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.

Androgen deprivation followed by androgen supplementation may increase the efficacy of radiotherapy

We have seen the ability of androgen deprivation to increase the efficacy of high dose IMRT in controlling prostate cancer (see this commentary). A new study from Johns Hopkins turns conventional logic on its head by demonstrating that sequential androgen deprivation and androgen repletion may be optimal for enhancing the therapeutic efficacy of radiation in prostate cancer… at least in mice.

I don’t often comment on lab studies because what works in the mouse world often does not work when tested in humans. Johns Hopkins has been a leader in exploring the possibility of androgen sequencing, and is currently conducting a trial of “bipolar androgen therapy (BAT)” in men undergoing lifelong ADT for advanced cancer (see this commentary).

Haffner et al. discovered that androgens, like testosterone or DHT, can activate an enzyme (TOP2B) that induces double-strand breaks (breaks on both sides of the double helix) in the DNA of prostate cancer cells that express the TMPRSS2:ERG fusion gene.  This gene has been implicated in prostate cancer development and has been detected in about half the cases of prostate cancer. Coincidentally, double-strand breaking is exactly how radiation kills cancer cells. They hypothesized that after androgen deprivation is used to kill off those cancer cells susceptible to it, that restoring androgens combined with ionizing radiation might increase the therapeutic potential over radiation alone. Hedayati et al. report that this is exactly what happened in mice.

This may or may not eventually translate into protocol changes in radiation therapy, but at the very least it gives us a healthy appreciation for the very complex biochemical machinery involved in cancer genesis and therapeutics.

Written February 4. 2016

SBRT Registries

Patient registries are potentially a rich source of information with which to evaluate outcomes. They often include patient characteristics, details of the therapies they received, and outcomes tracked over time. They provide full population data of all patients treated at participating centers, and can provide very large amounts of data over time.

Like a clinical trial, there are specific and uniform definitions used in capturing patient and treatment data, allowing for comparability on a variety of variables. Registries and clinical trials are internal review board (IRB) approved for ethical standards and must comply with HIPAA laws (patients must consent, and patient names are not entered in). In the US, they both have an insurance advantage as well: Medicare, Medicaid and insurance companies may cover the costs of clinical trials and registries for treatments that they would not ordinarily cover. In some situations, they will only provide coverage if the patient is enrolled in a registry or clinical trial.

Unlike a clinical trial, there are usually no detailed patient inclusion and exclusion criteria, and the treatments may vary from center to center and from patient to patient. Because patients are not excluded from the database, registries are capable of providing very large databases for analysis. There is no randomization, so there is selection bias – patients who received different treatments may have been selected for specific reasons. The quality of the data is only as reliable as the clinician entering it, and it is not necessarily subject to peer review as publication of clinical trial results are. As with other large database analyses, it may be possible to find matched cases for control, but that is not the same as randomization. While clinical trials have a hypothesis to be proved or disproved, a registry provides data for quality improvement and for generating hypotheses.

Registries are difficult and expensive to establish and maintain. The American Board of Radiology attempted to create a national brachytherapy registry, but abandoned those efforts in 2015 when issues in its development and implementation “proved to be more daunting and costly than initially anticipated.” In 2012, the American Society of Radiation Oncologists (ASTRO) announced plans to implement a National Radiation Oncology Registry (NROR) with Prostate Cancer as its first focus. A pilot was completed in June 2015, and there are plans for expansion.

The Registry for Prostate Cancer Radiosurgery (RPCR) was established in 2010. There are 45 participating sites in the US, and the database included nearly 2000 men as of 2014. They collect three kinds of data for each patient: screening, treatment, and follow-up.

Screening data include age, performance status, rationale for radiosurgery, initial TNM stage, Gleason score, number of positive biopsy cores, use of hormonal therapy, and several baseline measures, including pre-treatment PSA, IPSS, International Index of Erectile Function (IIEF-5) score, Bowel Health Inventory score, and Visual Analog pain score.

Treatment data include radiation delivery device details, treatment dates, dosimetry (e.g., doses, schedules, targets, margins, including doses to specific organs at risk: rectum, bladder, penile bulb, and testicles), and how image tracking was performed.

Follow-up data include periodic tracking of the baseline data collected at screening, as well as physician-reported toxicity. RPCR encourages sites to record follow-up data every 3 months for the first 2 years following SBRT treatment and every 6–12 months thereafter, for a minimum of 5 years.

