More on an anti-proton research paper

Today I came across an article that comments on the JAMA article by Sheets et al, mentioned in my October 28 post Material Provided by the Radiation Oncologist. This additional paper is

●Reviews in Urology, 2014, 16 (2)

Proton Beam Therapy for Localized Prostate Cancer 101: Basics, Controversies, and Facts, Eric S. Wisenbaugh, MD, et al.

After describing the results published by Sheets et al, the authors commented “However, among the several flaws of this study, the most fundamental was that outcome surrogates (ie, claims for colonoscopy) were used to measure toxicity rates. This would be an imprecise surrogate for any population, but is particularly so in PBT patients…this study should not be used to relay any important morbidity information to inquiring patients.

Pro-Proton Therapy Research

The material provided by my radiation oncologist (see my first October 28 post) was oriented against proton therapy (PT) for prostate cancer. However, other studies of PT put it in a more favorable light. The following article was included in the packet that UFHealth sent me. All of the authors are associated with UFHealth, and their research reports on UFHealth patients.

●International Journal of Radiation Oncology Biology Physics, 95(1)

Five-Year Biochemical Results, Toxicity, and Patient-Reported Quality of Life After Delivery of Dose-Escalated Image Guided Proton Therapy for Prostate Cancer.  Curtis Bryant, MD, MPH

From the last paragraph: “It is concluded that image guided PT provides excellent biochemical control rates for patients with low-risk, intermediate-risk, and high-risk prostate cancer."

Translation: Proton therapy is effective at controlling prostate cancer.

Continuing with the last paragraph: "The actuarial rates of CTCAEv4 grade 3+ GU and GI toxicity rates were low.”

Translation: CTCAEv4 means Common Terminology Criteria for Adverse Events, version 4, published by the National Institutes of Health, National Cancer Institute. Grade 3 means “Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL [activities of daily living]. Grade 3+ means Grade 3 and worse. GU means genitourinary (reproductive and urinary organs), and GI means gastrointestinal (digestive organs, such as the stomach and intestines). 

In other words: Proton therapy resulted in low rates of medically significant side effects.

UF Health in Jacksonville

There are many things to consider when deciding among cancer treatments. One of them is cost; will my insurance cover this? My insurance is with a local HMO, and I already knew they cover traditional radiation treatment. I called the HMO and asked about coverage for proton beam therapy. They said they would consider it, using their established protocols. Well, at least it wasn’t a flat NO.

For more information, I called the nearest facility to Tallahassee, the UFHealth Proton Therapy Institute, AKA the Jacksonville Proton Therapy Center. Web address: floridaproton.org. I call it UFHealth for short. It’s affiliated with the University of Florida’s medical school in Gainesville. The receptionist at UFHealth couldn’t guarantee my HMO would cover my treatment there, but she explained in great deal what paperwork would be needed and what treatment there would involve. Recognizing that I wasn’t going to remember everything, she said she would send me a packet of information. Overnight. This was yesterday afternoon, the 27^th. The packet arrived at 10:15 this morning. It’s full of useful information and forms to fill out, and paperback copies of two books. One of them was the Robert Marckini book I described in my October 26 post, and the other was Protons versus Prostate Cancer Exposed, by Ron Nelson (who was treated at UFHealth). I had previously downloaded this in Kindle, so I already knew that he was just as happy with his choice to get proton beam therapy as was Bob Marckini. One small part of the information packet was a sheet about SpaceOar (Spacing Organs at Risk) available at UFHealth. This is a new device that reliably separates the prostate from the rectum so that any radiation (traditional or proton) is much less likely to cause injury to the rectum (the primary location for the “gastrointestinal morbidity” mentioned in the Sheets paper in my earlier October 28 post).

Material Provided by the Radiation Oncologist

● Journal of the American Medical Association, 2012, 307(15)

Intensity-Modulated Radiation Therapy, Proton Therapy, or Conformal Radiation Therapy and Morbidity and Disease Control in Localized Prostate Cancer. Nathan C. Sheets, MD, et al

My comment: The authors of this four-year-old paper are all based at the University of North Carolina. They include four radiation oncologists, 3 epidemiologists, two statistical analysts, and two specialists in health policy and management. UNC does not have any proton beam equipment, and the author profiles do not show any personal experience with proton beam therapy. The study did not examine long-term survival or short-term side effects (less than one year). The worst thing they could say about proton therapy is “…proton therapy-related patients were more likely to receive a diagnosis of gastrointestinal morbidity and undergo gastrointestinal procedures.” They do not address the severity of the “gastrointestinal morbidity” nor do they mention the percentage of patients affected.

