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Introduction


By Mark Scholz, MD

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Introduction


By Mark Scholz, MD

Once the proper Stage of Blue is assigned (Chapter 1), the different treatments appropriate for that Stage can be considered. Overall, there are four broad categories of treatment available for prostate cancer: observation, local treatments, systemic treatments, and combination therapy.

Observation

Observation, commonly known as “active surveillance,” is the process of monitoring the cancer while reserving medical intervention until some aggressive behaviour is detected.

Local Treatments

Strategies that focus treatment on the prostate gland are called “local” treatments. Examples are surgery, radioactive seed implantation, varieties of external beam radiation therapy (IMRT, Proton, SBRT), and cryosurgery.  In addition, “focal” treatment options have been developed in which only a subsection of the gland is treated.

Systemic Treatments

The main danger from prostate cancer is the possibility of cancer spreading outside the prostate. Men with metastases (or potential microscopic metastases) require systemic treatment that circulates through the blood and treats cancer throughout the whole body. Examples of systemic treatments are hormonal therapies, chemotherapy, immunotherapy, and Xofigo.

Combination Therapy

When a local treatment is combined with a systemic treatment, or if multiple systemic treatments are used at the same time, it is called “combination therapy.” When combination therapy is being considered with the goal of improving survival, the survival advantages need to be balanced against the potential for greater side effects.


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Accessing the Medical Chart to Assign a Stage of Blue


By Peter Scholz

Accessing the Medical Chart to Assign a Stage of Blue


By Peter Scholz

Many treatments have irreversible consequences, so it is worth doing it right the first time. It is commonly understood in medical circles that long-term survival is improved by receiving optimal treatment up front. The first treatment is your best shot at eradicating the cancer. The initial step in the selection process is to determine your Stage of Blue.

First, obtain a copy of your medical records. You have every right to obtain and keep your records. Some offices may charge a small fee for providing you with the records. There is no universal format for charts, and some offices keep more complete records than others. It may be necessary to request the information from more than one doctor’s office to compile all the necessary information. You don’t need a complete understanding of everything in the chart. However, there are certain specific items you need to look for:

Prostate Specific Antigen (PSA) Chronology: Construct a chronological history of every PSA measurement that has ever been taken and the date that it was performed. The PSA results can be found your Lab Reports. The testosterone level is also found in this section of the chart.

 Clinical Stage: Information about the digital rectal examination (DRE) will be found in the Progress Notes section of the chart. Results indicate whether a nodule can be felt by the doctor’s finger. The type of nodule that is felt is recorded as the “T” stage. The doctor records his impression of the DRE in the Physical Examination section of the Progress Notes section of the chart per the following table:

T1:    No tumor is felt

T2:   Tumor feels confined within the prostate

T2a: Tumor that can be felt but involves 50% or less of one lobe

T2b: Tumor felt involving more than 50% of one lobe but not both lobes

T2c: Tumor felt in both lobes

T3:   Tumor felt that extends through the prostate capsule

T3a: Extracapsular extension is felt

T3b: Tumor felt that invades seminal vesicle(s)

T4:   Tumor felt that invades rectum or bladder

 

Radiology Reports (imaging studies): The radiology reports will be found in the Radiology section of the chart. Look for the Impression section of the report where the doctor who wrote the report summarizes the essential aspects of the scan results.

Biopsy Report:  The biopsy report will be in the Pathology section of the chart. For each of the biopsy cores that contain cancer, you should make note of the Gleason score and the percentage of the core that contains cancer. 

Finding Your Stage of Blue with The Quiz

The above information from your medical chart provides the data required to assign a Stage of Blue. The formula calculates your Stage by summing up the numbers written in response to the questions in the following quiz. 

The five pages that follow explain the basic components of the Stages of Blue—PSA, Gleason score, prostate scans, and body scans. Although the Stages of Blue can serve you perfectly well without all these background fundamentals, the goal of this book is to introduce basic vocabulary and thought processes that are utilized throughout the prostate cancer world. Becoming familiar with this information will take the level of conversation with your doctor to a higher level.


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Peter Scholz is the creative director of the Prostate Cancer Research Institute (PCRI). He received his B.A. in english literature from the University of California, Los Angeles. In addition to branding, design, and media production for the organization, his interests at PCRI are in simplifying, curating, and presenting prostate cancer information in ways that are understandable and accessible to patients. 

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The PSA Blood Test


By Stanley Brosman, MD

The PSA Blood Test


By Stanley Brosman, MD

PSA plays a variety of roles, the most familiar being screening to detect prostate cancer at an early stage. PSA also helps to define the Stages of Blue. Another role of PSA is to detect cancer relapse after surgery or radiation. Lastly, rises or declines in PSA after hormone therapy or chemotherapy help determine whether a treatment is working. 

 

Prostate Cancer Screening is Controversial

PSA screening often leads to the detection of small, essentially harmless cancers. However, doctors and patients frequently overreact, rushing into unnecessary radical treatment. Overtreatment of tiny cancers became such a big problem that in 2011 a government-sponsored team of experts, the U.S. Preventative Services Task Force, issued a warning against routine PSA screening. This recommendation was recently modified, acknowledging the possible value of PSA screening in well-informed patients.

 

Scans Measure the Size of the Prostate

Imaging with ultrasound or MRI improves the accuracy of PSA. Many men run high PSA levels from a condition called BPH that is totally unrelated to cancer. BPH is benign enlargement of the prostate gland, a common phenomenon associated with aging. The main issue is that PSA increases as the gland enlarges, but this rise in PSA has nothing to do with cancer.

 

There is a specific method for determining when the PSA is elevated higher than what would be expected for an enlarged prostate. It works by determining the prostate size in cubic centimeters(cc) using imaging (Chapters 4 and 5) and dividing the size by 10. For example, a noncancerous 30cc prostate should have a PSA of around 3.0; for a noncancerous 50cc prostate the PSA should be around 5.0.  A man’s PSA with a 100cc prostate will be approximately 10.  PSA is only abnormal (the official term is a “high PSA density”) when it’s 50 percent higher than would be expected, based on the prostate’s size. For example, a man’s PSA is abnormal if he has a 30cc prostate and his PSA is above 4.5.  An abnormal PSA for a 50cc prostate is above 7.5.  For a 100cc gland, PSA would need to be above 15 to be suspicious.

