Non Metastatic Prostate Cancer: Fill & Download for Free

Lead time biasLet’s presume two different people ‘A’ and ‘B’. ‘A’ is careful and religiously visits his doctor every 3 months while B cares a hoot about it.At age 40 ‘A’ has no symptom; his doctor orders a few tests, which accidentally pick up early signs of a slow growing cancer. He is started on treatment. He dies at age 60.‘B’ develops symptoms of cancer which forces him to see a doctor and is diagnosed to have cancer at age 50, he too dies at age 60.‘A’, ‘B’ and everyone else believe that with early diagnosis ‘intelligent A’ lived for 20 years, while ‘careless B’ died within 10 years of cancer diagnosis. (See red bidirectional arrow).But in reality the treatment and early detection has done no good to ‘A’. Even if ‘B’ had an early diagnosis, it would not have changed the time course of this particular cancer. The disease might have started at 40 in both, and killed them at 60; thats the natural history.This is called Lead Time Bias.Some cancers like slow growing non-metastatic prostate cancer does not spread whatever much doctors do or don’t do; and creates symptoms once they spread. A sensitive diagnostic test called PSA picks up cancer of prostate early, but PSA directed treatment has not shown to alter outcome. Most guidelines now advice not to have routine PSA testing done for asymptomatic adults.This is also true for many cases of chronic coronary artery disease, stable angina, and many genetic diseases which manifest later in life. Unless a treatment alters the natural course of the disease, the endpoint doesn’t change. Removing a cancerous mass or removing a coronary block gives excellent symptomatic relief, but does very little to prolong survival. (obviously not true for all cancers or heart disease).Next time someone says that a herbal concoction kept a cancer patient alive for 3 decades, smile.Remember, Quora gives you the Lead, the Time, in knowledge; without a Bias

Prostate cancer is one of the few diseases for which we have a blood test that is 99% accurate. When someone is treated curatively with radiation therapy, I check the PSA starting 1–3 months after treatment concludes, then every 3–6 months until we see it stabilize at a level around 0.5. Then, as time goes on, we gradually extend the interval to a year for the rest of the patient’s life. It usually takes 1–2 years to reach a stable level after external beam irradiation. It may only take 6–12 months when brachytherapy (implanted radioactive seeds) is used.When androgen deprivation therapy is combined with radiation ( for high grade prostate cancers), the PSA will drop to essentially non-detectable levels soon after the patient’s first injection (which starts about 2 months before the radiation) and will not rise again until the patient’s testosterone ultimately recovers - a few months to a few years after the completion of radiation. At that time, the PSA will rise and hopefully level off around 0.5. Occasionally, there is a PSA “bounce” where the level may go up a few points, then drop to a low stable level. We just can’t say whether or not treatment was effective until the PSAs go through this process.After surgery, the PSA should drop to non-detectable levels within a couple of months (the “half-life” of PSA is about 5 days, so ten half lives is almost 2 months). If it doesn’t drop all the way to “Zero” (which is <0.02 on the ultra-sensitive PSA scale), then there may be cancer left behind and post-operative radiation may be considered.Imaging (CTs, MRIs, bone scans, etc.) are not used in the follow-up of prostate cancer that has been treated curatively, but are often used to monitor the treatment of more advanced (metastatic) prostate cancer.

