Treatment delay in primary radiation therapy or surgery

(Updated) 

Patients are often concerned about delaying treatment. Will it give the cancer a chance to metastasize? What if the random biopsy didn’t detect existing higher grade cancer? This is particularly of concern to patients considering active surveillance.

Dong et al. reported on the cancer control outcomes of 4,064 patients treated with external beam radiation therapy at Fox Chase Cancer Center. The patient records included:

• 1549 low-risk patients, 1612 intermediate risk patients, and 903 high-risk patients
• Median time-to-treatment was 3.3 months

After a median follow-up of 64 months:

• There were no differences in 5-year biochemical failure, distant metastases, or overall survival depending on whether patients waited more or less than the median time to treatment.
• This was true for every risk group.
• This was even true for high-risk patients who did not receive any ADT.

This reflects the very slow natural history of prostate cancer progression, even with a high-risk diagnosis.

(Update) Lee et al. reported on the outcomes of 3,962 intermediate- and high-risk patients who all got a prostatectomy up to a year after their biopsy. After a median follow-up of 7 years:

• Longer delays were associated with a decreased risk of castration-resistant, regardless of their risk group
• Longer delays did not result in increased detection of metastases or deaths

The same holds true whether the final decision is surgery or radiation (or, of course, active surveillance). Koretz et al. tracked the oncological outcomes of men who delayed having surgery after a positive biopsy. They categorized the 1568 men into those who had an RP ≤60 days, 61-90 days, and >90 days after their biopsy. After 64 months of follow-up:

• All three groups had about the same pathology outcomes: Gleason upgrade, extracapsular extension, seminal vesicle invasion, positive margins, and positive lymph nodes.
• The 5-year biochemical recurrence-free survival was the same in all three groups.
• Treatment delay had no effect even among high-risk men

Even longer delays had no effect on outcomes. Gupta et al. looked at very high-risk (GS 9/10), high-risk (GS 4+4) and unfavorable intermediate-risk (GS 4+3) men who had surgery within 6 months of their diagnosis. They compared outcomes between those who were treated in less than 3 months of diagnosis vs. 3-6 months. There was no difference in 5-year biochemical recurrence-free survival or metastasis-free survival. Patel et al. found that surgical delays of up to 6 months following prostate biopsy were not associated with an increased risk of Gleason upgrading, EPE, SVI, positive surgical margins, or lymph node involvement. Similarly, Reichard et al. reported no difference in biochemical failure, metastases, prostate cancer mortality, or all-cause mortality among high or very high risk men who delayed prostatectomy the longest. Lee et al. found that a treatment delay of a year before prostatectomy in intermediate and high-risk men had no effect on risk of developing metastases or all-cause mortality.

Hirasawa et al. found than men who delayed surgery for over 6 months had no worse outcomes than men who were treated sooner in Japan. Zanaty et al. found that delaying surgery only affected the high risk patients in Canada. Morini et al. found no loss of efficacy when surgery was delayed for more than 12 months in Brazil. Aas et al. found no decline in pathological findings, freedom from relapse, or prostate cancer survival after delaying prostatectomy for 6 months with 8 years of follow-up among intermediate or high risk men in Norway

Prostate cancer patients have enough time to meet with a variety of specialists and make a well-considered decision, irrespective of their risk level at the time of diagnosis.

Patients who are considering which kind of therapy is right for them should take comfort from this. They have sufficient time to meet with a variety of specialists and to gather the information they need to make a well-considered decision.

Patients who are considering active surveillance should also take comfort from this. Oncological outcomes were the same as for immediate therapy, whether men were treated with surgery or radiation. Those choosing surgery after active surveillance, may have worse continence and potency preservation, however (see this link). Delay in seeking therapy is not likely to adversely impact cancer control, even if they harbor a riskier form of the disease, at least in the short term. Of course, a confirmatory follow-up biopsy, especially one that is targeted using multiparametric MRI, will provide a much higher degree of assurance.

I have come to believe that no doctor ought to accept as final any prostate cancer primary treatment decision made by a low, intermediate, or high risk patient within a month of receiving his diagnosis, and preferably within 3 months. The emotional temperature has too strong an effect on decision making, and time is our friend in this regard. Similarly, doctors should insist that second opinions have been acquired.