 

PSA Density

Doctors use a less intuitive way to determine when the PSA is higher than what can be attributed to an enlarged prostate. The net effect, however, is the same. Instead of dividing PSA into the gland volume, they do the opposite.  They divide the gland volume into the PSA. Using this inverted formula, an abnormal PSA relative to a specific-sized prostate is anything above 0.15.  Men above 0.15, using this formula, are said to have a high “PSA Density.”

 

A Suggested PSA Screening Protocol

It’s reasonable to start checking PSA yearly in men over the age of 45. Men with a family history of prostate cancer or men who are African-American should start annual testing at age 40.  Men over age 75 who are in good health should continue screening.

 

Using PSA to Stage Prostate Cancer

Despite the controversies that surround the use of PSA for screening, there are no controversies about using PSA for cancer staging. Men with a higher PSA at the time of diagnosis, above 10 or 20 for example, are more likely to have cancer that has spread outside the gland. The exact methodology for determining a man’s Stage of Blue, using PSA in combination with other factors, is explained in Chapter 1. 

 

PSA to Monitor for Cancer Relapse After Surgery or Radiation

Cancer recurrence is signaled by a rising PSA. Normally after surgery, the PSA should drop to undetectable levels. Even a small rise in PSA is significant. After radiation, the PSA should generally remain under 1.0, though exceptions certainly exist. The rate of PSA doubling is a very important indicator of the recurrent cancer’s aggressiveness. For example, recurrences associated with PSA levels that require over 12 months to double are low-grade. On the other hand, PSA that doubles in less than three months signals aggressive disease.

 

Determining the Response to Hormone Therapy or Chemotherapy

A PSA decline of more than 30 percent within a couple of months of starting chemotherapy provides a strong indication that the treatment is working. However, not every treatment, even when it is effective, makes an impact on PSA. Two new therapies for Royal—Xofigo and Provenge—clearly prolong life but may show little or no impact on PSA.

 

Conclusion

PSA results must be interpreted in the context of each patient’s overall circumstances by an expert with experience in managing prostate cancer. Unexpected PSA results should always be retested. Laboratory errors are possible and variations also occur between labs. 


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Stanley Brosman, MD is board-certified in Urology.  Former Chief of Urology at UCLA/Harbor General Hospital, a Clinical Professor of Surgery/Urology at UCLA,. and Associate Director of Urologic Oncology at John Wayne Cancer Institute. He is past president of the urology section of the California Medical Society and . Past president of the Los Angeles Urologic Society. He is author or coauthor of more than 80 peer-reviewed scientific articles and over 50 book chapters or monographs. He practices urology with a focus on prostate cancer in Santa Monica, California, at the Pacific

 

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Interpreting the Pathology Report and Gleason Score


By Jonathan Epstein

Interpreting the Pathology Report and Gleason Score


By Jonathan Epstein

The two major components of the pathology report from a random 12-core biopsy are the Gleason score, which measures how aggressive the tumor appears, and the quantity of cancer in the 12-core specimen.

 

What Is The “Gleason Grade” Or “Gleason Score”?

The Gleason grading system assigns a “pattern” to the cancer cells, depending upon their appearance under the microscope. The patterns are graded from 1 to 5. The pathologist assigns a higher number when the appearance of the cancer cells deviates more from the visual appearance of normal prostate gland tissue. The first number in the score is the grade that applies to the most common type of cancer seen in the biopsy. The second number in the score is the next most common grade. These two different grades are then added together to yield the Gleason score. In actual practice, the Gleason score only ranges between 6 and 10.  Therefore, a Gleason 6 is the lowest, most favorable grade possible.

 

What Does It Mean to Have a Gleason Score of 7?

A Gleason score of 7 can mean 3+4=7 or 4+3=7, depending on whether grade 3 pattern or grade 4 pattern is predominant. The biggest therapeutic difference between these grades is that more aggressive radiation therapy protocols are often recommended for Gleason scores of 4+3=7 and higher.

 

What Does It Mean to Have Gleason Scores of 8 to 10?

Gleason score 8 cancers are aggressive, and Gleason score 9 to 10 cancers are more so. However, some patients with Gleason scores 9 or 10 can still be cured. The actual outlook for a specific patient also depends on additional factors, such as PSA, clinical stage, and the extent of cancer on biopsy.

 

Can the Biopsy Gleason Score Determine the Grade in the Entire Prostate?

The Gleason score on biopsy usually reflects the cancer’s true grade. However, in about 25 percent of cases the biopsy underestimates the true grade, resulting in under grading. Somewhat less commonly, over-grading occurs. This occurs when the true grade of the tumor is lower than that which is seen in the biopsy.

 

How Can Patients Be Sure the Reported Gleason Grade Is Accurate?

Assigning the correct Gleason score is developed through experience and practice. It is often prudent to submit the biopsy material for a second opinion to a center managing large numbers of patients with prostate cancer, to confirm the accuracy of the initial Gleason score.

 

Concluding Thoughts

A few years ago, there was a news story about a polar bear attacking a man in Canada.  Shockingly, the report said that the bystanders did nothing to help the poor man. However, upon further review it turned out that the reporter had neglected to report that the bear was only a cub, whose reach was lower than the man's knees. When facing a monstrous behemoth like cancer, the most important question to ask is "What kind of cancer am I dealing with?" 


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Jonathan Epstein, MD received his doctorateMD degree from Boston University. He completed Following his residency in anatomic pathology at The Johns Hopkins Hospital in Baltimore, Maryland, and a fellowship in oncologic pathology at Memorial Sloan Kettering Cancer Center in New York., hHe then joined the staff at The Johns Hopkins Hospital asand has been there his entire career. At the Johns Hopkins Medical Institutions, he is Professor of Pathology, Urology, and Oncology; the recipient of the Reinhard Chair of Urological Pathology; and Director of Surgical Pathology. He is the past Ppresident of the International Society of Urological Pathology. Dr. Epstein has 744 publications in the peer-reviewed literature and has authored 50 book chapters with a H-factor of 118. His most-frequently cited first or last authored publications is ‘‘Pathological and Clinical Findings to Predict Tumor Extent of Nonpalpable (stage T1c) Prostate Cancer,’’ published in JAMA, which establisheds the criteria for active surveillance. 

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Prostate MRI and Targeted Biopsy


By Daniel Margolis, MD

Prostate MRI and Targeted Biopsy


By Daniel Margolis, MD

Multiparametric MRI (MP-MRI) provides a three-dimensional image of the prostate, giving important information about the cancer’s location, size, and how “aggressive” it appears. MP-MRI also greatly increases the confidence that higher-grade cancers are not being overlooked in men on active surveillance. MP-MRI is usually performed without an endorectal coil.

