Radiation in the Time of Covid-19

A panel of top radiation oncologists in the US and UK addressed the question of putting off or shortening various kinds of radiation treatments for prostate cancer at a time when it is best to maintain distance from institutions that treat patients.

Their recommendations depended on the disease setting. For detailed recommendations, see this table. They recommend:

• Consultations and return visits post-RT should be handled by telephone or online if possible.
• The preferred therapy for all favorable risk prostate cancers (very low, low, favorable intermediate risk) is active surveillance during the pandemic.
• 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.) should be used prior to primary RT for all unfavorable-risk patients (unfavorable intermediate risk, high risk, and lymph node positive). If there must be treatment during the pandemic, a shortened course of external beam RT using moderate (20 treatments) or extreme hypofractionation (5 treatments) is recommended.
• Brachytherapy should be avoided during the pandemic, and delayed until afterwards if desired,  due to high exposure of anesthesiological medical staff.
• Adjuvant/Salvage RT should be delayed. 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.) may be used during the delay.
• De-bulking the prostate with RT in patients with low volume metastases can be delayed with 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.).
• Treatment of oligometastases with one to three RT treatments may be delayed with 4-6 month depot injections of a GnRH agonist (e.g., Lupron, Eligard, Zoladex, etc.).

I only take issue with the recommendation for non-palliative oligometastatic RT. (They specifically excluded palliative RT from their guidelines.) They state that they recommend delaying treatments that fall into the category of "non-essential procedures that do not have evidence to support their impact on overall survival rates." Treatment of oligometastases is definitely in that category. Yet they state that RT±ADT is the preferred treatment during the pandemic. Anyone with metastases  (any number) should be on ADT or advanced ADT anyway. Painful metastases and those at danger of spinal compression should receive SBRT+ADT.

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only (Redux)

In August, Kishan et al. showed a preliminary analysis of oncological outcomes among Gleason score 9 and 10 patients treated with brachy boost therapy (EBRT+BT), external beam radiation therapy alone (EBRT) or surgery (see this link). Because of the limited sample size, some of the differences were not large enough to be statistically significant. Kishan et al. have now expanded their analysis to include 1,001 patients treated between 2000 and 2013, who were treated at several of the top institutions in the US: UCLA, Fox Chase, Cleveland Clinic, Mt. Sinai, and Wheeling Hospital. So far, only an abstract of the study has been presented at the GU Conference. The patient characteristics were as follows: 

• 324 were treated with radical prostatectomy (RP).
• 347 were treated with EBRT only.
• 330 were treated with EBRT + BT (BT was either low dose rate or high dose rate).
• All patients were Gleason 9 or 10 on biopsy.

Treatment specs

• Among the RP patients, 40% had adjuvant or salvage radiation therapy (68 Gy).
• Among radiation patients, 90% had adjuvant ADT
• Median dose of EBRT was 78 Gy.
• adjuvant ADT continued for 18 months, median.
• Median equivalent dose of EBRT+BT was 90 Gy
• adjuvant ADT continued for 12 months.

Oncological outcomes

After a median follow-up of 4.8, 6.4 and 5.1 years for EBRT, EBRT+BT and RP, respectively, the oncological outcomes were as follows:

• The 10-year rates of distant metastases were
  • 39.9% for RP 
  • 34.2% for EBRT
  • 19.7% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.
• The 10-year rates of prostate cancer-specific mortality (PCSM) were
  • 20.3% for RP
  • 25.2% for EBRT
  • 14.1% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant.

The authors conclude:

Extremely dose-escalated radiotherapy offered improved systemic control and reduced PCSM when compared with either EBRT or RP. Notably, this was achieved despite a significantly shorter median duration of ADT than in the EBRT arm. 

Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While this does not prove causality (only a randomized clinical trial can do that) it is highly suggestive that escalated dose can provide lasting cures. There may be good reasons why some high risk patients may have to forgo brachy boost therapy in favor of high dose EBRT or RP with adjuvant EBRT, but for most, brachy boost therapy with ADT will probably be the best choice.

Sadly, a recent analysis of the National Cancer Database showed that utilization of brachy boost therapy for high risk patients has declined precipitously from 28% in 2004 to 11% in 2013. If a patient sees anyone other than the first urologist, he often only sees a single radiation oncologist who only informs him about IMRT. In most parts of the US, there is a dearth of experienced brachytherapists.