The real risk of secondary malignancies due to prostate radiation

Some of the media (see this Medscape article) have already pounced on a meta-analysis published by a group of researchers from the University of Toronto. The media misguidedly focus on relative risk rather than absolute risk. We examined this very complex subject last year (see this link). Wallis et al. looked at 21 studies in which secondary cancers were reported. They found that men who had external beam prostate radiation also had a higher rate of bladder and colorectal cancers, but not lung cancer or hematological malignancies. This shows association, but not causation.

Incidence of secondary cancers ranges in men who had each therapy were:

• ·      External beam radiation (EBRT): 0.2-2.3%
• ·      Brachytherapy (BT): 0.1-2.1%
• ·      External beam plus brachytherapy boost: 0.2- 1.7%
• ·      No radiation: 0.3-2.3%

The absolute difference in secondary bladder cancers per 1000 men treated for prostate cancer were:

• ·      EBRT vs no radiation: +2 (range: -2 to +6)
• ·      BT vs. no radiation: 0 (range: -4 to +4)

The absolute difference in secondary colorectal cancers per 1000 men treated for prostate cancer were:

• ·      EBRT vs no radiation: +7 (range: +3 to +10)
• ·      BT vs. no radiation: 3 (range: -5 to +11)

Risk of secondary bladder cancers was the subject of 9 studies.

• ·      7 of the 9 did not find significantly increased risk
• ·      The average increase was 39%
• ·      Of the 3 studies that allowed for a 5 year lag time for secondary cancers to develop after radiation exposure,:

o   2 of the 3 did not find significantly increased risk

o   The average increase was 30%

• ·      Of the 2 studies that allowed for a 10 year lag time for secondary cancers to develop after radiation exposure,:

o   1 of the 2 did not find significantly increased risk

o   The average increase was 89%

• ·      Of the 4 studies that included a multivariate analysis that included age:

o   2 of the 4 did not find significantly increased risk

o   The average increase was 67%

Risk of secondary colorectal cancers was the subject of 10 studies.

• ·      5 of the 10 did not find significantly increased risk
• ·      The average increase was 68%
• ·      Of the 4 studies that allowed for a 5 year lag time for secondary cancers to develop after radiation exposure,:

o   2 of the 4 did not find significantly increased risk

o   The average increase was 94%

• ·      Of the 2 studies that allowed for a 10 year lag time for secondary cancers to develop after radiation exposure,:

o   1 of the 2 did not find significantly increased risk

o   The average increase was 56%

• ·      Of the 3 studies that included a multivariate analysis that included age:

o   1 of the 3 did not find significantly increased risk

o   The average increase was 79%

While the media focus on the increase in incidence when expressed as a percent, the actual incidence and the absolute increases are really very small.  This was the subject of an accompanying editorial by Eyler and Zietman. They also point out that many of the studies included in the meta-analysis included men treated with older forms of external beam radiation that lack the accuracy of today’s technology. We expect to report soon on an analysis of IMRT only.

Many of the studies lacked data on age and other risk factors that contribute to bladder and colorectal cancers. Patients who received EBRT are an average of 10 years older than patients receiving surgery and about 5 years older than patients receiving BT. It is established that bladder and colorectal cancer incidence increase with age, so it is difficult to separate the competing risk factors. The problem is compounded by the lag time necessary to observe secondary cancers. Other risk factors confounding any such analysis include smoking and ethnicity. Because we are increasingly vigilant after a first cancer diagnosis, we are more likely to detect other cancers. This also confounds our analyses.

All of these studies really only tell us about association but not causation. For that, we require randomized clinical trials with very long tracking. While such trials are a long way off, we can take comfort in the fact that the risk is really very small.  While any risk should be acknowledged, and may be a decision factor for choosing active surveillance in low-risk men, this should not be a reason for anyone to avoid needed and curative radiation therapy.

Why we should care about standard of care

“Standard of care (SOC),” is a legalistic term. As it applies to medicine, it means that the doctor has proceeded with reasonable caution, as any minimally competent doctor would exercise in such circumstances. It clearly protects the doctor from malpractice lawsuits. But is it always in the patient’s interest? Can following it too rigidly harm patients whose status requires adjustment for natural variation? Conversely, what are the risks of departing too far from the norms?