 

“Multiparametric” Means Four Scans in One

There are four different imaging components to MP-MRI. The first is called “T2-weighted,” which creates the clearest images and gives the most capsular detail. The second and third parameters are called diffusion-weighted imaging (DWI) and the apparent-diffusion coefficient (ADC). These provide information about the aggressiveness of the tumor. The fourth, called dynamic-contrast enhancement (DCE), maps the blood flow of the tumor.

 

“PI-RADS”

PI-RADS (prostate imaging reporting and data systems) compiles a score composed of all four parameters—T2, DWI/ADC, and DCE—on a 1-to-5 scale. Lesions with a score of 4 or 5 are more likely to represent clinically significant prostate cancer (Gleason 4+3=7 or higher). Once MP-MRI detects a suspicious lesion, a targeted biopsy can be performed.

 

Evaluating Undiagnosed Men with High PSA Levels

There are notable advantages of MP-MRI over the random 12-core biopsy. First, it is less likely to diagnose clinically harmless cancers, sparing patients from unnecessary anxiety. Second, well-performed MP-MRI only misses significant cancer about 10 percent of the time, and these missed cancers tend to be small and unlikely to spread. To put this in perspective, a well-performed 12-core random biopsy misses high-grade cancer 25 percent of the time.

MRI for Active Surveillance

Until recently, men on active surveillance have only been monitored with periodic random 12-core random biopsies and PSA testing. MP-MRI provides three advantages over random biopsy. First, imaging is noninvasive. Second, imaging can find suspicious areas that might have been missed by previous random biopsies. Third, imaging provides a baseline measurement of the cancer’s size that can be used for follow-up monitoring to detect enlargement. As logical as imaging sounds, active surveillance strategies currently performed in most academic centers do not yet routinely use MP-MRI to detect cancer progression. Nevertheless, this concept is gaining traction.

 

The Future of Prostate MRI

The same imaging techniques for identifying prostate cancer for targeted biopsy can also be used to direct treatment. Focal therapy spares much of the surrounding normal prostate tissue from unnecessary damage. Given the increasing reliance on accurate imaging for state-of-the-art care, the importance of finding centers of excellence with skilled and experienced physicians will assume greater and greater importance.


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Daniel Margolis, MD earned his Bbachelor’s degree from Berkeley and his doctorateMD from USC, followed by an internship in internal medicine at West Los Angeles Veteran's Administration Hospital. He completed his residency in Diagnostic Radiology at UCLA, and a prestigious fellowship funded by the National Cancer Institute at Stanford. When he was in medical school, his former college roommate’s wife was diagnosed with breast cancer while she was pregnant with their third child. She succumbed to her disease within a few years, which had a pronounced effect on him. He chose to pursue a cancer-based fellowship, after which he stayed in private practice in the Bay Area. During that first year, a high school friend of his was diagnosed with pancreatic cancer, which sadly overtook her, too, again leaving behind a grieving widow and young children. Dr. Margolis decided then that being purely a diagnostic radiologist was not making the most use of his training, and took a job at UCLA where he could apply his skills to cancer research, achieving the most success with prostate imaging. He now serves as the Associate Professor of Radiology and Director of Prostate MRI at Weill Cornell in New York

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Color Doppler Ultrasound and Targeted Biopsy


By Duke Bahn, MD

Color Doppler Ultrasound and Targeted Biopsy


By Duke Bahn, MD

In Chapter 4, MP-MRI technology combined with a targeted biopsy was discussed.  This chapter will discuss an alternative type of imaging, called color Doppler ultrasound (CDU). Unfortunately, CDU followed by targeted biopsy is available in only a few centers around the United States. Even so, this chapter will expound the many advantages of CDU for the diagnosis and staging of prostate cancer.

 

Imaging with CDU utilizes two components; grey scale imaging and color Doppler evaluation of vascularity. With CDU, cancerous lesions appear as a dark spot. In addition, cancer can show increased blood vessel density, or “hypervascularity.” High-resolution CDU readily identifies tumors over 5 mm in diameter. Cancers that are visible on CDU are more likely to be clinically significant (Gleason 4+3=7 or above). Hypervascularity tends to indicate tumors with a higher grade. 

 

PSA, Gland Volume, and Diagnosis

Using an arbitrary PSA level as a trigger for doing a 12-core random biopsy casts such a broad net that over diagnosis becomes inevitable. Men’s prostates vary greatly in size—so the amount of PSA they produce varies greatly. Rather than recommending a 12-core random biopsy to every man with a slightly elevated PSA, my policy is to use a relatively low PSA threshold of 2.5 as an initial trigger to recommend a CDU evaluation. However, in men with risk factors such as family history or African-American descent, I use an even more conservative PSA cut point of 2.0 to recommend a CDU. In older men who tend to have larger prostate glands, a threshold of 4.0 is reasonable.

 

The first step should be to measure the size of the prostate with CDU. If a patient’s PSA is higher than expected for the individual’s prostate size, it increases the likelihood that an underlying high-grade prostate cancer may be present (Chapter 2 explains how to calculate a normal PSA level with allowance for the prostate’s size). Men whose PSA levels are in the normal range for their prostate size should not be subjected to invasive diagnostic procedures unless other suspicious findings are uncovered during the performance of the CDU.

 

Questions that Color Doppler Ultrasound Can Answer:

●      Where is the tumor located within the gland?

●      Does the tumor remain confined within the prostate?

●      What is the tumor’s diameter in millimeters? Does the size of the lesion detected by imaging coincide with the length of cancer reported in the targeted needle biopsy as reported by the pathologist?

●      Is tumor size or vascularity on sequential scanning increasing over time for men who are on active surveillance?

 

Final Thoughts on Prostate Imaging

Prostate imaging dramatically reduces the need for random biopsy. If an abnormality is detected by imaging, a targeted biopsy provides information that is of higher quality using far fewer stabs of the needle. Imaging should precede random needle biopsy. When a biopsy is required, it should be targeted rather than random. 


