Alana Hippensteele, Editor

The development of gene therapy and targeted therapy for prostate cancer has been a significant breakthrough in the treatment of the most prevalent malignancy in men, explained Seon Jo Park, PharmD, BCOP, a clinical pharmacy specialist at Allegheny Health of the Network Cancer Institute, during a session at the Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference.

“If you look at the statistics, you see that there’s a startling number of patients who get diagnosed and die from their severe malignancy. Knowing that the family history and certain gene mutations increases the risk of prostate cancer, we are very excited to see more gene mutation research,” Park said during the session. “A lot of people will benefit from this research.”

For the purpose of framing the gene mutations within pancreatic cancer, Park explained that genes are contained within chromosomes, which are themselves contained within the cell nucleus. Conversely, a chromosome contains hundreds of thousands of genes.

In normal human cells, each individual cell contains 23 pairs of chromosomes for a total of 46. Within the chromosomes, the genes themselves consist of DNA, which hold the blueprint for the synthesis of protein.

In this way, germline DNA mutations specifically refer to the DNA that is the result of the unique combinations of genetic material within the DNA, half of which is from an individual’s mother and the other half from their father, Park noted.

Furthermore, germline genetic testing is able to identify the presence of inherited pathogenic mutations. Testing can be performed on lymphocyte DNA from blood or a combination of lymphocyte DNA and buccal cells from saliva. This is possible because germline DNA is nearly identical in all nucleated cells of an individual.

However, in contrast to germline mutations, somatic mutations are observed in tumor tissue from primary or metastatic site or blood, which also means that the mutation can change over time due to genetic instability and selected pressure from therapy. For this reason, repeated testing of tumor DNA may be necessary during the disease course to track such changes.

Germline mutations also vary in occurrence based on cancer subtype. After assessing the data, the investigators found that 11.8% to 16.2% of germline mutations occurred in metastatic prostate cancer, compared to 4.6% in localized prostate cancer, and approximately 2% to 3% in the general population who do not have prostate cancer, according to Park.

“They definitely found a higher prevalence of mutation in metastatic prostate cancer. The most common gene mutations they found were 

. They also found some mismatched repair mutations, such as MSH2 and MSH6 mutations,” Park said during the session.

Among the somatic mutations, approximately 89% of patients with metastatic castration-resistant prostate cancer have a potentially actionable mutation. Additionally, Park noted that these potentially actionable mutations can occur among both germline and somatic mutations.

There are 3 guidelines that give recommendations regarding germline testing: the Philadelphia Prostate Cancer Consensus (PPCC), the National Comprehensive Cancer Network guidelines for patients with prostate cancer, and the European Advanced Prostate Cancer Consensus. These guidelines all make recommendations that help clinicians make decisions regarding when to pursue germline mutation testing based on a patient’s family history.

The PPCC guideline specifically provided clarity on what constitutes a strong family history requiring germline mutation testing. First, they noted this testing was important to pursue for men with 1 brother or father or more than or equal to 2 male relatives who either were diagnosed with prostate cancer at an age younger than 60 years, died of prostate cancer, or had metastatic prostate cancer.

Second, the PPCC noted that patients with 2 or more relatives on the same side of the family who had hereditary breast and ovarian cancers or Lynch syndrome should pursue germline testing as well.

In terms of disease and tumor characteristics, all of the guidelines recommended patients who have metastatic prostate cancer have germline testing done. Additionally, for germline mutations, all of the guidelines strongly recommended patients with 

 mutations and MMR genes have the test done.

For somatic tumor testing, they also recommended all of the patients with metastatic prostate cancer to get this test conducted as well.

“If they happened to find any pathogenic mutations, such as 

 mutations, they recommended to get confirmatory germline testing done based on the genetic counseling and family history,” Park said during the session.

Park SJ. Genetic Testing for Prostate Cancer. Presented at: Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference; April 15, 2021; virtual. Accessed April 16, 2021.

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Among somatic mutations, approximately 89% of patients with metastatic castration-resistant prostate cancer have a potentially actionable mutation.

Assessing Germline, Somatic Genetic Testing for Prostate Cancer

Unlike movies and television, knocking someone out in real life takes quite a bit more than a well-timed punch in the face or a Vulcan nerve pinch. Before the advent of modern anesthesia, humans tried multiple avenues for effectively rendering other people unconscious before surgeries. Medical practitioners experimented with many potential solutions over the millennia before finding results that worked while also not killing their patients in the process, although they did a bit more of the latter prior to finding the answer.

Some cultures over the years found certain drugs that had a similar benefit as anesthesia, such as hashish in Ancient China and opium in Ancient Egypt. Later in Europe during the Middle Ages, physicians used a method they referred to as the “soporific sponge,” which involved soaking a sponge in opium, hemlock, henbane, and mandrake, and then letting it dry in the sun. After that, they would rinse it in hot water before squeezing it and stuffing it firmly under a patient’s nose.