In radiation therapy, SOC can be determined by professional organizations, consortiums of hospitals (like the National Comprehensive Cancer Network - NCCN), NGOs (like the American Cancer Society), individual hospitals, peer review, or by the customary practice of individual doctors. For clinical trials of new therapies, an Internal Review Board (IRB) is responsible for defining ethical constraints. In addition, the FDA, the Centers for Medicare and Medicaid Services (CMS), and insurance companies may define SOC by dictating which therapies are approved and reimbursable. The American College of Radiology (ACR), the American Society for Therapeutic Radiation and Oncology (ASTRO) and the American Brachytherapy Society (ABS) are the largest professional organizations of radiation oncologists.

For interested readers, here is a list of some guidelines and white papers on specific radiation therapies:

Low Dose Rate Brachytherapy for Prostate –(ABS) (ACR)

High Dose Rate Brachytherapy for Prostate (ABS)

High Dose Rate Brachytherapy (ASTRO)  (ACR)

IGRT (ASTRO) (ACR) (ACR)

IMRT (ASTRO) (IMRT)

SBRT (ASTRO)

Proton Beam Therapy  (ASTRO)

Adjuvant/Salvage IMRT after prostatectomy (AUA/ASTRO) (ACR)

Very few of the above are specific to radiation for prostate cancer. In some cases, there is a paragraph or short chapter. In 2013, the Radiosurgery Society (RSS) began writing guidelines for prostate SBRT, but has so far abandoned the effort. What’s the problem?

The problem is that developing guidelines is a lot of work, and the work is usually unfunded and thankless. The top practitioners in each field are often approached in order to enhance the credibility of the guidelines. These are often the clinicians who are busiest and who have the least to gain – they already know what works and what doesn’t through their own research and experience. They must compile and sift through massive amounts of data to summarize what’s known about the subject. Then they must issue draft guidelines, send them to peers, wade through peer comments, send out second draft guidelines, etc., until consensus is reached, or it becomes clear that no consensus can be reached. The consensus opinion is then peer-reviewed and published. By the time it is published, new information from studies and clinical trials may render some of the conclusions outdated, so revisions must be done continually.

While some patients (and clinicians) may worry that SOCs are too restrictive, well-written ones acknowledge the variance in the data and allow for adjustments depending on patient characteristics. Some doctors, fearful of being sued, may follow them too slavishly, but I think most will simply explain why adjustments must be made and are reasonable. This not only protects the doctor, but the patient as well. A patients deserves to know what adjustments to the SOC are planned for him, and why.

In some cases, the SOC fails to gain a consensus among practitioners. The abovementioned AUA/ASTRO guidelines on adjuvant/salvage radiation after prostatectomy are a case in point. Many doctors believe that following those guidelines would result in overtreatment; consequently, they are increasingly ignoring them. Unfortunately, they are not only delaying radiation, which might be prudent, but seem to be forgoing it entirely. This was discussed in a recent commentary (see this link).

SOCs also protect patients from being experimented on without their consent. Although we may conceptually admire the maverick doctor who thinks out of the box to come up with the next breakthrough, such miraculous treatments seldom occur in practice. At the very least, even the patient who is willing to be the test case of a new treatment, must sign a waiver acknowledging that the treatment is experimental, has unknown and possibly unsafe outcomes, and is outside the SOC.

This puts some clinical trials in a gray area. We have reported on some radiation clinical trials that are so far outside the SOC, that they are ethically questionable.  SOC continually evolves along with medical evidence from new clinical trials, so the two work hand-in-hand. Let’s look at a few that involve SBRT. Unfortunately, there are no published SOC guidelines for prostate SBRT. The lack of an official SOC has allowed some clinical trials to be implemented that have put patients at risk.

• We looked at the Bauman et al. study that had to be terminated because of higher than expected toxicity. SOC guidelines specific to prostate SBRT that included intra-fractional motion tracking and tighter dose constraints might have spared those patients injury.