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Duke Bahn, MD is the Ddirector of the Prostate Institute of America. Certified by the American Board of Radiology, his special areas of interest are the early detection and staging of prostate cancer using color-Doppler ultrasound with tissue harmonics. He is also a pioneer in using cryotherapy, as both a primary and salvage treatment for prostate cancer. His published data was the impetus for obtaining Medicare approval for cryotherapy as a viable treatment for prostate cancer. Dr. Bahn has held many academic and professional appointments, including clinical professor of urology, Keck School of Medicine, University of Southern California. 

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Body Scans and Other Predictive Factors


By Fabio Almeida, MD

Body Scans and Other Predictive Factors


By Fabio Almeida, MD

While multiparametric MRI and color Doppler ultrasound are excellent tools for monitoring disease inside the prostate, scanning the rest of the body for cancer that may have spread to the lymph nodes or bones is also critical. Body scans are necessary for every Stage of Blue except Sky. Traditionally, doctors have relied on CT scans and bone scans. However, their accuracy is disappointing. Undetected spread is the most common reason for cancer recurrence after the initial treatment.

Positron emission tomography (PET) scans provide three-dimensional images of the whole body. The most recent and exciting discovery is that prostate cancer relies on fat as its energy source. Prostate tumors rapidly absorb fat when it is injected into the bloodstream, and if the fat is made radioactive by the insertion of radioactive carbon (C11), the tumors “light up” on a scanner. Lymph node metastases as small as 5-6 mm can be detected.

After lymph nodes, bone is the second most common site of metastatic spread. Standard bone scans use a radiotracer called Technetium-99, which is unfortunately not very specific. Other changes in the bone, such as arthritis or benign lesions, can be mistaken for cancer metastasis. A PET scan called NaF18 (radioactive sodium fluoride) provides superior specificity and sensitivity when compared with Technetium-99. NaF18 PET imaging used in combination with C11 acetate PET imaging in the same patient offers the most comprehensive method currently available for detecting cancer metastases.

C11 acetate PET scanning for prostate cancer is a giant leap forward over older scanning techniques, but the C11 scan center must be located immediately adjacent to a cyclotron facility and relatively few such centers exist. Therefore, new types of scans are being explored. Preliminary studies with Ga68 PSMA provide excellent images. Another promising new agent is FACBC (Axumin), which detects increased amino acid metabolism in the cancer cells similar to how C11 exploits increased lipid metabolism.  FACBC is now FDA approved and has recently become commercially available.

This wraps up the introductory section of the book. Armed with the results from your quiz in Chapter 1, which enables you to determine your Stage of Blue, it is now possible for you to jump ahead to the Chapter that addresses your Stage specifically:

 

                                                Sky:                Chapter 7  

                                                Teal:               Chapter 15

                                                Azure:            Chapter 25

                                                Indigo:           Chapter 30

                                                Royal:            Chapter 36


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Fabio Almeida, MD graduated top of his class and with honors from The Chicago Medical School. He completed a residency and fellowship in Nuclear Medicine at the University of San Francisco, and is certified by the American Board of Nuclear Medicine and the Certification Board of Nuclear Cardiology. He was in academic practice at the University of California, San Francisco, and private practice until 2005. Dr. Almeida is one of the pioneers in the development and implementation of cross modality fusion for cancer imaging (SPECT, PET, CT and MRI) and PET/CT. He also worked for the Centers for Disease Control after 9/11 for several years as a physician and informatics specialist consultant.

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Permanent Radioactive Seed Implants


By Peter Grimm, DO and John Blasko, MD

Permanent Radioactive Seed Implants


By Peter Grimm, DO and John Blasko, MD

Permanent seed implantation, also known as brachytherapy, involves the insertion of small, carefully spaced, radioactive pellets into the prostate. After implantation, the seeds emit a low but continuous energy over a period of two months, which accrues to a large total dose of radiation inside the prostate. Seed implants are performed as an outpatient procedure, which takes about 60-90 minutes. 

On average, cure rates from seed implants are superior to either surgery or IMRT. This bold claim is based on the findings of the Prostate Cancer Results Study Group, a compilation of every reputable study performed that reports cure rates. In addition, a randomized study called the ASCENDE-RT trial was completed which arrived at the same conclusion. Here are the findings of the ASCENDE-RT trial:  

Cure rate at 5 years              

IMRT + hormone therapy: 84%            

IMRT + hormone therapy + seeds: 96%    

Cure rate at 9 years

IMRT + hormone therapy: 70%

IMRT + hormone therapy + seeds: 94% 

This randomized study demonstrates a dramatic 24% improvement in cure rates in patients who received a seed implant compared to those who received IMRT without seeds. 

What is the status of seed utilization in the United States? Shockingly, there has been a dramatic decrease in the use of seeds between 2002 and 2010. Prostate treatment has migrated away from seed implants, not because of science, but because of economics and politics. All the other treatments pay doctors at a much higher rate. It’s interesting to note that the popularity of brachytherapy is growing rapidly in many countries, where physicians are paid the same rate regardless of which treatment is selected.  


Peter Grimm, MD was a radiation oncologist in Seattle, affiliated with Swedish Medical Center-Cherry Hill. He received his medical degree from Chicago College of Osteopathic Medicine and was Adjunct Assistant Professor of Radiation Oncology, UCLA Department of Radiation Oncology. He practiced 36 years as a seed implant expert. He received various awards including an American Cancer Society Fellowship and the President’s Award from the American Brachytherapy Society. He held at least six patents related to radioactive seed implantation and authored or coauthored more than 60 peer-review publications. Dr. Grimm also created a popular prostate cancer educational website that provides comparative outcomes for many types of treatment: www.pctrf.org.  

 


John C. Blasko, MD is the former director of clinical of research for the Seattle Prostate Institute and a clinical professor in the Department of Radiation Oncology at the University of Washington School of Medicine. A member of the board of directors of the American Brachytherapy Association, Dr. Blasko has published several hundred articles, abstracts, and book chapters on the subject of radioactive seeding. He received his medical degree from the University of Maryland School of Medicine, and served his residency at the University of Washington School of Medicine.

 

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High Dose Rate Temporary Seed Implants


By Jeffrey Demanes, MD

High Dose Rate Temporary Seed Implants


By Jeffrey Demanes, MD

High dose rate brachytherapy (HDR) is done in 4 steps. The first step is placement of catheters into and around the prostate. Once the catheters are in position, the two next steps are called “simulation” and “dosimetry.” Simulation involves taking either a CT scan or ultrasound image of the prostate with the catheters in place. Calculations are then made to determine the dosage of radiation. A robotic delivery device controlling a single, tiny, but potent, radioactive seed attached to the end of a fine cable is inserted into each of the hollow catheters to deliver the therapy. Each treatment takes about 15-30 minutes. 