The problem with many of these cures was the amount of drug needed were also the quantities needed to poison someone. Due to these problems, some health care professionals resorted to instead surprising their patients by whacking them over the head in order to knock them unconscious before surgery. This method was recorded as being used in pre-modern China, with varying results.

As another alternative to whacking patients over the head, the British physician Henry Hill Hickman in the 19th century tried the method of suffocation in order to render patients unconscious. Due to his awareness that suffocation can also lead to death, he first tested his theory on puppies to assess its potential efficacy.

“I took a puppy a month old…and placed a glass cover so as to prevent the access of atmospheric air; in ten minutes, he showed great marks of uneasiness, in 12 respiration became difficult, and in 17 minutes ceased altogether, at 18 minutes I took off one of the Ears…and the animal did not seem to be the least sensible of pain,” Hickman wrote in an article.

Unfortunately, not all of Hickman’s test subjects survived this ordeal, which Hickman did not believe to be as much of a problem as his colleagues did. His published conclusions regarding his (subjectively) positive results at using suffocation as a form of anesthesia were not well received by pretty much anyone.

In one review of Hickman’s research published in 

 titled “Surgical Humbug,” the author, who signed his name “ANTIQUACK” in the article, explained that the medical community would “laugh him to scorn if he were to recommend a man who was about to have a tooth drawn to be previously hanged, drowned, or smothered for a few minutes, in order that he may feel no pain during the operation.”

However, Hickman was not the first to recommend this method of anesthesia pre-surgery. Some writing from Assyria suggest that they may have strangled children into unconsciousness to perform circumcisions. This was also recorded as a method to knock out children before circumcisions in 17th century Italy as well.

For other physicians, the discovery of a drug’s ability to work as an anesthesia was accidental during a more primary investigation into its potential recreational use. The 19th century Scottish physician James Young Simpson was attempting to get his buzz on with colleagues by sniffing random chemicals in their vicinity, when they observed that sniffing chloroform resulted in quite exceptional results.

They found that the sickly sweet smell first resulted in a giddiness, accompanied by buzzing in the ears, proceeded by their limbs beginning to feel heavy as the effects progressed. They then noticed they all started conversing excessively before suddenly being knocked unconscious.

After they awoke, they noted the unexpected results, and then decided to try it a few more times to (presumably) confirm their findings. One of the physician’s brought their niece on board, who exclaimed, “I’m an angel! Oh, I’m an angel!” before passing out on the dining room floor.

In light of chloroform’s potential success as an anesthesia, Simpson began championing the drug for its use before surgeries among other health care professionals. Additionally, in a less professional capacity, he continued to enjoy its more recreational effects. During the mid-19th century, the drug began to spread for use at parties by enthusiasts of the similar ether sniffing craze.

Chloroform began to show up in a lot of other pharmaceutical products, with some less medical in nature than others. People—laymen and pharmaceutical manufacturers alike—associated chloroform’s ability to make them feel nice as being a sign it was also beneficial to their health. This led to chloroform being sold at pharmacies in the forms of Gibson’s Linseed Licorice, Chloroform Lozenges, and Bee Brand White Pine and Tar Cough Syrup. The manufacturers claimed that these products cured all manner of illnesses associated with the throat and lungs, while additionally curing tuberculosis.

Unfortunately, chloroform is in fact an irritant to these parts of the body, and it accomplished very little for patients with tuberculosis besides making them feel giddy before knocking them out. Additionally, chloroform is also sometimes deadly, with the term “sudden sniffer’s death” being coined due to the frequency of this issue among patients who died inexplicably following chloroform use.

Modern medicine has more recently been able to identify some of the reasons “sudden sniffer’s death” may have occurred, as chloroform is now understood to cause liver and kidney toxicity, while also likely being a carcinogen. For this reason, chloroform fell out of favor as both an anesthesia and a recreational drug due to its toxicity profile. However, it remains in the zeitgeist due its primary use of effectively knocking people unconscious, while also somewhat less effectively being used for murder.

Kang L, Pedersen N. Quackery: A Brief History of the Worst Ways to Cure Everything. New York, NY: Workman Publishing; 2017.

Before the advent of modern anesthesia, humans tried multiple avenues for rendering people unconscious before surgeries, with varying results.

Pharmacy Fact: Before Modern Anesthesia, Knocking People Unconscious Was Hit Or Miss

The delivery of intravenous cancer therapies in the home has been a topic of great importance since the start of the COVID-19 pandemic, explained Stephanie Kang, PharmD, MS, BCPS, a clinical manager from University of North Carolina (UNC) Homecare Specialists at UNC Health, during a session at the Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference.