While COVID-19 has obviously been the medical focus of the world for most of 2020, and with good reason, that doesn’t mean that cancer research has stalled. It is still a key area of work because cancer remains a leading cause of death.Cancer, of course, is not a single disease, but a collection of dozen, hundreds, of different diseases with similar topical pathology. Because of that, there have been too many developments to list in any efficient way. Although there are some exciting discoveries that I would like to highlight.Development 1: Cancer VaccinesThe University of Queensland is ready to start large-scale clinical trials of their novel cancer vaccine.[1] This is following an encouraging pre-clinical trial. When many people think of a “vaccine” their minds automatically go to viral vaccines, which makes sense. Especially in the current climate But a vaccine is any biological preparation that provides effective immunity to a given condition or disease.And cancer is one such disease.Dr. Kristen Radford[2] and her team have developed a novel way of combining human antibodies with tumor-specific proteins. What happens is the vaccine targets immune cells, and teaches them to recognize the tumor, allowing a more advanced immunotherapy guideline.More so, because it is “off the shelf” as Dr. Radford put it, it avoids many of the pitfalls of patient-specific immunological treatments. The logistics are simplified because the material is far easier to work with, and it’s more generalized, so there is reduced cost compared to custom prepared immunotherapies for a specific patient.Because it is a more generalized treatment modality, it could work for a variety of cancers; myeloid leukemia, non-Hodgkin”s lymphoma, multiple myeloma, and various pediatric leukemias. There is also hope that it could be used to treat solid tumors as well, such as; breast, lung, renal (that’s kidney if someone wasn’t aware), ovarian, and pancreatic cancers, as well as glioblastoma.And it’s glioblastoma that I would like to focus on for a moment.(Image credit: Middlesex Hospital)As we have seen the survival rates for many other cancers go up and up[3], one area that hasn’t been as successful is the treatment of glioblastomas.[4] A glioblastoma is a type of tumor that occurs within the glial cells in the brain. But more specifically, they commonly (commonly in terms of disease pathology, not the general populace) occur in the astrocytes (star-shaped cells that support the nerves, and they are a type of glial cell), oligodendrocytes (which support the synapses, and generate the myelin sheath that surrounds nerves, this is the sheath that multiple sclerosis attacks, as an aside), and neurological stem cells.[5][6]Glioblastomas, even with increasingly effective treatments, have poor 5-year survival rates, 22% for those between the ages of 20–44, 9% for 45–54, and 6% for 55–64. They are not great.They are hard to treat, partly because they grow so fast, and partly because crossing the blood-brain barrier is difficult for many medications, so the medical treatments are more limited compared to other cancers. Let’s look at a glioblastoma image:(Image credit: The Scientist Magazine)And another:(Image credit: Healthcare in Europe)If we look closely at the image, we see something quite apparent. The borders of the glioblastoma are highly irregular, which would make surgery very difficult. At least if we are speaking about 100% tumor removal through surgical excision, and we deal with the complications that it’s in the brain, which means we have functionality, thought, mental health, etc to consider.Radiotherapy is a commonly used option, but that can only go so far. The chemotherapy drug temozolomide[7] can pass through the blood-brain barrier, however, glioblastoma cells are often resistant to it. They produce a protein called MGMT[8], which can reduce the effectiveness of temozolomide.Being that most antibodies struggle with crossing the blood-brain barrier, how this treatment modality can impact glioblastoma remains to be seen, but it’s an avenue that the team wants to explore. I look forward to reading the results. Additionally, if it can, they have to make sure an overreaction doesn’t occur, which can cause autoimmune encephalitis[9]Questions regarding glioblastoma’s aside, I’m optimistic about this approach. It will be several years before it would see widespread clinical use, but it looks promising.Just today, we received an update on Modern’a cancer vaccine candidate; mRNA-4157. Right now most people are more familiar with Moderna through their efforts to find a vaccine against SARS-CoV-2 and help control the pandemic, but the fact is Moderna’s messenger RNA based technology is active across many treatment areas.There have been some positive trends among a small Phase-I clinical study group suffering from Head and Neck Squamous Cell Carcinoma (HNSCC).[10] When combined with Keytruda, Modern/Merck saw shrinkage in tumors in 50% (five of ten study patients). However, the combination didn’t produce any difference in those suffering from Micro-Satellite Colorectal Cancer (MS-SCC)[11] which was disappointing. MS-SCC has been noted to be resistant to immunotherapy, and this continues to be a challenge. However, the small study of mRNA-4157 with Keytruda is encouraging for HNSCC, even though it’s a small study.