• Kim et al. used a dose schedule as high as 50 Gy in 5 fractions, far above what others use for SBRT. As a result, 6 of the 61 patients treated with this extreme dose suffered Grade 3 and Grade 4 rectal toxicity. Four of them had to have a colostomy, 2 suffered rectourethral fistulas, and one had grade 4 bleeding that was treated with cauterization. Toxicity like this has never been reported in SBRT literature before or since. One might understand a study like this if they were trying to find an optimally effective dose, but the stated purpose was only to find the dose-limiting toxicity – they found it.

• As we commented earlier, the City of Hope is conducting a clinical trial of SBRT salvage radiation after prostatectomy (NCT01923506). While SBRT for salvage is potentially a low cost and beneficial therapy worthy of a clinical trial, their dosimetry is far outside of the SOC. They propose to use a dose as high as 45 Gy in 5 fractions to the prostate bed. This is higher than the dose typically delivered to the intact prostate during primary SBRT radiotherapy. Doses for salvage radiotherapy are usually reduced, not increased. They want to find the dose such that up to a third of patients will experience dose-limiting toxicity. A third is a lot of toxicity.

• The Moffitt Center is conducting an SBRT clinical trial  (NCT02572284) that is questionable for several reasons. First, they misinform with the statement, “The standard dose is 10 Gy per day when SBRT is the only treatment to the prostate and no surgery is planned.” That dose far exceeds customary practice, and is quite toxic, as we saw in the Kim et al. study. Fortunately, they will be using far lower doses of 25, 30, or 35 Gy across 5 fractions. Only the 35 Gy dose is used in customary practice for prostate SBRT.  All high-risk patients will also have a prostatectomy 2 weeks or 4 weeks after the radiation. Considering the known safety issues involved in salvage surgery after radiation, even by very experienced surgeons, I am perplexed that they would do this adjuvant surgery at all, let alone that soon. I think there will be horrendous harm at all dose levels, and they will be unable to find an optimal dose level. I also wonder if patients are being informed that either therapy alone might be curative. Furthermore, I hope patients are told that there will be no salvage therapies available to them if this combo treatment fails.

Dose escalation studies are usually done to find the optimal dose. The “dose-response curve” is S-shaped. At the bottom, at very low doses, there is little increase in cancer control. Then on the steep part of the curve, cancer control increases rapidly with increasing dose. Finally the curve flattens again as increasing dose adds little cancer control, but adds significantly to toxicity. The goal is to locate the dose at the top of the steep part, just before it flattens out. How are we to find that optimal dose – the new SOC - without pushing the envelope of SOC so far that patient safety is compromised?

Memorial Sloan Kettering Cancer Center is conducting an SBRT dose escalation study (NCT00911118) that illustrates how this can be done safely and ethically. The first group of 30 patients received 32.5 Gy in 5 fractions. If fewer than 10% suffered dose-limiting toxicity, the next group of 30 patients received 35 Gy. The next group received 37.5 Gy; and the next, 40 Gy. A patient told me that owing to low toxicity rates, they added an additional cohort of 30 patients receiving 42.5 Gy. This is the way to find the SOC for SBRT – in incremental steps with care taken to assure patient safety all along the way.

I hope ASTRO, ACR or the RSS will develop SOCs for prostate SBRT and the other forms of prostate radiation for which SOCs are lacking. They protect both the patient and clinician, and provide the ground above which improvements can be made ethically and safely.

Risk Stratification for Radiation Therapy

Risk stratification involves assigning patients to categories based on diagnostic risk factors. The goal is to identify those patients who are more or less likely to respond to specific therapies (or active surveillance).  It is an aid to judgment for the patient and doctor, and helps assess prognosis and define the standards of care. It also provides for consistency between research studies so that they are more comparable. Because we depend on those studies for treatment guidelines, we don’t want to change the risk categories frequently.

In 1998, Anthony D’Amico introduced the most widely accepted risk stratification system. It has since been tweaked somewhat by consensus of the National Comprehensive Cancer Network (NCCN). It mainly relies on 3 risk factors – PSA (in 3 groups), Stage (in 3 groups), and Gleason score (in 4 groups) to create 3 risk categories (low, intermediate and high) with 2 sub-categories in each of the three. The “very low risk” sub-category also includes number of positive cores, highest % cancer in those cores, and PSA density. The “very high risk” sub-category also includes number of cores with Gleason score 8-10.