HDR in combination with intensity modulated radiation (IMRT) produces consistently better cure rates than surgery. A randomized clinical trial from England reported that HDR plus IMRT is better than IMRT alone. HDR can also be used by itself. HDR monotherapy cure rates are so similar to the cure rates with HDR plus IMRT that it raises the serious question as to whether the addition of IMRT provides any additional benefit. Men with Low-Teal, Basic-Teal and Sky can have HDR alone. Azure or High-Teal patients generally receive HDR plus IMRT with or without hormone therapy.

Side Effects

Temporary urinary side effects are expected to last 1 to 2 weeks then taper off. Prostate swelling or urinary bleeding immediately after the procedure occasionally requires a temporary urinary catheter. Urinary incontinence occurs in less than 1% of cases; stricture may occur in 1 to 5%. The risk of sexual dysfunction is similar to other forms of radiation. 


Jeffrey Demanes, MD received his bachelor of arts degree from UC Berkeley and his medical degree from the David Geffen School of Medicine at UCLA. He completed residencies in internal medicine and radiation oncology at UCLA and his medical oncology fellowship at UCSF. He is the past chairman and president of the American College of Radiation Oncology. Dr. Demanes specializes in brachytherapy, the surgical subspecialty of radiation oncology. He founded the California Endo Curietherapy Center (CET) in 1981 and has performed more than 10,000 surgical radiation implants. He is a professor emeritus in the Department of Radiation Therapy at UCLA. 

 

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Intensity Modulated Radiation Therapy (IMRT)


By Zachary Zumsteg, MD and Howard Sandler, MD

Intensity Modulated Radiation Therapy (IMRT)


By Zachary Zumsteg, MD and Howard Sandler, MD

Intensity modulated radiation therapy (IMRT) is a specialized form of external beam radiotherapy. A device called a linear accelerator is used to administer high-energy photon beams to the prostate. IMRT is delivered in small, daily doses over a course of 7 to 9 weeks. Each treatment usually takes only a few minutes. When undergoing IMRT, it is imperative that the patient be in the exact same position for each radiation treatment, so a lot of time and attention is paid to ensuring accuracy.

Why Choose IMRT?

IMRT has the longest track record and the largest supporting body of evidence in the scientific literature. In contrast to surgery, IMRT is non-invasive and has a much lower risk of bleeding, pain, infection, urinary leakage, and shortening of the penis. In contrast to seed implants, IMRT can treat a larger border around the prostate, which is more advantageous for High-Teal patients. In some clinical studies IMRT has also been suggested to have lower toxicity than Stereotactic Body Radiation Therapy (SBRT) (Chapter 21) or combined external radiation and seed implants (Chapter 19).

Is Hormone Therapy Necessary for Teal Patients Receiving IMRT?

The benefit of combining hormone therapy, also known as testosterone inactivating pharmaceuticals (TIP), with radiation for Teal and Azure is arguably the most well validated treatment strategy in all prostate cancer. Clinical trials show that the addition of TIP to radiation prolongs survival and decreases the risk of prostate cancer recurrence. If TIP is recommended, most patients require only 4 to 6 months of treatment, beginning 2 to 3 months prior to radiation. TIP can cause its own unique spectrum of side effects, though most side effects wear off with time after TIP is discontinued. Chapter 29 discusses TIP’s potential side effects and how to manage them.

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Zachary S. Zumsteg, MD completed a residency at Memorial Sloan Kettering Cancer Center and is presently a faculty member in the Department of Radiation Oncology at Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute. In addition to his clinical practice, he is actively engaged in research spanning epidemiology, health services, clinical trials and translational applications. Through this work, Zumsteg has developed a novel risk stratification system for patients with intermediate risk prostate cancer that is currently widely used by oncologists in clinical practice and cited in National Comprehensive Cancer Network Guidelines. He is the author of numerous peer reviewed publications, with articles appearing in journals such as Lancet Oncology, Journal of Clinical Oncology, JAMA Oncology, European Urology, Clinical Cancer Research, Cancer, and the International Journal of Radiation Oncology, Biology and Physics


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Howard Sandler, MD graduated from the University of Connecticut, Summa Cum Laude, where he also received his doctorateM.D. and Mmaster’s degree in Pphysics. He is the Newman Family Pprofessor of Rradiation Ooncology at Cedars-Sinai Medical Center and Cchair of Ronald H. Bloom Family Chair Cancer Therapeutics. He is the Pprincipal investigator for a national Radiation Therapy Oncology Group study examining radiotherapy and chemotherapy for prostate cancer. He is coauthor of more than 200 peer-reviewed scientific articles. 

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Combination Therapy


By Sean McBride, MD and Michael Zelefsky, MD

Combination Therapy


By Sean McBride, MD and Michael Zelefsky, MD

The treatment we recommend at Sloan Kettering is dependent upon which subtype of Intermediate-Risk a patient’s cancer falls into (see Appendices I and II). For example, in patients with favorable Intermediate-Risk prostate cancer who are eligible, we tend to prefer permanent seed implants alone (Chapters 16). On the other hand, the Unfavorable Intermediate-Risk subtype tends to behave more like High-Risk. In these men we recommend using a combination of seed radiation and intensity modulated radiation therapy (IMRT).

The distinction between permanent and temporary seeds (Chapter 17) lies in the rate at which radioactivity is deposited into the prostate. There is no evidence that either type of seed implant is superior to the other in terms of cancer cure rates. When combined with seeds, IMRT is usually delivered over an approximately four to five-week period and may commence several weeks prior to or after the seed implant. At Sloan Kettering, our preference is to perform the seed implant prior to the IMRT. The total course of combined therapy with seeds plus IMRT is usually completed over two months.

Compared to using either type of radiotherapy by itself, there is a two-fold rationale for using them in combination: 1) delivery of a significantly higher dose of radiation to the tumor within the prostate; 2) the addition of IMRT to seed placement allows for the treatment of microscopic prostate cancer that may have spread through the capsule but still remains closely adjacent to the prostate. By expanding the size of the radiation field so it includes the area just outside the edge of the prostate IMRT allows for a more robust “halo” of treatment.  Studies demonstrate that, when compared to IMRT alone, the combination of HDR seeds and IMRT reduces the chance of the prostate cancer’s return. 

