Originally published 4/21/2018
Since we posted the original blog below, proton beam therapy (PT) for prostate cancer (PCa) has been struggling with insurance issues. That’s because PT is significantly more costly than conventional radiation types, yet has not demonstrated better cancer control. However, the minds of many patients, it offers a better chance at cure. In fact, recurrence rates are comparable to other forms of radiation such as intensity modulated radiation therapy (IMRT) and stereotactic body radiotherapy (SBRT). Three recent studies report the following biochemical disease-free rates (that is, no rise in PSA):
| Kubeš, et al.[i] 5 years |
Takagi, et al.[ii] 5 years |
Takagi, et al.[iii] 10 years> |
|
| Very low-risk PCa | 100% | ||
| Low-risk PCa | 96.9% | 99% | 88% |
| Intermediate-risk PCa | 91% | ||
| Favorable intermediate-risk PCa | 91.7% | 86% | |
| Unfavorable intermediate-risk PCa | 83.5% | 79% | |
| High-risk PCa | 86% | 68% | |
| Very high-risk PCa | 66% | 63% |
Note that when PSA is rising after any form of radiation, include brachytherapy, it is assumed that PCa is back—though only a biopsy proves it. In any case, such recurrence rates have not persuaded insurers that proton beam is worth the extra cost. Discouraged patients often resign themselves to another choice. The National Association for Proton Therapy has a website for coaching patients on strategies they can implement to appeal a denial decision. Generating an effective appeal takes tenacity and a big commitment to do the research and documentation needed to mount a campaign. For someone who’s already dealing with a cancer diagnosis, the effort may not be worth it.
When the National Cancer Institute (NCI) publishes a case study in prostate cancer (PCa) treatment, it’s an experience in very respectable clinical detail. An example is the 2015 analysis of one man’s recurrent PCa following primary (first) prostate cancer treatment with proton beam radiation. The study, “Upgrading Prostate Cancer Following Proton Beam Therapy,”[iv] includes co-author Dr. Peter Pinto, a name that might be familiar to many of you.
The purpose of the authors is to discuss the physical effects of radiation on prostate tissue, and how this could make it challenging to distinguish recurrence on biopsy. In a sense, this case study is a cautionary tale, and I’ll explain why.
The patient was 45 years old when he was diagnosed with PCa. His PSA was 8.6 ng/mL, and his Gleason score was 4+3. He was determined to be stage T1c, meaning he was considered to have disease still localized within the gland. He looked like a very good candidate for radiation therapy – in his case, proton beam.
Effects of radiation
A lot of people assume that radiation kills cancer quickly, but this is not the case. Unlike thermal ablation such as focal laser ablation, which destroys cancer at the time of treatment, radiation acts on the DNA of cancer cells over time, making it difficult for the cells to reproduce themselves. Healthy cells are less susceptible to the effects of radiation, though the scatter effect of all radiation can also do some harm to normal cells.
The more radiation you give, the greater the effects. This is called a dose-dependent response, and the authors inform us that radiation-induced effects “can be heterogeneous among a single tumor and patients. These changes can be so pronounced that they can affect assessment of residual disease.” This is what I take to be the main point of this article: the changes in tissue due to exposure to radiation can make it difficult to accurately diagnose recurrence.
Here’s what happened
His PSA reached a nadir (lowest point) of 3.2 ng/mL at 3 months after treatment. Then it began to rise, eventually reaching 9.39 at 21 months. Meanwhile, the patient had a 12-core TRUS biopsy at 18 months. It was diagnosed as negative for PCa, only showing the unusual cell formations typical of radiated prostate tissue. But something wasn’t adding up, so he was sent for a multiparametric MRI (mpMRI) of the prostate – the same type of imaging we do at our Center – which the NCI excels at.
Not surprisingly, the mpMRI scan found two suspicious areas in the prostate plus what appeared to be invasion of the seminal vesicles; however, there was no evidence at that point of PCa in the lymph nodes or bone. A 6-core targeted biopsy into the suspicious lesions found “all six targeted cores demonstrating high-grade disease (five cores with Gleason 4 + 5 = 9 disease) with perineural and seminal vesicle invasion.”
The patient then underwent a salvage robotic prostatectomy and extended removal of 33 lymph nodes. Examination of the entire prostate specimen showed that the whole gland as “atrophied” from radiation effect, and was found to have “multifocal Gleason 5+5 disease with extracapsular extension and seminal vesicle invasion.” PCa was found in two of the lymph nodes. There is some hopeful news for this patient: At 1 and 3 months post-surgery, his PSA was stable at 0.07 ng/mL.
Important take-aways
Here the important points I gained from this article:
- It appears that proton beam radiation affects tissue in ways similar to other forms of radiation, though more research is needed
- When examining recurrent PCa in radiated glands, one must be aware that some tumor areas will show radiation effects while others may not. The authors advise against grading the affected areas, and only grading the non-affected areas.
- The reason to grade the non-affected areas is because PCa tumors that escape radiation’s effects tend to come back more aggressive than the parent tumor, as demonstrated by Gleason grade and changes in the DNA itself (called ploidy)
- If recurrence is suspected, it’s better to wait a year to biopsy tissue, because “it is believed tumor regression continues for 6-12 months after radiation treatment” (remember: radiation does not kill cancer quickly) so at 1 year, if what a biopsy finds looks like cancer, it probably IS cancer.
Although this article is a single case study, the in-depth tissue analysis of the surgical specimen helps explain why the biopsy at 18 months was inconclusive for cancer: the changes brought about by radiation made it challenging to characterize the cells under the microscope. On the other hand, the mpMRI detected tumor clusters with significant (high grade) characteristics, and the targeted biopsy harvested large enough samples to distinguish radiation effect from active tumor.
There is, of course, a place for radiation therapy in the toolkit we use against prostate cancer, especially for nonsurgical candidates with multifocal disease. It is still a very good option for appropriate patients. However, articles like this case study help make us aware that the cancer-destroying power of radiation is based on a completely different action, and even proton beam cannot completely spare non-PCa cells.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
References
[i] Kubeš J, Haas A. Vondrá?ek V, Andrlik M et al. Ultrahypofractionated Proton Radiation Therapy in the Treatment of Low and Intermediate-Risk Prostate Cancer-5-Year Outcomes. Int J Radiat Oncol Biol Phys. 2021 Jul 15;110(4):1090-1097.
[ii] Takagi M, Demizu Y, Terashina K, Fujii O et al. Long-term outcomes in patients treated with proton therapy for localized prostate cancer. Cancer Med. 2017 Oct;6(10):2234-2243.
[iii] Takagi M, Demizu Y, Fujii O, Terashima K et al. Proton therapy for localized prostate cancer: long-term results from a single-center experience. Int J Radiat Oncol Biol Phys. 2021 Mar 15;109(4):964-974.
[iv] Logan JK, Rais-Bahrami S, Merino MJ, Pinto PA. Upgrading prostate cancer following proton beam therapy. Urol Ann. 2015 Apr-Jun;7(2):262-4.
About Dr. Dan Sperling
Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.