There are competing risk stratification systems. UCSF, for example, uses a system called the CAPRA score that includes age and % positive biopsy cores. Each risk factor is assigned points, and the points are summed to determine the risk category. It is also possible to use nomograms based on historical statistics to help with prognosis. While nomograms will always produce a risk probability as a%, those probabilities may, in some cases, be projected off of a very small dataset and their accuracy is questionable.

A risk stratification system is created through a multistep process. The risk factors are assessed to find the ones that independently predict recurrence after treatment.  For example, stage, Gleason score and PSA, although they are somewhat correlated, independently predict recurrence. Those risk factors are then grouped such that the risk is about the same within the group, but is different between the groups. For example in the NCCN system, Gleason scores of 8, 9 and 10 are all roughly the same at predicting recurrence, but carry much greater risk than lower Gleason scores. Then the risk factors are combined (either by selection or by adding points) such that the risk is about the same within the risk category, but significantly different between risk categories.

D’Amico developed his risk stratification system based on data from patients treated from1989 to 1997. His dataset comprised 888 surgery patients treated at the University of Pennsylvania, as well as 766 patients treated with external beam radiation, 66 patients treated with LDR brachytherapy monotherapy and 152 patients treated with LDR brachytherapy plus ADT at the Joint Center for Radiation Therapy in Boston. He only looked at biochemical progression, which was defined as PSA≥0.2 ng/ml for surgery patients and 3 consecutive rises for radiation patients. External beam radiation was only 67 Gy – far below what is now considered curative. Biochemical recurrence after radiation has since been redefined because the previous definition over-predicted clinical recurrence. Radiation therapies did not include combined modalities, HDR brachytherapy, SBRT or proton therapy.

In 2007, Johns Hopkins validated D’Amico’s risk groups among 6,652 prostatectomy patients. In 2008, the Mayo Clinic validated D’Amico’s data among 7.591 patients treated with radical prostatectomy only. They also broadened outcome data to include clinical recurrence, evidence of systemic progression, overall and cancer-specific survival. I am not aware of any validation studies for external beam radiation or brachytherapy.

Because treatments and outcomes have changed so much for radiation therapies, it may be time to take another look at the risk stratification used for radiation therapy. An Italian group looked at data on 2,493 patients treated at 10 centers between 1997 and 2012. Patients were treated with a median dose of 76 Gy of EBRT and 62% also received ADT (almost half were high risk as defined by NCCN.) They call their risk stratification system the Candiolo Classifier. Like the CAPRA score system, it assigns points to each risk factor. Classification is based on the sum of those points.

They found that age and% positive cores at biopsy significantly added to their model’s ability to stratify the risk of patients. The following table shows the breaks that discriminated best, and the number of Candiolo points assigned to each risk factor.

Risk Factor	Candiolo  (points)	NCCN
Age	<70 (0) ≥70 (22)	NA
% Positive Cores	1-20% (0) 21-50% (29) 51-80% (50) 81-100% (81)	<3 positive cores, ≤50% cancer in a core, and PSA density <0.15 ng/ml/g used in “very low risk” definition. <50% positive cores used in “favorable intermediate risk” definition. >4 cores with GS8-10 used in “very high risk” definition.
PSA (ng/ml)	<7 (0) 7-15 (42) >15 (96)	<10 10-20 >20
Gleason scores	3+3 (0) 3+4 (35) 4+3 (48) 8 (76) 9-10 (106)	3+3 3+4 4+3 8-10 5+(5,4,or 3)
Stage	T1 (0) T2 (17) T3-T4 (58)	T1-T2a T2b-T2c T3a T3b-T4

They defined 5 risk classes that discriminated well with risk of biochemical recurrence. The following table shows the biochemical progression-free survival (bPFS) for each risk class at 5 and 10 years. The relationship is similar for clinical progression-free survival, systemic (metastatic) progression-free survival, and prostate cancer specific survival.