When treating with IMRT alone, studies show that adding a short course of hormone therapy improves overall survival. Although there is no data to guide us, with the high radiation doses achieved using combination therapy, the anticancer effects may be sufficient enough so that the added boost from hormone therapy may no longer be necessary. However, because combination radiation therapy does not target prostate cancer that has spread outside the prostate to distant areas of the body, a certain proportion of patients with Unfavorable Intermediate-Risk prostate cancer—those who may have microscopic and thus undetected prostate cancer cells that have traveled to distant sites—may still benefit by receiving a short course of hormone therapy. It is for this reason that we will consider adding four to six months of hormone therapy in Unfavorable Intermediate-Risk prostate cancer patients receiving combination therapy. What would trigger such a recommendation in these patients? We routinely obtain an multiparametric MRI of the prostate. Should that detect a larger-sized tumor that is pushing through the prostate capsule or into the seminal vesicles we would typically recommend the addition of hormone therapy. 

Ultimately, if the toxicities of combination therapy were excessive, we could not in good conscience recommend using seeds and beam radiation together if the cure rates were only marginally better. However, studies indicate that combination therapy provides a 20 percent improvement in cure rates. It is true that the side effects of seeds and beam radiation are increased in the short term and are marginally increased in the long term. The risk of serious disruptions to urinary and bowel function, however, is equivalent to either seeds or beam alone and, more importantly, quite low. The rates of urinary incontinence (the inability to control urine flow) are dramatically less than the rates that are typical after prostatectomy. 


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Sean M. McBride, MD, MPH a board-certified radiation oncologist with an expertise in treating primary genitourinary (prostate, bladder, kidney, and testicular) and head and neck (oral cavity, base of tongue, tonsil, larynx, hypopharynx, sinus, nasopharynx, and thyroid) malignancies. Dr. McBride works with a dedicated team of medical oncologists, surgeons, and medical physicists to help deliver individualized care using sophisticated radiation therapy techniques including image-guided, stereotactic radiosurgery (IGRT), intensity modulated radiation therapy (IMRT), and brachytherapy. 


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Michael Zelefsky, MD is Chief of Memorial Sloan Kettering’s Brachytherapy Service. In addition, he was instrumental in pioneering the use of IMRT and IGRT for prostate cancer.  He is Editor-in-Chief of Brachytherapy, Chairman of the National Patterns of Care Study for Genitourinary Cancers, and past president of the American Brachytherapy Society. He has received several awards including the Boyer Award for Excellence in Clinical research, the Outstanding Teaching Award in the Department of Radiation Oncology at Memorial Sloan Kettering, the 2009 Henschke Medal, and the 2009 Emanuel Van Descheuren Award for Excellence in Translational Research.

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Proton Beam Therapy


By Carl Rossi, MD

Proton Beam Therapy


By Carl Rossi, MD

Proton therapy is simply using a beam of protons to deliver precision radiation therapy. In a fashion identical to intensity modulated radiation therapy (IMRT), patients are treated daily on an outpatient basis. A typical treatment session lasts 15 to 20 minutes with most of that time devoted to patient positioning. The treatment delivery—beam-on-time—is usually less than 60 seconds. Unlike the photon radiation used in IMRT, protons come to an abrupt stop at their target point within the body. Photons, and thus IMRT, expose a larger volume of healthy tissue outside the target area; men who are considering IMRT might want to consider proton therapy instead. 

Recent Advances

A recent development in proton treatment is the development of intensity-modulated technology for protons. Intensity modulated proton therapy (IMPT) permits coverage of the pelvic lymph nodes. The Scripps Proton Treatment Center, which opened in San Diego in 2014 is the first center in the United States to use IMPT.

Clinical Trials

Initial clinical data published in 1994 confirmed the safety and efficacy of proton beam therapy. A subsequent publication that looked at over 1,200 patients was published in 1997, revealing that proton beam therapy could achieve cure rates equal to radical prostatectomy with a lower rate of toxicity. Using proton therapy, greater dose-specificity and better normal tissue sparing can be achieved over the results achievable with the older proton techniques.

 


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Carl Rossi, MD is a radiation oncologist specializing in proton beam therapy, specifically for prostate cancer and lymphomas. He is also the current medical director for the Scripps Proton Therapy Center, which will provides treatment to target tumors with high control and precision. In addition to treating a variety of cancers with radiation, it is also used to treat some non-cancerous conditions. Dr. Rossi has a research focus on the quality of life and cure rate in prostate cancer and lymphoma treated with proton beam radiation.

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Stereotactic Body Radiation Therapy


By Michael Steinberg, MD

Stereotactic Body Radiation Therapy


By Michael Steinberg, MD

Stereotactic Body Radiation Therapy (SBRT) delivers a much larger dose of radiation per patient visit than IMRT. SBRT technology is relatively new. Thus, there are fewer clinical trials comparing it with other therapies. Despite this, SBRT has become an accepted form of radiotherapy and meets the National Cancer Network “standard of care” guidelines for prostate cancer. The treatment course is one week as opposed to 9 weeks for IMRT. 

SBRT Technology

An average of five fractions of high-dose radiation are administered every other day, or sometimes on five consecutive days. The robotic system called CyberKnife is still the most commonly used form of SBRT, though there are now several different radiation platforms for the delivery of SBRT. 

Cure Rates and Side Effects

Five-years after therapy, the PSA relapse-free survival rates are 95 percent for Sky,* 84 percent for Teal, and 81 percent for Azure.  Preliminary studies indicate that cure rates are similar with or without hormone therapy. Side effects are similar to IMRT or seed implantation. Early side effects occur in the first 3 months and then dissipate. The most common early side effects are urinary issues such as increased frequency. Urinary and bowel incontinence are very rare with any form of radiotherapy. Rectal issues include occasionally loose bowel movements, more frequent movements, or occasional bleeding from pre-existing hemorrhoids. The risk of erectile dysfunction is roughly 5o percent, similar to other types of radiation. SBRT is becoming mainstream therapy due to its greater convenience and reduced cost. 

*The selection of treatment for prostate cancer is changing quickly. Ten years ago Sky was considered life-threatening and 100% of men were advised to have treatment. Back then, in 2008, practically no one was managed with active surveillance. Can treatment for Sky be justified in this modern era? Some argue for it as follows: “Since a well-performed, random, 12-core needle biopsy misses higher grade disease 20-30% of the time (when the initial Gleason grade is initially as 6), treatment is still indicated, “Just to be safe.” 