Currently, home infusion within the larger ambulatory infusion setting poses some specific advantages and disadvantages in relation to the other location options available. There are 3 main ambulatory infusion locations that are used for intravenous cancer therapies: hospital-based clinics, freestanding infusion clinics, and the patient’s home.

Of the 3 locations, hospital-based clinics have the advantage over the others of being held to the highest regulatory standards, especially in terms of United States Pharmacopeia compliance, according to Kang. Additionally, the hospital affiliation of these clinics provides the greatest level of access to specialized care.

The disadvantages presented in hospital-based clinics include price, as they are the most expensive location option for infusion, as well as their inconvenience for patients. Inconvenience may especially be a factor if the clinic’s hours of operations are limited, which may also contribute to longer wait times for scheduling treatments.

Alternatively, freestanding infusion clinics may be slightly more convenient because they are dispersed around the community, while also providing a lower cost than hospital-based clinics. However, if not affiliated with the patient’s primary oncology team, these location options can cause issues regarding fragmented care due to difficulties around communication between each care team involved.

Within the home infusion setting options, the lower cost of this setting in relation to hospital-based clinics poses specific advantages, although the cost remains about the same as the cost of freestanding infusion clinics. However, the convenience of the infusion location being in the patient’s home makes this option more advantageous for the patient than freestanding infusion clinics, which will still require transportation considerations.

However, if the home infusion provider is a third-party company that is external to the patient’s primary care team, the issue of fragmented care may also arise in the home infusion setting. Additionally, concerns regarding the patient’s limited access to their care team may pose problems, since removing the need to visit the clinic for each infusion limits patients' interaction with their provider. There are also other problems that may arise around the patient’s potential limited access to emergency services if a negative reaction or adverse event (AE) occurs during the infusion.

Currently, there are 2 issues that have caused a shift in focus toward the home infusion setting, according to Kang. The first issue is the payer’s side of care mandates, which has arisen as a point of interest due to the lower cost of home infusion and freestanding infusions, bringing about a shift among payers toward requiring that patients receive treatments in either of these settings, rather than in the hospital-based clinic setting.

The second issue that has caused a shift toward the home infusion setting is the COVID-19 pandemic, which led to an overall push for home infusions as a way of mitigating the spread of COVID-19 among patients and health care professionals.

In light of this, the Centers for Medicare and Medicaid Services (CMS) issued a new interim final rule during the pandemic that was intended to allow additional beneficiaries, particularly among high-risk patients, to receive home infusions to reduce COVID-19 transmission concerns. As a result of this interim final rule, CMS made it easier for patients to receive home infusions of a wider variety of medications, including cancer therapies.

Within the past 2 years, several national oncology organizations have released position statements related to home infusion of cancer therapies. For example, in the position statement of the American Society of Clinical Oncology (ASCO), the organization explained several concerns around safety, which included the lack of double checks prior to administration, the risk of life-threatening AEs, the potential for chemotherapy spills or exposure to non-cancer patients in the home, the question of liability if there was an error in the drug preparation, and the lack of oncology-trained nurses going out into the home.

However, ASCO also acknowledged some advantages to patients being able to receive infusions in the home, such as increased participation in clinical trials, as well as increased access to care, specifically for patients located in rural regions.

In light of these advantages to the home infusion setting, ASCO made 6 recommendations for administering cancer therapies in the home. The first recommendation was to use public funds to formally research the safety and efficacy of cancer therapies because there is currently not significant primary literature on this topic.

ASCO’s second recommendation was for CMS to not extend the interim final rule established during the pandemic that makes available a wide variety of therapies for infusion in the home. The third recommendation was that CMS looks to work closely with oncology experts to ensure that the provider and patient agree to the home setting as the most appropriate setting for care. 

Upon the agreement of this setting, ASCO recommended that CMS require quality reporting of oncology-specific measures to further evaluate safety and efficacy outcomes, primarily due to the lack of available data in these areas.

ASCO’s fourth recommendation was to limit cancer therapies to exceptional circumstances in which the benefit to that patient would outweigh the risk, while the fifth recommendation was to require a consultation with the oncologist before allowing any delivery of pre-prepared cancer therapies. Lastly, ASCO recommended that payers require proof of safety protocols and precautions for home infusion providers.

Conversely, the Community Oncology Alliance (COA) released a position statement stating that they fundamentally oppose the home infusion of chemotherapy, cancer immunotherapy, and supportive drugs for cancer treatment due to serious patient safety concerns.

COA’s specific reasoning for their opposition was that patient’s need face-to-face, high-touch evaluation with each treatment cycle, that the number of treatments increases incidence of AEs and interactions, that the specialty care-trained team is not available in the home, and that home infusions have limited access to emergency medications, equipment, and personnel.