Toxicity equal for SBRT and conventional external beam radiation

There has been some question as to whether the toxicity of delivering very high doses of external beam radiation per treatment (or fraction) in fewer fractions (called “extreme hypofractionation” or SBRT) would be high compared to conventional dose rates per fraction. While SBRT practitioners have reported very low toxicity rates (see table in this link), there has always been some doubt because there may have been some bias in how patients were selected in the various studies.

The HYPO-RT-PC trial was the first trial ever to randomly assign patients to one kind of radiation or the other. Between 2005 and 2015, they enrolled 1200 intermediate-risk patients in Scandinavia to receive either:

1.  Conventional fractionation: 78 Gy in 39 fractions
2. SBRT: 42.7 Gy in 7 fractions

The biologically effective dose is 19% higher for SBRT in terms of cancer control. The biologically effective doses are equivalent in terms of toxicity.

There were a few differences from some US practices:

• “Intermediate risk” was defined as one or two of the following 3 risk factors:

1. Stage T1c-T3a (T3a is a high risk factor in the commonly used US definition)
2. PSA> 10 ng/ml (PSA> 20 ng/ml is a high risk factor in the commonly used US definition)
3. Gleason score ≥7 (Gleason scores greater than 7 are a high risk factor in the commonly used US definition)

• 80% of the men were treated with a technology called 3D-CRT, which is seldom used for external beam therapy anymore at major tertiary care centers. It is never used for SBRT in the US because it is considered not precise enough, and too toxic.

• SBRT is usually delivered in 4 or 5 fractions in the US. CyberKnife and VMAT are the most common technologies in use, and use of sophisticated image guidance throughout each treatment is a common practice.

The toxicity results are based on 866 patients who had 2-year follow-up results. There were some differences in acute toxicity:

• Acute urinary toxicity was 27.6% for the SBRT group and 22.8% for the conventional fractionation group, but the difference was not statistically significant.
• Acute rectal toxicity was 9.4% for the SBRT group and 5.3% for the conventional fractionation group. The difference was statistically significant, but narrowed by 3 or 6 months.

Neither physician-reported toxicity nor patient-reported late-term toxicity differed by the fractionation schedule they received. By two years:

• Late-term urinary side effects were reported by 5.4% of the SBRT group and 4.6% of the conventional fractionation group. The difference was not statistically significant.
• Late term rectal side effects were reported by 2.2% of the SBRT group and 3.7% of the conventional fractionation group. The difference was not statistically significant.
• Impotence was reported by 34% of both groups, up from 16% at baseline.
• Patient-reported bother from urinary, rectal and sexual side effects were not different.

Given their use of the largely outmoded 3D-CRT technology, it was not surprising that acute toxicity would be elevated. I’m frankly surprised that late-term toxicity was not higher for SBRT.

They plan to present their findings on oncological outcomes at a future time.

Patient-reported outcomes from ProtecT - the first randomized trial comparing surgery, radiation, and active surveillance

While there were no differences in 10-year mortality when patients were randomized to surgery (RP), external beam radiotherapy (EBRT), and active surveillance (AS) (see this link), the side effects patients suffered from those treatments differed markedly. Johnson et al. have published the patient-reported outcomes of the ProtecT trial in the New England Journal of Medicine (see this link).

In the ProtecT trial, all participants (or actually 85% of them) filled out a series of validated questionnaires (EPIC and others) that probed issues of urinary function, rectal function, sexual function, and general health. I will ignore the overall health, vitality and mental status questions for now. Suffice it to say that they did not differ among therapies, nor were they very much affected by them. Questionnaires were filled out before the biopsy (the baseline), and at 6 and 12 months after randomization, and annually thereafter until 6 years from the initial biopsy.

What is especially interesting is seeing how equivalent patients (they are equivalent because they were randomized to the 3 treatments) did over the 6 years after receiving each treatment. This means that, for the first time, the side effect profiles are completely comparable (well, almost) and almost without bias.

Some messy data

I say "almost" because there was some switching of treatments that did occur. 22% of the men did not get the therapy they were originally randomized to, and they self-selected some other therapy or no therapy. However, in the analysis they are treated as if they got therapy that they were originally intended to get. Strange, huh?

In addition, they may have received salvage therapy after biochemical failure, and 55% of those assigned to AS did get a radical therapy eventually. So for each intended therapy:

• Among those 291 men who started on AS but got radical treatment: 49% had surgery, 33% had radiation as specified, and 18% had another kind of radiation or HIFU
• Among those 391 men who started on RP, 14 (4%) had adjuvant or salvage radiation, and 1 went on lifelong androgen deprivation therapy (ADT) within a year.
• Among those 405 men who started on EBRT,  3 had salvage RP, 14 (3%) went on lifelong ADT, and 1 had HIFU.