(Note: other similar immunotherapies have been combined with Keytruda and performed well initially, only to fail in larger clinical trials. While this could be exciting, larger work and patience will be required)Development 2: Metastatic Prostate Cancer TreatmentThe PORTER Trial is something to be excited about in the research into prostate cancer. While it may surprise some people that prostate cancer is an active area of ongoing research, there is one very good reason for it. The 5-year survival rate of prostate cancer is quite good, at nearly 100% for early detected, localized, and regional cases.[12] This doesn’t tell the whole story though, because a full 1/3 of all cases will reemerge as metastatic disease. For those patients, the survival rate drops to ~ 30%[13] And that’s not something that is widely discussed.(Image credit: Prostate Cancer Foundation of Australia)Standard treatment for early-stage prostate cancer is hormone modulation because hormones have been found to be a significant contributing factor to tumor growth. Androgens, specifically testosterone and dihydrotestosterone, are what is blocked by various medications and procedures to slow or stop tumor growth. [14] And while this, combined with radiation, surgical excision, or other drugs, can cure cancer, it doesn't do anything for metastatic prostate cancer. This progresses into castration-resistant-prostate cancer (mCRPC), [15] which is considerably harder to treat.The PORTER Trial has arranged three different clinical study cohorts for testing three different treatment approaches, and you can read more about it here: The PORTER Trial | Parker Institute for Cancer Immunotherapy(Image credit: The Parker Institute and the PORTER Trial)These three different approaches are promising in that one of them could lead to a breakthrough in metastatic prostate cancer. While they are quite different from each other, based on the drugs’ mode of action, and how they modulate the immune system to fight the tumor, they are all innovative and go well beyond the boundaries of hormone therapy.Development 3: BiomarkersBoth genetic analysis, detailed imaging, and computing increase in ability and power, biomarkers are getting increased attention. Already somewhat well known, further advances have given us insight into the fact that it more than likely isn’t a single biomarker that is a “fingerprint” of a specific cancer type. And therefore a single biomarker won’t inform diagnosis and treatment planning as much as was once thought. In fact, clinicians will be looking at panels of biomarkers[16] [17] to give a more accurate view of the activity of the patient’s immune system and the genetic identity, and weaknesses, of the tumor.New development in “liquid biopsies”[18] and more advanced imaging, will help reinforce the validity of existing biomarkers, as well as find new ones. More validation will allow better incorporation into clinical practice.Development 4: Microbiome’s ImpactThere is clear data that the microbiome, or multiple different microbiomes, affect cancer formation and treatment.[19] But there are many different types of microbiome,[20] and a deeper understanding of the types of microorganisms than comprise them, and their specific impact on various bodily systems is going to be required before more detailed work into cancer can be broached. Once we have that information, it will be possible to manipulate it for treatment, or even prevention.At this time, we still don’t know enough about the microbiome, and it will continue to be an active and valid area of research going forward. We can see this in the National Institute of Health’s Human Microbiome Project (an overview of which is linked in the 20th footnote).Development 5: Photodynamic Therapy (PD)While not a new treatment modality, it has seen a bit of progress as of late. In PD a patient is injected with a chemical called a photosensitizer,[21] which reacts to light. Once it’s near the malignancy (the tumor) it is activated by a laser. The reaction creates singlet oxygen[22] (singlet oxygen has the formula O=O, its electrons are spin-paired[23]) which destroys the nearby cells. As you can imagine, it’s very effective for cancers close to the skin; such as breast cancer, prostate cancer, lymphomas, and other skin proximity tumors.Professor Jan C.M. van Hest at the University of Endhoven[24] and his team have created a new type of nanoparticle that can meet the unique, and difficult, demands of PD. Principal among them is that many tumors produce a molecule to break down singlet oxygen.[25] Quite ingeniously, the nanoparticle is coated in polymers that are triggered by the tumor’s acidic environment and it then attaches to the tumor.