cannabis and its attendant risks are beginning to erode
  • The idea of cannabis as an evil drug is a relatively recent phenomenon
  • Plants have been the historical source of medicine for most of human history, and cannabis is no exception
  • There is a large and growing pharmacological and clinical interest in cannabis as medicine
  • Two distinct legal markets for cannabis are emerging: the tightly regulated pharmaceutical market and the less regulated market of herbal preparations
  • The FDA has approved cannabis-related drugs, which are used for a number of indications
  • There may be a recognizable pathway leading to more cannabis compounds becoming medicine
  • To become accepted as a medicine that doctors prescribe, pharmacists supply and healthcare providers support, cannabis compounds need to demonstrate their biochemical uniformity, stability, safety and efficacy
 
Medical cannabis and modern healthcare

Today, cannabis medicine for most people involves the black market with its attendant risks and lack of quality control. But this is changing to a more desirable alternative. As legal opinion changes, and clinical studies increase; the clandestine nature of cannabis and its attendant risks are beginning to erode, and two distinct legal markets for medical cannabis are emerging. One is the tightly regulated pharmaceutical market where medical cannabis provides safe and effective pharmaceutical solutions, which doctors prescribe, pharmacists’ supply, and healthcare providers support, and the other is the less regulated market of herbal preparations. A report by ArcView Market Research reported that 2016 annual sales of legal cannabis in the US grew by 25%, to US$6.7bn, and projects sales will reach US$21.8bn by 2020. This Commentary focuses on the pharmaceutical market, which relies on randomized clinical studies to demonstrate biochemical consistency, safety and efficacy.
 
The cannabis plant and its main properties

Cannabis is a genus of an annual herbaceous flowering plant, which includes 2 familiar sub-species or chemovars: ‘C sativa’, and ‘C indica’. Modern molecular techniques applied to the taxonomic classification of cannabis have resulted in many more classifications, which, in time, will become increasingly relevant as the plant’s medicinal qualities are increasingly identified. Cannabis is an indigenous plant of central Asia and India, but can be grown in almost any climate in any part of the world, and is increasingly being cultivated by means of indoor hydroponic technology. The cannabis plant contains more than 100 cannabinoids, which are chemical compounds secreted by cannabis flowers. About 60 of these have been identified as pharmacologically active, with the primary active cannabinoids being delta-9-tetrohydro-cannabinol, commonly known as THC, and cannabidiol, which is commonly known as CBD. THC provides the principal mind-altering ingredient, while CBD does not affect the mind or behavior.
 
Cannabis as medicine

Medical cannabis refers to using extracts from the cannabis plant - cannabinoids - to treat a range of conditions or their symptoms. Cannabinoids can be administered orally, sublingually, or topically; they can be smoked, inhaled, mixed with food, or made into tea. When cannabis is consumed, cannabinoids bind to receptor sites throughout the brain and body. Different cannabinoids have different effects depending on which receptors they bind to. For example, THC binds with receptors in the brain called CB-1, while CBD has a strong affinity for CB-2 receptors located throughout the body. By aiming the right cannabinoid at the right receptors, different types of relief are achievable. THC is the most active cannabinoid; it has dominated research into medical cannabis and resulted in FDA-approved drugs. Although CBD is one of the least active cannabinoids, it has come to dominate more recent research into medical cannabis as it is considered to have a relatively wide scope of potential medical applications with fewer side effects than THC.
 
Pot-ted history

Plants have been the historical source of medicine for most of human history, and continue to account for the base material of about 25% of modern pharmaceuticals. Approved medicines of botanical origin are relatively common, but require evidence-based randomized clinical studies to demonstrate their biochemical uniformity, stability, safety and efficacy. Medical cannabis is no exception, and the FDA has approved drugs derived from cannabinoids and synthetic cannabinoids. However, regulators have not approved the entire cannabis plant as medicine because there are insufficient clinical studies to demonstrate its benefits against its potential risks to patients it is meant to treat.