Based on these observations and recommendations from prominent oncology organizations, Kang explained that there are clearly benefits for the home infusion setting, but there remain barriers to this setting that need to be addressed for this to be a successful site of care.

In light of this, the Gorski Model for Safe Home Infusion Therapy outlines 4 factors that are required for safe care in the home, although this model is more generally intended for home infusion for all medications. The requirements include appropriate patient selection, comprehensive assessment and monitoring, appropriate patient education, and interprofessional communication and collaboration.

“If I put this into my own words, I would say the safe model for home infusion therapy requires the right patient, the right regimen, the right resources to the patient, as well as the right level of communication across care teams,” Kang said during the session.

Kang S. Intravenous Cancer Therapies in the Home - Innovative or Dangerous? Presented at: Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference; April 14, 2021; virtual. Accessed April 14, 2021.

Home infusion within the larger ambulatory infusion setting poses some specific advantages and disadvantages in relation to the other location options available.

Assessing the Advantages, Disadvantages of Intravenous Cancer Therapies in the Home 

Patients with cancer are at a significant risk of developing a thrombotic event for multiple reasons, with the occurrence of these events directly associated with a significant increase in mortality, explained Victoria Nachar, PharmD, BCOP, clinical pharmacist specialist-ambulatory hematology oncology at the University of Michigan Rogel Cancer Center, during a session at the Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference.

Even while therapeutically anticoagulated, patients with cancer have risk factors for both recurring venous thromboembolism (VTE) and bleeding, which makes clinicians’ assessments of the treatment prospects in relation to cancer-related VTE quite complex, especially for patients with a fluctuating clinical status. Additionally, the molecular mechanisms that cause this predisposition remain poorly understood, which makes treatment difficult.

Nachar explained that the oldest and most dominant theory regarding the potential predisposition for VTE in patients with malignancy is that there are 3 components for clinicians to assess: the blood, the blood vessel wall, and the blood flow.

“We often see that our patients have multiple abnormalities in each of these 3 components, and so likely, the mechanisms behind cancer-related VTE are multiple and they are probably synergistic,” Nachar said during the session.

In this way, all cancers may not lead to a predisposition for VTE at the same rate, explained co-speaker Allison Schepers, PharmD, BCOP, clinical pharmacist specialist in Inpatient Medical Oncology at the University of Michigan Medicine, during the session. Although almost all cancer subtypes do present with a markedly increased risk of VTE in comparison to non-cancer control, patients with the highest risk of VTE are specifically those with pancreatic or thoracic malignancies.

However, the site of malignancy is not the only factor that puts patients with cancer at an increased risk.

“In addition to the site of malignancy, there are a variety of patient malignancy and treatment-related factors that also increase risk,” Schepers said during the session. “We know that comorbidities such as obesity, renal dysfunction, and infection can increase a person’s risk, as well as disease characteristics, such as metastatic disease or being in the first few months since the cancer diagnosis.”

Schepers noted that for pharmacists, of utmost concern are the treatment modalities available in light of these risk factors, and which cancer treatments may contribute to them. Common cancer treatments such as cisplatin, vascular endothelial growth factor (VEGF) inhibitors, immunomodulators, and hormonal therapies are some of the greatest culprits of the increased risk for the development of VTE in patients with cancer, according to Schepers.

Additionally, Schepers explained that since cancer-related VTE has such a high morbidity and mortality rate, the identification of those patients at the highest risk can allow for a prophylactic approach, which is optimal because it allows for the avoidance of such complications before they occur.

“Luckily, we do have a validated scoring tool, the Khorana Score, that takes a variety of factors into account and assigns a score, with a higher Khorana Score being associated with a higher risk of developing a VTE,” Schepers said during the session.

However, although cancer-related VTE is a relatively common complication for patients, the treatment for VTE continues to be anything but simple, Schepers explained. Patients with cancer are at a 6 times increased risk of recurrent VTE than non-cancer patients, but they are also at higher risk for other adverse effects as well, such as bleeding.

Additionally, these patients often need anticoagulation treatment in the longer-term, which has a significant effect on quality of life for this population, as well as bringing forth concerns regarding adherence due to the extended duration of treatment and issues that may arise as a result.

“All of these factors really come together to form a very complex picture of how best to treat cancer-related VTE,” Schepers said during the session.

Nachar V, Schepers A. Cancer-Related Thrombosis: The Great Debate on the Best Way to Anticoagulate. Presented at: Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference; April 13, 2021; virtual. Accessed April 14, 2021.

Even while therapeutically anticoagulated, patients with cancer have risk factors for recurring venous thromboembolism and bleeding, according to a session at the Hematology/Oncology Pharmacy Association 2021 Virtual Annual Conference. 