● Journal of Applied Clinical Medical Physics, 2015, 16(3)

Proton-beam therapy: are physicists ignoring clinical realities? R. J. Schulz, PhD

My comment: This study is mostly theoretical and focused on economics. They do say that “…the clinical outcomes of PBT [proton beam treatment] are no better—nor any worse—than those achieved by IMRT [intensity modulated radiation treatment] or SBRT [stereotactic body radiation treatment]. “Of four retrospective studies that compared toxicities following PBT or IMRT, three showed but minor differences between the two modalities, while the study by Sheets et al showed significantly higher GU toxicity following PBT.” The Sheets study is the one described above, and this paper does not address that paper’s deficiencies. 

● NCCN [National Comprehensive Cancer Network] Clinical Practice Guidelines in Oncology

Prostate Cancer, Version 3.2016

This group does not find any increase in any side effects for PBT compared to radiation. “The NCCN panel believes no clear evidence supports a benefit or decrement to proton therapy over IMRT for either treatment efficacy or long-term toxicity. Conventionally fractionated prostate proton therapy can be considered a reasonable alternative to x-ray-based regimens at clinics with appropriate technology, physics, and clinical expertise.”

My summary: The proton beam therapy is just as effective as radiation (which is about as effective as surgery), but it’s more expensive. It might be a little worse for gastrointestinal side effects (the least severe of all the possible side effects), but that has not been shown definitively.

Radiation Oncologist, Part 1

During the brief meeting with my urologist on October 5^th I did have a chance to ask about getting a second opinion from the radiation oncologist I’d heard about. My urologist agreed, and said he’d contact his office right away. I didn’t get a call back from the radiation oncologist’s office to set up an appointment for almost a week. I don’t know why it took so long. By then, the earliest available appointment was for October 26.

The radiation oncologist was very informative. He answered most of my questions about the biopsy report, reviewed my PSA history and symptoms, and described in detail the pros and cons of the major treatment forms. For me, he recommended either radiation or surgery (not brachytherapy, aka radioactive seeds). When I asked about proton beam therapy, he agreed that it would do as good a job of getting rid of the cancer as surgery or radiation. However, he expressed doubts about the side effects and gave me copies of several journal articles on the topic. He also had the opinion that proton beam therapy is best for a small number of situations where surgery is difficult and radiation may be problematic. These include some brain tumors, some cancers of the eye, and some cancers in small children. He believes that proton therapy centers are branching out into prostate therapy mostly to help pay for the expensive equipment they need when it’s really appropriate. 

The oncologist answered my questions so thoroughly and discussed options in such detail that we ran out of time. Rather than cut me off, however, he immediately had his staff make an additional appointment for the following Monday. That gave me time to review the material he’d given me and think up new questions.

Biopsy Results, Finally

I arrived early for my 3:55 appointment on October 5^th, as usual. After a long wait, I found out that my urologist had run out of time to see the remaining patients. Fortunately, he was able to squeeze me in later that afternoon. He described the results, primarily in terms of the Gleason score.

Of the 20 cores, two had mostly or entirely missed the prostate, eight were clear, two had “atypical small acinar proliferation (ASAP),” four had some suspicious cells, and four had definite cancerous cells. Three of those last four had Gleason scores of 3+4=7, and the fourth was 4+3=7. The Gleason score therefor was essentially the same as in the previous biopsy. Two of those four had “perineural invasion.”

I didn’t see the biopsy report itself until I got a copy after the appointment. Because of that delay, I didn’t get a chance to ask about notes mentioning the cores with no prostate tissue, ASAP, or perineural invasion. I also didn’t know that the core locations would be described in the form of a grid system, with no explanation of how the grid coordinates related to the locations of cores taken in the first biopsy.

A Google search told me that ASAP is nothing to worry about, and perineural invasion probably isn’t. I also searched for prostate biopsy grid system images and figured out more or less how the grid was used in my biopsy. Comparing it to the locations of the cores in the 2015 biopsy, I found that basically it was the same regions that were problematic. Conclusion: not much had really changed in the last year and a half, although it certainly hadn’t improved.

Looking Ahead While Waiting for Results

While waiting for the biopsy results I heard from several men who’d already been treated for prostate cancer. One of them had had surgery in Tallahassee. After the surgery, he had years of dealing with bad side effects; he advised me if I had surgery at least to not get it in Tallahassee. Two others had external beam radiation therapy (EBRT) in Tallahassee, with the same radiation oncologist. Both were very happy with the process…with both the oncologist and with his office staff.

Another man had been treated for prostate cancer with proton beam therapy. He had such excellent results—both with getting rid of the cancer and with the lack of side effects--that he strongly recommended I consider proton therapy. He also provided me with a book, You Can Beat Prostate Cancer and You Don’t Need Surgery to Do It, by Robert Marckini. Mr. Marckini also has a website, www.ProtonBob.com. Mr. Marckini provides detailed descriptions about what it’s like to get the proton therapy, day by day. The book was published in 2006 but after reading it I did Google searches on proton beam therapy. I also downloaded a couple of more recently published books. The consensus seems to be that proton beam therapy is at least as good as surgery and external beam radiation at getting rid of the cancer…and it has side effects that are much less problematic than with other treatments. I decided to look into this further.