Whether men had the assigned therapy or not, and irrespective of any other therapy they had, they are included with the group they were originally assigned to. It's messy.

Fortunately, there's hope in sight. In one of the Appendices (Section S3), they added the note:

"In future analyses, we intend to present patient-reported outcomes according to treatment received and an economic evaluation including assessment of therapies received for treatment impacts, as well as details about the reasons for change of management in the active monitoring arm to further inform individual and clinical decision-making"

That will give us a much truer picture of the side effects associated with the treatments they actually received.

The treatments

RP was open and nerve sparing. While most men now have robotic surgery rather than open surgery, it seems to make little difference, except for some higher incidents of issues arising during the operation (see this link).

AS did not have required follow-up biopsies, so their side effects may be a little better than on contemporary AS programs. Biopsy complications are never long-lasting anyway.

EBRT was different from contemporary standards. The dose was lower (74 Gy vs. 80 Gy), so there may have been fewer complications due to dose. They used an older delivery technique (3D-CRT vs IMRT) which had higher rates of side effects. And it was given together with short term (3-6 months) of ADT, which would certainly increase the early sexual side effects. ADT is seldom given to favorable risk patients today.

note: all of the patient-reported outcomes include the effect of whatever remedies they used to treat them.

1. Urinary Adverse Outcomes

a. Incontinence

This was a big issue for RP, of course, but not for AS or EBRT. The percent using one or more pads per day is one commonly used measure. As one can see in the following table, incontinence was highest at the 6-month time point, but had gotten somewhat better by the end of the first year. 20% were incontinent by the end of two years, with little improvement from that point.

For EBRT, incontinence peaked at 5% at 6 months. Remember, this was 3D-CRT - a technology that has greater toxicity than the IMRT predominantly in use now. It hovered around 3-4% thereafter.

For AS, incontinence also peaked at 4% at 6 months, and stayed at that level for the next couple of years. From then, it steadily rose to 8% by the end of the 6 year study. Remember that for the purposes of this trial, men were still included in the AS cohort whether they were eventually treated or not. By 6 years, more than half the men had been treated, primarily with surgery.

Table 1. Incontinence: The percent who used one or more pads per day

Time point	AS	RP	EBRT
Baseline	0%	2%	0%
6 months	4%	46%	5%
1 year	4%	26%	4%
2 years	4%	20%	4%
3 years	5%	20%	3%
4 years	7%	17%	4%
5 years	7%	17%	3%
6 years	8%	17%	4%

b. Urinary Irritation/Obstruction

The researchers examined the question of whether urination become more difficult or more frequent after therapy. One way to look at this is a set of questions on the EPIC questionnaire asking about urinary frequency and retention. On that questionnaire, a score of 100% means that function is perfect in that regard, no issues whatever.

On this dimension only EBRT had a clinically detectable effect, and it was only at the 6 month mark. EPIC score dropped from 93% to 84%. After that, it returned quickly to baseline levels.

Table 2. Urinary Irritation/Obstruction EPIC scores, where 100% would be the best possible score.

Time point	AS	RP	EBRT
Baseline	93%	92%	94%
6 months	92%	89%	84%
1 year	93%	93%	93%
2 years	92%	93%	93%
3 years	91%	93%	93%
4 years	91%	94%	93%
5 years	92%	94%	93%
6 years	92%	94%	93%

2. Rectal Adverse Outcomes

The researchers asked the trial participants about their bowel function at baseline and after treatment. There were no discernable effects of AS or RP. Bowel function among the men enrolled for EBRT declined by 6 months (from a score of 93% to 86%). Thereafter, bowel function scores returned to near baseline levels. Other than the 6 month time point, there were no significant differences among the 3 treatments.

Table 3. Bowel function EPIC scores, where 100% would be the best possible score.

Time point	AS	RP	EBRT
Baseline	92%	91%	93%
6 months	91%	92%	86%
1 year	92%	93%	90%
2 years	92%	93%	90%
3 years	92%	93%	91%
4 years	92%	93%	91%
5 years	92%	93%	90%
6 years	92%	92%	91%

3. Sexual Adverse Outcomes

This is one of the few trials that asked men detailed questions about their sexual function at baseline and for 6 years thereafter. One of the key measures of sexual function is the ability to have erections firm enough for intercourse. At baseline, about two-thirds of these 62 year old men (range 50-69), some with other comorbidities like diabetes, cardiovascular disease, and smoking, had suitable erectile function. 