Some interim findings have been published by Freeman et al. So far, they have only reported 2-year data on 1,743 patients. Oncological control was reported as biochemical disease-feee survival:

·      Low Risk: 99% (n=111)

·      Favorable Intermediate Risk: 97% (n=435)

·      Unfavorable Intermediate Risk: 85% (n=184)

·      High Risk: 87% (n=168)

There was no severe late-term urinary toxicity, and one patient developed severe late-term rectal bleeding. Erectile function was preserved in 80% of men under 70 years of age, and 55% of men over 70.

The other SBRT registry is called the Radiosurgery Society Search Registry (RSSearch Registry) and includes data from 17 community centers treating prostate cancer patients. There were 437 prostate cancer patients enrolled between 2006 and 2015. The data collected is similar to the RPCR Registry. All patients in their first report were treated using the CyberKnife platform (this registry was originated by Accuray, the manufacturer of CyberKnife), although they allowed other platforms in later enrollments.

Davis et al. recently reported their interim findings. Oncological control was reported as 2-year biochemical disease-fee survival:

·      Low Risk: 99.0% (n=189)

·      Intermediate Risk: 94.5% (n=215)

·      High Risk: 89.8% (n=33)

There was no severe (grade 3) acute urinary or rectal toxicity, and very little grade 2. There was no severe (grade 3) late-term urinary or rectal toxicity. The highest incidence of grade 2 late term symptoms was 8% with urinary frequency, They did not collect baseline data on sexual function.

Both of these registries are administered by Advertek. The results of the RSSearch Registry were reported in Cureus, which is their own publication. RPCR results were published in Frontiers in Oncology, which is an independently peer-reviewed journal. It is important to note this because questions about the reliability of the data may arise.

If these data look a little too good to be true… well, let’s dig a little deeper. The biochemical disease-free survival figures only reflect 2 years of follow-up. In that short amount of time, many patients have not yet reached their nadir PSA let alone had time to rise 2 points above that nadir. Most of the low-risk patients and many of the intermediate-risk patients would not have had a rise of 2 points in their PSA even if they’d had no treatment.

The toxicity data are very suspect. Unlike a clinical trial where experienced researchers are carefully evaluating patients on a regular schedule, patient evaluations by community clinicians are haphazard. The clinicians may introduce affirmation bias into their assessments – they have incentive to make their numbers look good. The best way to evaluate toxicity is with patient-reported outcomes on validated, guided-response questionnaires, like EPIC. This was not done in either of these registries. 

I think SBRT is actually quite a good therapy (I chose it for myself!), but we have to look to other sources for more reliable data. With longer term follow-up, the cancer control data from these registries may become more reliable, and may help us generate better hypotheses about which treatment variants work best and on which patient groups.

Infection from fiducial placement

Most of us who have gone through image-guided external beam radiotherapy have had TRUS-guided transrectal placement of gold fiducial markers or radio transponders placed in out prostates. Some who have had salvage radiation have had them placed in the prostate bed. Fiducial placement carries a risk of infection, a risk that may be growing because of increased resistance to fluoroquinolone antibiotics. The procedure is similar to a transrectal biopsy, and carries many of the same risks.

Loh et al. reported the results of an Australian study among 359 patients who had fiducials placed between 2012 and 2013. All patients had received standard prophylactic fluoroquinolone antibiotics. The men were all sent a brief questionnaire within 2 years of the procedure. Responses were confirmed based on patient records. They got a very good response rate (79%) with the following findings:

• ·      27% experienced increased urinary frequency and dysuria
• ·      11.6% experienced chills and fever
• ·      7.7% received subsequent antibiotics for urinary tract infection
• ·      2.8% were admitted to the hospital for sepsis

A similar study by Berglund et al. of Calypso radio transponder placement in 50 men reported that 10% had subsequent infections, with 6% going on antibiotic therapy. One patient suffered an epidural abscess that required open debridement and lumbar fusion. One patient suffered a prostate abscess with MRSA.

This rate of infection is higher than what is reported by physicians, which is 1.3% or less, but is consistent with current infection rates reported after transrectal biopsies. Liss et al. reported biopsy-related resistant infections of 8% among men who received only fluoroquinolone prophylaxis and 6% were hospitalized. Almost all of them were found to have fluoroquinolone-resistant infections. Rectal culture of all the men in the study revealed fluoroquinolone-resistant bacteria, predominantly E. coli, in 1 in 5 men. The rate of infection has been steadily increasing. Resistant E. coli infections can cause potentially fatal septic shock and intractable chronic prostatitis.

Loh et al. go so far as to recommend that radiation oncologists forgo the use of fiducials for IMRT (but not for SBRT). They point to a dosimetry study that showed that the difference in prostate localization without fiducials was almost always less than 5 mm. However, it also showed differences could be as high as 1 cm. It is the extremes of motion that fiducial image guidance controls for so well, and it is those extremes that accounts for most of the toxicity.