Saturation Biopsy

By late June, 2016, my PSA was up to 6.4. This still wasn’t grounds for panic, but my urologist wanted to do another biopsy to make sure the cancer wasn’t getting out of hand. My first biopsy had been a standard 12-core sample. The saturation biopsy was to include 20 cores, including 17 via rectal probe and 3 external, through the perineum. This required a hospital visit, with full anesthesia.

The biopsy was on September 12, 2016. I had no discomfort during the procedure, of course, as I was unconscious. The hospital prescribed strong pain pills for my recovery, but I didn’t need them. At the hospital after the procedure, I learned that the results would be available in 5 business days. 

That afternoon and the following day I called my urologist’s office a total of four times to find out when my appointment was scheduled. I was cut off all four times, and able to do no more than leave my name and reason for calling. No one called back. The following day, Thursday the 14^th, I sent a “secure message” via the urologist’s web site. I got no response until Monday the 19^th, when I got an automated message saying that my message had not been read. I called again, and this time I was able to talk without being cut off. They told me then that due to some sort of mix-up no appointment had been made for me. By then, the earliest appointment available was on October 5, nearly three and a half weeks after the biopsy—far more than the five days for the results of my first biopsy, or for the “five business days” I had expected this time.

Prolaris, by Myriad Genetic Laboratories

Prolaris is a test to determine the aggressiveness of prostate cancer, based on an examination of changes to the DNA of a biopsy sample. It’s relatively new, but has had good results in giving a better idea of how the cancer is developing than just looking at the slides under a microscope. It was suggested by my urologist, who noted that my HMO had approved it for other patients of his. I immediately agreed during my February 17, 2015 appointment that I wanted the Prolaris test. I don’t know when the staff at my urologist’s office sent the request to the HMO, but the HMO did not respond until March 20, more than a month later.

When the HMO did respond, it was to deny coverage. I appealed that decision, providing specific reasons it was important to me. My urologist sent the official appeal to the HMO on March 24. After some communication issues between my urologist’s staff and the HMO, the Prolaris test was finally approved on May 14.

The next step was to get the biopsy slides sent to Myriad Labs for the Prolaris test. There was another paperwork delay in Tallahassee before the pathology lab sent the biopsy slides to Prolaris.

On June 15, 2015, Myriad Labs notified me that the results were ready, and being sent to my urologist. I was able to make an appointment with him for June 18. The whole process of getting the Prolaris results had taken four months, from February 17 to June 18. This was not because of Myriad Labs, which has excellent customer service.

The Prolaris result was a score of -0.5. This means the aggressiveness of my cancer fell into the middle of the range of men whose biopsies show low-to-intermediate cancer risk. This was not bad enough to get immediate treatment, nor good enough to stop worrying about it.

Second Opinion at Moffitt

My urologist suggested several places I should consider to get a second opinion. I picked the Moffitt Cancer, in Tampa…mostly because it is covered by my HMO (Capital Health Plan, CHP). The original biopsy slides went to Tampa, and Moffitt had re-analyzed them before I arrived in Tampa on May 20, 2015.

A doctor at Moffitt reviewed the biopsy slides, and agreed with the conclusions of the previous pathology lab. He described the pros and cons of surgery, which is his specialty, and noted that he had much experience with the DaVinci (robotic) surgery. He also suggested that I contact a radiologist (specialist in using radiation for prostate cancer treatment), noting that there are several excellent ones in Tallahassee. However, having heard my urologist (a surgeon) describe the problems with radiation therapy, I didn’t pursue that.

Early Diagnosis

My primary care physician believes in the value of PSA (prostate specific antigen) tests as part of a routine semi-annual review of blood test results. My PSA scores drifted gradually upward, and when they crossed the 4.0 threshold in January, 2014, he referred me to a urologist to find out why.

I had no family history of prostate cancer, and for years the DREs (digital rectal exams) had been negative. Still, after ruling out a prostate infection, and seeing my PSA rise to 4.6, my urologist thought I should have a prostate biopsy to make sure there was no cancer. On February 12, 2015, he did a standard 12-core biopsy. It made use of a rectal probe and required only numbing--no anesthesia. It was uncomfortable, but not really painful, and didn't take long.

After a couple of weeks I got the results: several small cancerous and suspicious areas, resulting in a Gleason score of 3+4 = 7. That's only a little bit worrisome, and rather than immediate treatment I chose "active surveillance" That sounds more proactive than "wait and see what happens."