Risk Class	Points	5-yr bPFS	10-yr bPFS
Very Low	0-56	94%	90%
Low	57-116	85%	74%
Intermediate	117-193	80%	60%
High	194-262	67%	43%
Very High	263-363	43%	14%

The Candiolo system beat the 3-tiered (low, intermediate and high risk) NCCN system in predicting all measures of progression after external beam radiation. For bPFS, its concordance index (a measure of how accurate its predictions are) was 72% vs. 63% for the NCCN system. It predicted metastases and prostate cancer survival with an accuracy of 80% vs. 69% for the NCCN system.

The Candiolo Classifier certainly seems to be an improvement, but should be validated by another group of researchers before it gains wider acceptance. Ideally, we would also have data on risk categories suitable for other kinds of radiation therapy, boost therapies, use of adjuvant ADT, and whole-pelvic radiation.

This “new, improved” system raises some interesting questions:

• The D’Amico/NCCN risk stratification system is based on antiquated data and a small dataset for radiation. Is it time for a make-over?

• Do we have to have a single risk stratification system against which all therapies should be assessed? It certainly facilitates comparisons between therapies if we have a single system. However, different risk factors (e.g., age and % positive cores) may be important in determining the risk associated with one therapy but not another.

• At what point has our ability to measure risk factors changed enough that the entire stratification system should be altered? The ability of multiparametric MRIs and advanced PET scans to more accurately assess stage and to target biopsy cores to more suspicious areas may increase the detected risk beyond what it was when the system was first set. Also, the Gleason scoring system and the AJCC staging system has changed over the years.

• How do we maintain comparability with older clinical trials and with our databases if we change our risk stratification? Many trials were established a decade or more ago with pre-set risk groups. When the data mature, will they be hard to analyze? A similar effect occurred when biochemical recurrence after radiation was redefined by the Phoenix consensus in 2005. In many studies, both definitions were presented for a while.

• Can a stratification system from Europe gain acceptance in the US and particularly by the NCCN? How do we get widespread agreement on which system is the “gold standard.” As far as I know, the CAPRA Score is only used by UCSF, even though it is an NCCN member.

• What is the role of other biochemical measures? PHI, 4KScore, PCA3, Oncotype Dx and Prolaris all measure risk. Should any of them be used in a risk stratification system? Should first-degree relatives who have had prostate cancer be included as a risk factor? What about African-Americans? And how should PSA be counted when the patient is taking 5ARis (Proscar or Avodart) for BPH?

Patient compliance with radiation schedules

A new study by Ohri et al. (with additional information in the ASCO Post) found that for certain cancers, there was a 22% non-compliance rate at the Montefiore/Albert Einstein Cancer Center in NY. Non-compliant patients extended their total treatment time by about a week. The recurrence rate was 7% among compliant patients, but was significantly higher, 16%, among non-compliant patients. Now, the authors only looked at compliance with radiation schedules for head and neck, breast, lung, cervix, uterus and rectal cancers. Should prostate cancer radiation oncologists and their patients be concerned?

All cancers are different. It is impossible to generalize from one cancer to another. This is as true for radiation treatments as it is for medical treatments. Prostate cancer has some very unique characteristics that affect radiation treatments:

(1) Prostate cancer is very slow growing. For certain cancers like some head and neck cancers, the tumor growth is so fast that multiple radiations sessions must be scheduled each day (called hyperfractionation) in order to keep ahead of the high cancer cell repopulation rate. In fact, the repopulation rate increases as radiation progresses for such cancers. In contrast, even high-risk prostate cancers repopulate so slowly that delays of a few days to a week are insignificant. In fact, some treatment schedules for SBRT and HDR brachytherapy are a week apart with no apparent loss of efficacy.

(2) Prostate cancer responds to fewer, higher doses of radiation – hypofractionation. Prostate cancer has a peculiarly low radiobiological characteristic, called an alpha/beta ratio, which means it is killed more effectively by hypofractionated radiation. Two major randomized clinical trials have proved that shortened radiation schedules (20 fractions or 28 fractions) have equivalent effectiveness and no worse toxicity than the traditional fractionation of 40-44 treatments. The most extreme kinds of hypofractionation, SBRT and HDR brachytherapy, typically only need 4 or 5 treatments. Recent HDR brachytherapy protocols are using as few as 2 treatments. Therefore, patient compliance isn’t much of an issue. For cancers with a high alpha/beta ratio, more fractions with lower dose per fraction are needed to kill the cancer. Showing up every day for many weeks can be burdensome to the patient.