[26] The polymers are held together by the photosensitizing drug. It breaks down hydrogen peroxide from the tumor to produce oxygen.Of course, further testing is needed to see efficacy, as this is very early state technology, but it is rather interesting. Beyond that, Professor van Hest is examing both light-driven motor function, which would drive the nanoparticles deeper into the tumor, multiplying its effectiveness. Nanomotors are too deep of an area to begin to describe here, if one is interested, the Wikipedia page is a good place to start reading about them: Nanomotor - Wikipedia.Development 6: ATR-InhibitorsBerzosertib[27] is one of the new class of drugs called ATR-Inhibitors. These work by blocking the function of the ATR protein, which cancer cells use to fix damaged DNA, which allows the cells to sustain reproduction. [28](static visualization of the ATR Protein. Image credit: Sino Biological)Without functioning ATR, DNA can be damaged, and the cells can't properly reproduce, the tumor stops growing. Berzosertib is a first-in-class drug, and it’s early-stage results have some clinicians and research scientists wondering if it’s the next stage in precision medicine. Investigators announced as part of an early-stage trial that a patient with advanced bowel cancer showed defects in the repair genes, principally CHEK1[29] and ARID1A[30], both key to cell-cycle. The patient responded well to berzosertib, on its own. Which was surprising as it was primarily designed for combination treatment. Another patient received combination therapy, after PARP therapy,[31] didn’t work as planned, and had good results. [32]The drug is going to move into more advanced, and larger, clinical trials where it will be observed for performance, side effects, and compared with medications like Olaparib and rucaparib, which are examples of the aforementioned PARP inhibitors.Development 7: Visualization.This one is a direct treatment, but it allows better understanding on the part of clinicians, research scientists, and laypeople, which can lead to better treatments and outcomes. This one is one of personal favorites, and I’m excited to see their work:WEHI.TVWEHI-TV provides a stunning amount of computer visualization to the basic biomolecular processes, in a way that is quite mesmerizing. I can watch these videos for fun. And it’s been inspiring enough to try to learn more about graphics in my own time. In one of WEHI-TV’s newest videos, they display the p53 protein, perhaps one of the most important proteins in cancer.Animation reveals secrets of critical tumour proteinA default in p53[33] has been tied to more than half of all human cancers. What this protein does is analyze the cell, and it appears to be damaged it begins the molecular process to repair the cell. If the cell is too damaged for repairs, the p53 protein triggers the production of cell-death proteins, causing what is called apoptosis,[34] the packaging of cellular contents to be destroyed by the immune system. [35]When p53 malfunctions, damaged cells can produce uncontrollably, causing tumors to develop. Understand p53 deeply is going to be key in fighting cancer, and this visualization helps in that a great deal.(Static visualization of p53. Image credit: Sino biological)I’ve really only scratched the surface of the advances that cancer treatment has made in 2020, and will continue to make, building on this work. But these are some of the more exciting, to me, findingsMake no mistake, the power of medical tools continues to grow, quickly. we live in a different age. And while we are a long way from being able to cure everything or even a variety of things, we cannot question that we have come a long way.We can see that with the preliminary success of COVID-19 vaccines in record time, we can see it in increasingly capable precision medicine, and we can see it in a more detailed analysis of our bodies, and how to prevent the disease in the first place.If you’ve made it this far, and I know it was long, thank you for reading.Footnotes[1] Major breakthrough in cancer vaccination[2] Associate Professor Kristen Radford[3] Cancer survival rates[4] Survival Rates for Selected Adult Brain and Spinal Cord Tumors[5] The cellular origin for malignant glioma and prospects for clinical advancements[6] Cell of Origin for Malignant Gliomas and Its Implication in Therapeutic Development[7] Temozolomide - Wikipedia[8] https://www.genecards.org/cgi-bin/carddisp.pl?gene=MGMT[9] Hello from the Other Side: How Autoantibodies Circumvent the Blood–Brain Barrier in Autoimmune Encephalitis[10] Head and Neck Cancers[11] What is MSI vs MSS? | Fight Colorectal Cancer[12] Survival Rates for Prostate Cancer[13] Prostate Cancer Prognosis[14] Hormone Therapy for Prostate Cancer[15] NCI Dictionary of Cancer Terms[16] A Framework for Evaluating Biomarkers for Early Detection: Validation of Biomarker Panels for Ovarian Cancer[17] FDA-Approved Biomarker Panels: The Good, The Bad, and The Ugly - Amplion[18] NCI Dictionary of Cancer Terms[19] The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View[20] NIH Human Microbiome Project defines normal bacterial makeup of the body[21] New photosensitizers for photodynamic therapy[22] http://nathan.instras.com/MyDocsDB/doc-557.pdf[23] Research - What is Singlet Oxygen?[24] Jan van Hest[25] Oxygen Dependence of the Photosensitizing Effect of Hematoporphyrin Derivative in NHIK 3025 Cells[26] Significant leap forward in method for cancer treatment[27] Berzosertib - A Novel ATR Inhibitor in Development[28] Ataxia telangiectasia and Rad3 related - Wikipedia[29] CHEK1 - Wikipedia[30] ARID1A - Wikipedia[31] Targeted Therapy for Ovarian Cancer[32] Are ATR Inhibitors The Next Precision Medicine to Improve Cancer Outcomes[33] The p53 tumor suppressor protein[34] Apoptosis (article) | Developmental biology | Khan Academy[35] Primary information of p53 gene