For centuries the cannabis plant has been used throughout the world for medicinal purposes. Only in recent history has it acquired the status of a dangerous drug and banned. Its first recorded use is 4000 BC when an extract from the cannabis plant was used in China as an anesthetic during surgery. The Chinese went on to use cannabis compounds extensively for a range of conditions including malaria, constipation, rheumatic pains, "absentmindedness" and "female disorders."
 
From China, cannabis travelled throughout Asia into the Middle East, Africa, Europe, and eventually to the US. Galen, a prominent Greek doctor and scientist in the Roman Empire, noted cannabis as a remedy. In India it was used to lower fevers, quicken the mind, induce sleep, cure dysentery, stimulate appetite, improve digestion, relieve headaches, and cure venereal disease. The Vikings and medieval Germans used cannabis for toothache, and for relieving pain during childbirth. In Africa it was used for a variety of fevers including malaria. Despite its extensive medicinal use in early history, there were warnings against the over-use of cannabis as it was said to result in “seeing demons”.

 
Opinion changing

The idea of cannabis as an evil drug is a relatively recent phenomenon. Despite its contemporary clandestine status, there is a large and growing pharmacological and clinical interest in cannabis as medicine, and a recognizable pathway leading to its return to mainstream medicine. As early as 1985 the FDA approved cannabinoids as medicine. As of June 2016, 25 American states and Washington DC, have legalized cannabis for medical use. Germany is now expected to follow suit. In the UK, more than half of its national parliamentarians, including the former deputy Prime Minister, want to see the legalisation of medical cannabis. In March 2017, Oxford University announced that it is to launch a £10m global centre of excellence in cannabinoid research. The program, which is a partnership between the University and Kingsley Capital Partners, a private equity business based in London, will examine the role of cannabis medicines in treating pain, cancer and inflammatory diseases.
  
FDA approved

The FDA has approved two cannabis-related drugs: dronabinol and nabilone. The former contains the psychoactive compound THC extracted from the resin of C-sativa. The latter contains a synthetic cannabinoid, which mimics THC; the primary psychoactive compound found naturally occurring in cannabis. Both treat chemotherapy-induced nausea and vomiting (CINV), and extreme weight loss caused by HIV/AIDS, among a number of other indications.

Nabiximols, a CBD extract of cannabis, has been approved in 27 countries as a mouth spray to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Although it has not yet undergone clinical studies, scientists have recently developed Epidiolex, a CBD-based liquid drug to treat certain forms of childhood epilepsy.

 
Chemotherapy-induced nausea and vomiting
 
Chemotherapy-induced nausea and vomiting (CINV), is one of the most common and feared adverse events that can be experienced by cancer patients. Its occurrence depends on the dose and the type of chemotherapy agent used, but it tends to be more prevalent in anxious woman under 50 who do not drink alcohol, and who have a history of sickness during pregnancy. Despite advances in the prevention and treatment of emesis, of the 70% to 80% of cancer patients who experience CINV, many delay or refuse future chemotherapy treatments, and contemplate stopping all treatments because of fear of further nausea and vomiting. 
 
There are several drug classes for the prevention and management of CINV. In 1985 the FDA approved a cannabinoid, dronabinol, for the treatment of CINV in patients who have failed to respond adequately to conventional antiemetic treatment. The number of people taking cannabinoids for therapeutic purposes is increasing, but very few medicines based on cannabis have yet been developed on rigorous scientific principles. Ahmed Ahmed, professor of gynaecological oncology at Oxford says, “This field holds great promise for developing novel therapeutic opportunities for cancer patients.
 
The endogenous cannabinoid system is a significant pathway involved in the emetic response. Cannabinoids can reduce or prevent chemotherapy-induced emesis by acting at central CB-1 receptors by preventing the pro-emetic effects of endogenous compounds, such as dopamine and serotonin. In addition, by acting as an agonist to CB-1, cannabinoids used as a treatment result in an antiemetic effect. Notwithstanding, few studies have evaluated medical cannabis alone or in combination to treat CINV. The published studies that have been conducted have mixed results. THC has to be dosed relatively highly, so that resultant adverse effects may occur comparatively frequently. Some investigations suggest that THC in low doses improves the efficacy of other antiemetic drugs if given together.