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Dr. Steinberg is Professor and Chair of the Department of Radiation Oncology at the David Geffen School of Medicine at UCLA. His professional career spans private, corporate and academic practice and is known for the development of multi-site radiation oncology care networks that are characterized by clinical excellence and community based clinical research. The UCLA Radiation Oncology network includes the department at Ronald Reagan Medical Center at UCLA, academically oriented community practices as well as Children's Hospital Los Angeles.

Dr. Steinberg has specific expertise in the treatment of tumors of the GU system, breast and head and neck. He specializes in the use of technically advanced treatment modalities such as Stereotactic Body Radiation Therapy (SBRT) and brachytherapy for the treatment of malignancy. Dr. Steinberg publishes and is a speaker on issues related to health policy including quality of care, technology assessment, healthcare economics and disparity. He served as the PI for a National Cancer Institute Cancer Disparity Research grant and as a health services research investigator and manuscript author at the RAND Corporation.

Dr. Steinberg has been influential in providing input regarding health policy and economic issues on behalf of patients and his specialty through his various leadership roles in radiation oncology. He is the founding Chair of the Health Policy Council of American Society of Radiation Oncology (ASTRO) and served as a member of the board of that organization. Dr. Steinberg is the radiation oncology representative to the American Medical Association's CPT Editorial Panel, served two terms on the Medicare Evidence and Coverage Advisory Committee (MCAC) and chairs of the Health Policy Committee of the Commission on Radiation Oncology of the American College of Radiology. He also currently serves on the Carrier Advisory Committee (CAC) for his regional Medicare carrier. Dr. Steinberg graduated Occidental College Phi Beta Kappa, was elected to AOA at University of Southern California School of Medicine and did his radiation oncology residency and fellowship at UCLA.

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Hormone Therapy Alone as Primary Therapy for Teal


By Mark Scholz, MD

Hormone Therapy Alone as Primary Therapy for Teal


By Mark Scholz, MD

Prostate cancer cells are dependent on testosterone for their survival, so when testosterone is removed, they shrivel and die. Radiation and surgery can’t cure cancer that has already spread outside the prostate. Only hormone therapy, otherwise known as testosterone inactivating pharmaceuticals (TIP), circulates throughout the whole body attacking potential micro-metastasis in the lymph nodes or bones. 

Over the years, we have treated hundreds of men with newly-diagnosed disease with TIP. Twelve-year outcomes evaluating 73 men who embarked on TIP as primary therapy have been published. After treatment, 29% never needed any further therapy; 33% required periodic retreatment with TIP to keep their PSA levels under 5, and 38% underwent delayed local therapy such as surgery, seeds, or radiation a median of 5 years after their first dose of TIP. Out of the 28 men who had delayed local therapy, only 3 developed a PSA relapse. Upon review of this data set, we found that older men tended to have longer remissions after TIP. Less durable remissions occurred with higher starting PSA levels and higher Gleason scores. 

One of the advantages of TIP is how easily treatment can be monitored with PSA and scans. Normally, the PSA will decline to less than 0.05 within 8 months of starting therapy. Primary TIP, therefore, is an effective way to smoke out the rare but serious types of prostate cancer in those patients whose PSA fails to decline below 0.05. Such patients should consider a more aggressive treatment with some form of radiation. 

Considering the rapid improvements occurring in the medical world, delaying radiation or surgery keeps the option open for a better type of treatment down the line. So, what is the catch?  First, TIP is not curative. Most men eventually require additional treatment. Second, while TIP’s side effects are manageable and reversible, they are not trivial (Chapter 29). Despite these drawbacks, with TIP, men can “test the water” without risking the irreversible side effects commonly associated with immediate surgery and radiation.


Mark Scholz, MD is the executive director of the Prostate Cancer Research Institute. He is also the medical director of Prostate Oncology Specialists Inc. He received his medical degree from Creighton University in Omaha, NE. Dr. Scholz completed his Internal Medicine internship and Medical Oncology fellowship at University of Southern California Medical Center. He is co-author of Invasion of the Prostate Snatchers.  He has authored over 20 scientific publications related to the treatment of prostate cancer.

 

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Robotic Assisted Radical Prostatectomy (RARP)


By Timothy Wilson, MD

Robotic Assisted Radical Prostatectomy (RARP)


By Timothy Wilson, MD

Surgery has several advantages over radiation and other non-surgical options. These advantages are: 

  1. Examination of the surgically-removed prostate allows for accurate staging, enabling us to make rational decisions regarding the need for immediate treatment after surgery.
  2. Surgery provides relief of obstructive voiding symptoms by getting the prostate out of the way of the bladder.
  3. Overall side effects of surgery are no worse than those of radiation. 
  4. Hormone therapy with TIP will not be necessary (unless after the operation a new, unsuspected degree of cancer spread is detected).
  5. The accuracy of PSA monitoring for relapse is much greater after surgery than after radiation and other non-surgical options. 
  6. Salvage therapy (for recurrence) is effective and safe after surgery. 

State of the Art Robotic Surgery for Prostate Cancer

Robot Assisted Radical Prostatectomy was FDA-approved for prostate cancer treatment in 2001. RARP improves accuracy, reliability and reproducibility of surgery. Compared to open surgery, blood loss is less, hospitalization time is shorter, and men tend to recover bladder control and sexual function more quickly and to a better degree. 

RARP generally takes between one and a half to three and a half hours. Thirty to sixty additional minutes are required when the lymph nodes are removed. After the operation, men wake up with a catheter that protects the new connection between the urinary bladder and the urethra. Most men will be able to go home from the hospital the following day. The catheter is removed a week later. Most can return to work within 2 to 3 weeks.  

Preventative measures improve the likelihood of recovering erectile function. I recommend regular doses of Viagra. In addition, I recommend at least one dose (100 mg) of Viagra on the third day prior to surgery. There is preliminary evidence that this decreases the shock to the nerves. Six weeks after the operation, if men are getting at least partial erections, then continuing Viagra or a similar drug is probably fine. For men who want to be proactive and for men who are having zero erections, I recommend starting injection therapy. We teach our patients how to inject a small amount of medicine with a tiny needle directly into the penis. It is analogous to diabetics giving themselves insulin. With the correct dose, a full erection will result within about 10 to 15 minutes and last about an hour. This is repeated two to three times weekly at home. It keeps the penis healthy while the nerves are waking up. It will also allow the patient to have intercourse. Men under 65 who have good erections prior to surgery have about an 85 percent chance of having erections (without injection therapy) sufficient for intercourse within a year.  