(3) Fatigue increases with the number of fractions, so reducing the number of prostate cancer treatments helps maintain vigor. With normally fractionated prostate radiation, fatigue peaks at 4-6 weeks after the start of therapy (See this link.). While fatigue scores increased a month after SBRT, it was not a clinically meaningful change (See this link.). Fatigue reported from prostate cancer radiation is less than from radiation to head and neck, alimentary and lung cancers (See this link.); therefore, non-compliance due to fatigue from radiation is probably less important for prostate cancer, particularly with hypofractionation. Other issues sometimes associated with extended fractionation include anxiety, nausea, lost days of work and financial burden. Ohri et al. found that compliance was worse among those of lower socio-economic class.

(4)    Prostate cancer’s alpha/beta ratio is much lower than the ratio attributable to healthy surrounding tissues – a therapeutic advantage. This means that prostate cancer cells are more efficiently killed by the hypofractionated regimen, but the healthy tissues of the bladder and rectum that respond quickly to radiation are not killed at all efficiently. So a total SBRT dose of, say, 40 Gy in 5 fractions, has much more cancer killing power than an IMRT dose of, say 80 Gy in 40 fractions, but less acute toxicity to healthy tissues.   This contrasts with other cancers where the alpha/beta ratio of the cancer is similar to that of nearby healthy tissues. In that case, the only way to mitigate damage to healthy tissues is to deliver the radiation in much smaller fractions, and allow time in between for sub-lethally damaged healthy tissues to self-repair. It doesn’t take long, only a few hours, but for practical purposes, treatments are a day apart.

(5) Prostate cancer is multi-focal in at least 80% of men. Tumors are almost always distributed throughout the entire prostate, so the entire organ is irradiated. This contrasts with many other cancers where there is a single large tumor growing in the organ, at least for a long time. For non-prostate cancers, it is rare for the entire organ to be treated.

(6) There are many important organs (including the bladder, rectum, penile bulb and femur) that fall, at least in part, within the radiation field. Prostate radiation requires sophisticated image-guidance and intensity modulation to treat the prostate and nothing else. Unlike radiation for other cancers where there are toxic effects due to treating the organ itself, there is almost no toxicity due to irradiation of the prostate itself (other than loss of seminal fluid). Discomfort from bladder and rectal toxicity arrives only towards the end or after the end of treatments, so there is little reason to discontinue or miss treatments.

(7) Unlike the other organ cancers that were treated in the study, the prostate is deep within the body. Higher energy X-rays are needed for that depth, and that spares closer-to-surface organs. Consequently, radiation burns of the skin rarely occur, and there is no discomfort associated with each treatment. There are exceptions in men who are hypersensitive to radiation, but burns, necrosis, and fistulas have rarely been reported.

There are some radiobiological considerations that are similar to other cancers that respond to radiation (not all of them do). Some cancer cells may self-repair sub-lethal damage to the DNA, and poor tumor-tissue oxygenation (hypoxia) may protect the tumor from radiation damage. For these reasons, it is important to deliver enough radiation to overcome the hypoxia and kill all the cancer cells. Dose escalation has improved the curative potential of radiation for prostate cancer.

An argument in favor of longer treatment regimens is that cancer cells are more vulnerable during certain phases of their cell cycle; therefore, there will be more opportunities to kill them over a longer treatment schedule. Another argument for longer schedules is that hypoxic protection of the tumor is worn away by the treatments, and subsequent growth of blood vessels around the tumor will re-oxygenate it, thus radio-sensitizing it. The greater local control we’ve seen with extreme hypofractionation suggests that it may elicit unique radiobiological mechanisms that might overcome hypoxia and cell cycle phase issues.

Because of prostate cancer’s low repopulation rate, higher quality of life during treatment, and with increasing use of hypofractionation (both moderate and extreme) there is no reason why patient compliance with prostate cancer treatment schedules should be a problem as it is for other cancers.

(Update 12/6/20) In the National Cancer Database, patient non-completion of SBRT for prostate cancer was 1.9% vs 12.5% for conventionally fractionated treatment.