There are less radical measures that can be taken:

• ·      Careful screening of patients for previous fluoroquinolone use, major surgeries with antibiotics, hospital workers and their families, diabetes and other comorbidities that may increase risk of infection. Men with a number of previous biopsies, as may happen with Active Surveillance, are especially susceptible.
• ·      Rectal swab culture for resistant bacteria, and selection of more specific antibiotics based on it.
• ·      Use of a different class of prophylactic antibiotic, like aminoglycosides, Flagyl, clindamycin, Bactrim, amoxicillin or carbapenems.
• ·      Applying povidone-iodine to clean the rectum (as in this study).
• ·      Transperineal fiducial placement carries insignificant risk of infection, but may require a spinal block or local anesthesia.

Patients should raise this concern with their doctors prior to fiducial placement. As someone who got a UTI from fiducial placement, I wish, in hindsight, that I had.

Extraprostatic extension (EPE) alone is not enough to justify adjuvant radiation

Patrick Walsh and Nathan Laurentschuk wrote an opinion piece in European Urology taking issue with the 2013 AUA/ASTRO recommendation that adjuvant radiation is indicated for men with a pathological finding of extraprostatic extension (EPE, stage pT3a) after surgery, regardless of the surgical margin status. The combination of EPE and negative surgical margins is the most common adverse finding, accounting for 60% of them. Therefore, the AUA/ASTRO guideline would lead to gross overtreatment if it were followed. They believe that it is fortunate that that guideline is increasingly ignored (see this commentary).

They looked at the three randomized clinical trials of adjuvant radiation vs. wait-and-see, for evidence that EPE alone justified adjuvant radiation.

• ·      Although it concludes that all patients with EPE should have adjuvant radiation, SWOG 8794 never looked at that subgroup separately.
• ·      In ARO 96-02, men with EPE and negative margins received no statistically significant benefit in terms of freedom from biochemical failure from adjuvant radiation.
• ·      Not only was there no benefit, but EORTC 22911 found a 78% increased risk of dying among men with EPE and negative margins who received adjuvant radiation.

They conclude with a set of recommendations about adjuvant radiation:

“Who should NOT receive it:

 • Men with extraprostatic extension (capsular penetration) with negative margins

 • Men aged >70 yr unless they are very healthy and have high grade or positive margins

 • Men with bladder neck contractures or significant incontinence who have marginal indications

Who should receive it:

 • Men with Gleason ≥7 with positive surgical margins

Marginal benefit:

 • Men with positive seminal vesicles

In a commentary published in Practice Update, Christopher King, a radiation oncologist at UCLA, takes tissue with their recommendations. He argues that until the findings of randomized clinical trials provide more reliable data, current evidence does not justify adjuvant radiation based only on adverse pathology. Instead, based on several retrospective studies (reviewed on this site), he advocates waiting for some evidence of measurable disease. He believes that early salvage (before PSA rises above 0.2 ng/ml) will have equivalent oncological outcomes to adjuvant radiation, but will avoid the toxicity of overtreatment.

SBRT Boost Therapy

Recently we have seen evidence of improved cancer control in high-risk patients treated with external beam radiotherapy with a brachytherapy boost to the prostate. This has been demonstrated with both HDR brachytherapy boost and with LDR brachytherapy boost. Can the same cancer control be obtained with IMRT and an SBRT boost to the prostate?

Anwar et al. reported the outcomes of 48 intermediate and high-risk patients treated with SBRT boost therapy between 2006 and 2012 at UCSF. 71% (34 patients) were high risk, 39% (14 patients) were intermediate risk.

The treatment consisted of:

• ·      IMRT: 45-50 Gy in 25 fractions to the entire pelvis if the risk of lymph node involvement was > 15%, otherwise with a 1 cm margin.
• ·      SBRT boost: 9.5 or 10.5 Gy in 2 fractions to the prostate, seminal vesicles + a 2 mm margin, 0 mm on the rectal side.
• ·      Heterogeneous planning was used to mimic HDR brachytherapy dosimetry.
• ·      Gold fiducials were used for daily (IMRT) and intra-fractional (SBRT) image tracking.
• ·      Intermediate risk patients had 4-6 months of adjuvant hormone therapy.
• ·      High-risk patients had up to 2 years of adjuvant hormone therapy

After a median of follow-up of 42.7 months, they reported the following results:

• ·      5-yr  biochemical no evidence of disease: 90%
• ·      PSA nadir (median): 0.05 ng/ml
• ·      2 patients had a PSA bounce over 2 ng/ml, which declined with longer followup
• ·      4 patients had a clinical recurrence outside of the radiation field
• ·      Local control (within the radiation field) was 100%.
• ·      Acute toxicity:

o   Urinary, grade 2: 17%

o   Rectal, grade 2: 10%

• ·      Late toxicity:

o   Urinary, grade 2: 25%; grade 3: 1 patient

o   Rectal, grade 2 or higher: none

Clearly, these are excellent results for cancer control.  The table below shows outcomes in similar trials of SBRT boost treatments and of SBRT monotherapy.