Twenty-five percent of my patients experience immediate return of complete bladder control. Fifty percent have no need for pads by 6 weeks; 85 percent are dry by 3 months; and 90 to 98 percent by one year. Results are influenced by a patient’s age, preoperative bladder control, prostate size and the nerve-sparing technique used. In the few men who do not regain urinary continence, medical therapy can sometimes be successful (Chapter 12). Death from prostate cancer after RARP is rare; most men recover completely and go on to live full and productive lives. Men who have recurrence after RARP can commonly be treated successfully with radiation.  


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Timothy Wilson, MD is a board-certified urologist who specializes in minimally invasive, laparoscopic and robotic-assisted urologic oncology. He is one of the top six surgeons in the world, in terms of volume, that performs robotic-assisted laparoscopic prostatectomy. Dr. Wilson is a member of the American Urological Association and the Society of Urologic Oncology. Throughout his tenure that spans nearly 30 years, he has published numerous peer-reviewed articles and book chapters in the areas of urologic oncology, urinary reconstruction, and robotic surgery. In 1995, Los Angeles magazine deemed him one of 25 “Doctors who are making a difference,” and in 1998, he was voted “Professor of the Year” by urology residents in training at the University of Southern California School of Medicine.

 

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Comparing Treatments for Teal


By Mark Scholz, MD 

Comparing Treatments for Teal


By Mark Scholz, MD 

 

Many patients operate under the mistaken belief that doctors are generally similar. However, I claim that medical oncologists like myself are quite different. This is because oncologists have no innate preference for surgery over radiation. They perform neither. In my practice in Marina del Rey, I work with two additional medical oncologists—Dr. Richard Lam and Dr. Jeffrey Turner. The three of us compiled a table comparing all the different treatment approaches for Teal based on our perspective as medical oncologists

The Pros and Cons of Various Treatment Options for Teal

Favorable aspects of a treatment are signaled by plus (+) signs, with a single plus being the least favorable and multiple plus signs being the most favorable.  Negative problems are likewise reported with minus (-) signs with multiple minus signs being even less favorable.

Additional Issues to Consider:

  • Previous operations or radiation in the pelvic area increases the risk of side effects from radiation and surgery.  
  • Prostate glands over 100cc can present a problem for men considering radiation. 
  • Treatment intensity should be knocked down to what would be appropriate for a lower Stage of Blue—for example, Teal to Sky or Azure to Teal—in very elderly or frail men with multiple preexisting health problems.

Permanent loss of sexual and urinary function has huge consequences, affecting a man’s capacity for intimacy and his self-esteem. Doctors in the industry often gloss over potential side effects, implying that the risks are just about the same with every type of treatment. Studies do not support this conclusion. In a survey of patients at the University of Virginia, 785 men were questioned about their sexual and urinary function every 6 months for up to 3 years after surgery or seed implantation. Half of the men who received seed implants reported recovery of sexual function back to the same level as prior to treatment. Only one-fifth of the men who had surgery reported a similar degree of full sexual recovery. Regarding urinary control, about four-fifths of the men were “back to normal” after seeds, whereas only one-half of the men reported they were normal after surgery. Clearly, the claim that side effects are equal is wrong

Men must put in the time to research their options. When it comes time to make the final choice, create a list of all the options still under consideration. Draw a line through the “worst” option and continue to eliminate options until only one remains. The final remaining option, unattractive as it is, is probably the best way to proceed.  

 

Now that patients with Teal have finished this Section, they can skip ahead to Chapter 43 to complete the remainder of the book.


Mark Scholz, MD is the executive director of the Prostate Cancer Research Institute. He is also the medical director of Prostate Oncology Specialists Inc. He received his medical degree from Creighton University in Omaha, NE. Dr. Scholz completed his Internal Medicine internship and Medical Oncology fellowship at University of Southern California Medical Center. He is co-author of Invasion of the Prostate Snatchers.  He has authored over 20 scientific publications related to the treatment of prostate cancer.

 

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Teal Treatments & Side Effects


Teal Treatments & Side Effects


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Teal Subtypes


Teal Subtypes


 

Teal Overview


By Mark Scholz, MD

Teal Overview


By Mark Scholz, MD

Teal splits into three subtypes: Low-Teal, Basic-Teal and High-Teal. Treatment is different for each subtype. Low-Teal has only one intermediate risk factor, with all the remaining factors being like those of Sky. Low-Teal is very similar to Sky and treatment with active surveillance is feasible. As such, men with Low-Teal should read Section II starting at Chapter 7. Men with Basic-Teal have somewhat more extensive disease in their biopsy specimen, but less than 50 percent of their cores are cancerous. High-Teal, on the other hand, has two or more intermediate-risk characteristics, a Gleason grade of 4+3=7, or Gleason 7 in more than 50% of the cores. (See Appendices I and II for further information about Teal’s subtypes.) High-Teal, and even Basic-Teal can metastasize. So a staging bone scan and an MRI or CT scan of the abdomen and pelvis should be performed before starting any treatment. 

Using Scientific Studies to Compare Treatment Options

Scientific studies are the main basis for evaluating a treatment’s effectiveness. Unfortunately, many studies of varying quality exist and studies can be found that will support almost any point of view. This means that not all studies are equally valid. To protect yourself from being misled, learn how to assess the quality of a study. First, don’t confuse yourself by considering any nonhuman study. Second, realize that retrospective database queries are untrustworthy. The best studies are prospective. They compare outcomes by randomly allocating patients into separate treatment groups that can be compared over time. 

When Teal is managed appropriately, the vast majority of men will be cured. And even if a relapse occurs, most men will live out a normal life expectancy. Therefore, as consideration is given to the various treatment options, selecting a treatment with fewer side effects should be the priority. 


Mark Scholz, MD is the executive director of the Prostate Cancer Research Institute. He is also the medical director of Prostate Oncology Specialists Inc. He received his medical degree from Creighton University in Omaha, NE. Dr. Scholz completed his Internal Medicine internship and Medical Oncology fellowship at University of Southern California Medical Center. He is co-author of Invasion of the Prostate Snatchers.  He has authored over 20 scientific publications related to the treatment of prostate cancer.

 

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Teal Resources


Teal Resources