 
Some additional indications

In addition to its ability to reduce nausea, THC is effective as an appetite stimulant in both healthy and sick individuals, and is used to boost appetite in patients with cancer, HIV-associated wasting syndrome, and patients with anorexia.

Another common use of medical cannabis is as an analgesic. Studies suggest that THC activates pathways in the central nervous system, which work to block pain signals from being sent to the brain. THC has been shown to have some effect against neuropathic, cancer and menstrual pain, headache, and chronic bowel inflammation.

The high, which users get from cannabis THC is also associated with temporary loss of memory. For most people this would be concerning, but for people with post-traumatic stress disorder (PTSD), memory loss can be positive. PTSD is a chronic, disabling mental health condition triggered by a significant event, and results in traumatic flashbacks, nightmares, and emotional instability. A 2013 study published in the journal Molecular Psychiatry reported a correlation between the quantity of cannabinoid CB-1 receptors in the human brain and PTSD, and concluded that oral doses of THC could help relieve PTSD-related symptoms.

Review of clinical studies

In 2015 a systematic review of the pros and cons of cannabinoids was published in the Journal of the American Medical Association. The paper analyzed 79 clinical studies of cannabinoids, involving 6,462 participants, for a number of indications including: CINV, chronic pain, appetite stimulation in HIV/AIDS, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, and Tourette syndrome.

Most studies in the review showed improvement in symptoms that were correlated with cannabinoids, compared with a placebo. However, symptoms positively correlated with cannabinoids did not reach statistical significance in all studies. The review reported that there was an increased risk of short-term adverse effects associated with cannabinoids, some of which were severe. Common among these were dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

The review concluded that, “There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were correlated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were also correlated with an increased risk of short-term adverse effects.”

 
Clinical studies design challenges

Although cannabis compounds are currently used to treat disease or alleviate symptoms for a number of conditions, their efficacy for some specific indications is not altogether clear. This reflects the relative dearth of clinical studies that have been carried out on cannabinoids. Further, there are several design challenges associated with clinical studies that involve THC. One is whether cannabis components beyond THC contribute to its medicinal effects. Another is connected with the ability of studies to provide adequate blinding for psychoactive compounds such as THC. Clinical studies generally are known to show a degree of subjective improvement associated with the additional attention participants in a study are given, and this is compounded when a clinical study outcome measures subjective responses, such as pain and mood, as in the case of THC.
 
Gold standard
 
To be accepted by doctors, supplied by pharmacists and supported by healthcare providers, a medical cannabis product must be standardized and consistent, and display a quality equal to any recognized pharmacological compound. It must have a secure supply chain, possess an appropriate low-risk delivery system, and have minimal adverse effects. Although there are entities working to bring this about, the fact remains that the overwhelming majority of cannabis available today is unregulated, and this provides significant challenges, which include the biochemical variability of one chemovar to another, the possibility of the presence of bacteria and pesticides, and the variation in potency.
 
Nabiximols
 
A significant success of medical cannabis is nabiximols, an oromucosal spray produced from whole cannabis extracts, which is used to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis. Currently nabiximols is available in 27 countries, is biochemically uniform and provides an easy-to-use, reliable delivery system with immediate onset, allowing a therapeutic window for control of symptoms without intoxication. This suggests a gold standard benchmark, which other cannabis-based medicines will be required to follow.

 
Takeaways
 
There seems to be a clear pathway for medical cannabis to increase in importance in modern pharmacology. Modern technology, which facilitates advanced cultivation and extraction processes appear to be well positioned to facilitate the creation and development of cannabis products to target specific medical needs for maximum relief of a number of chronic conditions.
 
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