	Anwar et al. SBRT boost	Katz & Kang SBRT boost	Katz & Kang SBRT monotherapy	Lin et al. SBRT boost
Risk levels treated (# of patients)	Intermediate (14) High (34)	High (45)	High (52)	High (41)
Relative BED*	1.27-1.52	1.13-1.17	1.06-1.13	1.17
ADT used	88%	62%	50%	100%
Biochemical Disease-free survival	90% at 5 years	70% at 5 years	68% at 5 years	92% at 4 years
Late-term urinary toxicity	27%	5%	12%	none

* Biologically Effective Dose for cancer control relative to 80 Gy in 40 fractions

Compared to these other small trials, Anwar et al. used significantly higher effective radiation doses and got perhaps better control (remembering that almost a third were intermediate risk), but late-term urinary toxicity was high. Lin et al. used lower doses, had similar control in their all high-risk group trial at 3 years, and none suffered from late-term urinary toxicity. Katz treated consecutive high-risk patients with SBRT boost and with monotherapy, respectively, but had the same cancer control in both groups, and the late-term urinary toxicity was not significantly different. Katz concluded that the SBRT boost accomplished nothing compared to the monotherapy, and also found that ADT use did not contribute to cancer control in his patients. He treated all subsequent high-risk patients with SBRT monotherapy only and without ADT.

We can also look at the Anwar outcomes next to those of a recent LDR brachy boost therapy trial and an HDR monotherapy trial in the table below.

	Anwar et al. SBRT boost	ASCENDE-RT LDRBT boost	Hoskin et al. HDR-BT monotherapy
Risk levels treated (# of patients)	Intermediate (14) High (34)	Intermediate (122) High (276)	Intermediate (103) High (86)
Relative BED*	1.27-1.52	1.21	1.21-1.35
ADT used	88%	100%	80%
Biochemical Disease-free survival	90% at 5 years	Int.Risk-94% High Risk-83% at 7 years	Int.Risk-95% High Risk-87% at 4 years
Late-term urinary toxicity	25% Grade 2 2% Grade 3	NA Grade 2 18% Grade 3	19% Grade 2 10% Grade 3

SBRT boost therapy seems to provide similar rates of cancer control, but with less late term urinary toxicity compared to brachy boost therapy or HDR-BT monotherapy.

In an interesting twist, Memorial Sloan Kettering Cancer Center is running a clinical trial of SBRT supplemented with an LDR-BT boost to the prostate in intermediate-risk men (NCT02280356). I would guess that this would have considerable toxicity, but the clinical trial will prove or disprove that hypothesis.

So far, trials of SBRT boost therapy are too small to draw anything but provisional conclusions. There is a larger trial nearing completion at Georgetown University Hospital next month. Based on these pilot studies, SBRT boost therapy seems to be capable of providing good cancer control in high-risk patients and may be able to accomplish that with less toxicity than brachytherapy-based treatments. As we’ve seen, SBRT monotherapy and HDR brachy monotherapy are emerging therapies for high-risk patients as well. It would certainly be a lot more convenient to accomplish the same cancer control, at lower cost, and with perhaps less toxicity using just 5 SBRT monotherapy treatments instead of 27 treatments with SBRT boost. Only a randomized comparison clinical trial can tell us whether one therapy is better than another. The most appropriate radiation dose level, dose constraints, the size of margins, lymph node treatment, and whether adjuvant ADT provides any benefit are variables yet to be determined.

This is an area of active investigation. If readers are interested in participating in a clinical trial of SBRT boost therapy, below is a list of open trials and their locations:

Fountain Valley, CA (NCT02016248)

Sacramento, CA (NCT02064036)

San Francisco, CA (NCT02546427)

Miami, FL (NCT02307058)

Park Ridge, IL (NCT01985828)

Boston, MA (NCT01508390)

Madison, WI (NCT02470897)

21^st Century Oncology- Scottsdale, AZ, Ft. Myers and Plantation, FL, Farmington Hills, MI, Myrtle Beach, SC (NCT02339948)

Sydney, Australia (NCT02004223)

Gliwice, Poland (NCT01839994)

Poznan, Poland (NCT02300389)