None of the questionnaires asked about perceptions of penile shrinkage in length and girth, climacturia (urination at orgasm), or Peyronie's (abnormal penile curvature), which are often symptoms that affect sexual function post-prostatectomy. Nor do they ask about how the loss of ejaculate has affected sex. That is a certainty with surgery, a near-certainty after radiation, and is not affected by AS. Their definition of erectile function includes the effect of any erectile function aids (e.g. ED meds, injections, pumps, or implants) they may have been using.

For those randomized to RP, erectile function was reduced to 12% at 6 months (remember: they all had nerve-sparing surgery). It recovered somewhat to as much as 21% at 3 years but did not recover beyond that. At every time point, their erectile function was significantly worse than the other treatment cohorts.

For the AS cohort, erectile function declined by 6 months and continued to deteriorate thereafter as they elected to have radical therapies, predominantly surgery. 11% of this cohort had already elected to have radical treatment by the 6-month mark.

For the EBRT cohort, erectile function had dropped to a minimum value of 22% at 6 months. This may be largely attributable to the fact that all of the men in the EBRT cohort had 3-6 months of ADT. It is unknown how much, if any, of their testosterone came back after that and how long it took to recover. Erectile function snapped back a bit post-ADT, getting as high as 38% at 1 year, and declined to 27% by 6 years. Again, this was based on the 3D-CRT technology, and is below the rates usually seen for this age group with IMRT, brachytherapy, or SBRT.

Table 4. Erectile function - the percent who had erections firm enough for intercourse

Time point	AS	RP	EBRT
Baseline	68%	65%	68%
6 months	52%	12%	22%
1 year	49%	15%	38%
2 years	47%	19%	34%
3 years	41%	21%	34%
4 years	37%	20%	32%
5 years	35%	20%	27%
6 years	30%	17%	27%

Myths Exploded by this study:

Myth #1: The side effects end up about the same for surgery or radiation

That's clearly not true for incontinence or erectile function, It is true for urinary irritation and rectal function, which are at baseline levels and similar in all cohorts at 6 years.

Myth #2: With surgery, you get the side effects all at once and steadily recover; with radiation, the side effects come on steadily and may hit you many years later.

What we've seen here belies that myth. There is some recovery of continence up to two years later, but not thereafter. After radiation, incontinence was a minor symptom (except to those who had it, of course), but it did not increase over the years. Urinary irritation/obstruction increased at 6 months for EBRT, but returned to baseline permanently thereafter. Rectal function scores also permanently returned to baseline levels after the 6-month time point.

Myth #3: Over time, erectile function is about the same for surgery and radiation. 

As we've just seen, erectile function is much worse after surgery, and it never recovers much beyond 2 years. It is worth tracking this myth down to its source. I have even heard John Mulhall, the eminent Memorial Sloan Kettering sex specialist quote this myth.

I believe this myth started with the PROSTQA study published in 2008. Until the ProtecT trial, it was our best source of patient-reported outcomes after the various treatments. The patients were not randomly assigned, however, and differed markedly in their characteristics. Those characteristics, especially age, varied greatly with the treatments they chose. In the following table, hidden in an appendix (all the good stuff is usually back there), we can extract the following table:

Table 5. Percent with preserved erectile function sufficient for intercourse 2 years after treatment, broken down by age at treatment 

Age	RP	EBRT	BT
<50	55	100*	75*
50-59	43	52	67
60-69	27	39	44
70+	8*	30	24
Total	35	37	43
Median Age	60 years	70 years	66 years

* small sample size

Although the potency doesn’t seem to vary much between treatments in total (range 35% to 43%), it is only because the men who received EBRT and BT were older than the men who were treated with RP. Within every age group, potency preservation was higher with radiation.

There are other differences between the two studies, such as: 
• this table only includes men who were potent before therapy, which would exclude about a third of men in the ProtecT trial. This would lower all the percentages in Table 5 relative to Table 4. 
• ProtecT included only men in the 50-69 age range, while half of the findings in ProstQA came from men treated with radiation over the age of 70. 
• Finally, ProtecT didn't yet report erectile function according to the therapy or therapies they actually received.

It is gratifying to see these myths shattered. Patients are the beneficiary.