Is there an optimal treatment schedule for high dose rate brachytherapy?

Protocols for high dose rate brachytherapy (HDR-BT) monotherapy vary. In recent years, practitioners have adopted various schedules for patient and physician convenience. Jawad et al. reported on the HDR-BT experience at William Beaumont Hospital. They treated 494 favorable risk patients using three different treatment schedules. Their definition of “favorable risk” was a Gleason score ≤7 and stage≤T2b and PSA≤15 ng/ml. The 3 treatment schedules they utilized, the number of patients who received each, and the relative biologically effective dose  (BED) were as follows:

1. 38 Gy in 4 fractions (n=319) – 1.29 relative BED 
2. 24 Gy in 2 fractions (n=79) – 1.00 relative BED 
3. 27 Gy in 2 fractions (n=96) – 1.25 relative BED

Dose schedules #1 and #3 delivered much higher relative dose compared to dose schedule #2. The questions addressed by the study are whether the higher dose is justified by greater cancer control, and whether dose increased at the expense of increased side effects.

After 5.5 years median followup for schedule #1, 3.5 years for schedule #2, and 2.5 years for schedule #3, the toxicity outcomes were as follows:

• No difference in clinical outcomes (cancer control) among the 3 treatment schedules.
• Acute (appearing in less than 6 months) and chronic (appearing 6 months or more after treatment) grade ≥2 genitourinary (GU) and gastrointestinal (GI) side effects were similar for all treatment schedules.
• Grade 2 acute GU toxicities:

o   Frequency/urgency: 14%

o   Dysuria (painful urination): 6%

o   Retention: 7%

o   Incontinence: 1.5%

o   Hematuria (blood in urine): 1.5%

• ·      Grade 2 chronic GU toxicities:

o   Frequency/urgency: 20%

o   Dysuria (painful urination): 7%

o   Retention: 4% (Urethral stricture: 2%)

o   Incontinence: 2%

o   Hematuria (blood in urine): 7%

• ·      There was minimal grade 3 GU toxicity
• ·      Grade 2 acute GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: <1%

o   Rectal bleeding: 0%

o   Proctitis: <1%

• ·      Grade 2 chronic GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: 0.5%

o   Rectal bleeding: 2%

o   Proctitis: 1%

• ·      No Grade 3 or higher GI toxicity
• ·      Time to maximal appearance of symptoms was similar across treatment schedules
• ·      They did not report ED rates, which are typically low for HDR-BT.

Given the equivalence of cancer control and toxicity with treatment schedule, and the lack of any effect due to increasing the biologically equivalent dose, there seems to be little basis, other than cost and convenience, for choosing among these treatment schedules, at least with the available follow-up reported here.

Aspects of treatment scheduling that affect the convenience of HDR-BT are the number of implantations of the catheters, and the time frame in which the fractions are delivered.  William Beaumont Hospital uses a single implantation of catheters for all treatment schedules. Schedule #1 involves a longer (overnight) hospital stay because they wait for several hours between fractions for healthy tissue to recover. It also means that anesthesia must be administered over a longer period.

The California Endocurietherapy Center at UCLA has typically used a different protocol. They deliver 42 Gy in 6 fractions, with 3 fractions delivered one week and 3 fractions delivered a week later. This involves 2 overnight hospital stays, with anesthesia each time. Recently, they added a protocol where they deliver 27 Gy in 2 fractions (similar to schedule #3), but those fractions are still inserted a week apart. While this is certainly a cost reduction for the patient, who can now be treated as an outpatient, the patient is inconvenienced by having to go through the full procedure twice. It is a convenience for the treatment team that no longer has to attend the patient over an extended timeframe.

The William Beaumont Hospital experience demonstrates that HDR-BT treatment schedules can be constructed so as to lower costs and increase convenience for patients and doctors, without sacrificing cancer control or quality of life.

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.

Longer time between treatments reduces SBRT rectal toxicity.

There are many details of Stereotactic Body Radiation Therapy (SBRT) that may be optimized over the coming years. Among them is the optimum treatment schedule – how far apart should the treatments be spaced?

With radiation therapy of some rapidly growing cancers, there have to be multiple treatments each day. Prostate cancer is very slow growing in early stages, so the frequency of treatment is less a matter of oncological control, and more a matter of reducing toxicity.

Healthy tissue apoptosis or self-repair is thought to occur remarkable quickly after radiation, the self-repair half-life is less than two hours after treatment. This was the logic behind the treatment schedules devised for high dose rate (HDR) brachytherapy where there may be two or three treatments with only a break of several hours in between them. HDR brachytherapy has remarkably low levels of associated urinary, rectal and sexual toxicity in spite of the intense and frequent doses. It was originally thought that with SBRT, which is radiologically modeled upon HDR brachytherapy, the treatment schedule would not make much of a difference.

In a five-year follow-up study of 67 patients, King et al. found there was an increase in the most severe (Grade 3) late urinary toxicity from 3% in those treated every other day to 6% among those treated 5 days in a row, but the difference was not statistically significant, and the numbers were small. The differences were more marked in the lower grade late toxicity: Grade 1 and 2 urinary toxicity was 56% among those treated 5 days in a row and 17% if they were treated every other day. Low-grade late rectal toxicity was 44% on the everyday schedule but only 5% when treated every other day.

In a randomized clinical trial, Quon et al. studied the effects of two very different SBRT treatment schedules. They define acute toxicities as those appearing in the first 3 months following treatment; late term effects crop up later than 3 months, but usually appear within the first two years of treatment. Both acute and late-term effects are typically transient. This was an interim analysis. They randomly assigned 152 favorable risk men treated with SBRT (40 Gy across 5 treatments) at 3 Canadian centers to either of two arms:

1.      11 day arm - 5 treatments, every other day (excluding weekends), across 11 days

2.      29 day arm - 5 treatments, once per week, across 29 days

Patients self-evaluated their urinary, rectal and sexual function using the EPIC questionnaire. To help distinguish small differences, the researchers determined the% of patients whose EPIC scores increased (worsened) by half of a standard deviation or more from baseline – they labeled this a minimally clinically important change (MCIC). Their doctors also graded their urinary and rectal morbidities using RTOG/CTCAE 4.0 criteria. This interim analysis had a median of follow-up of 13.1 months. Table 1 below shows the toxicities and the MCIC for each group. It may be that not all Grade1 symptoms were reported by patients because they were expected, mild, and transient; also, some patients had mild symptoms at baseline, so I lumped together Grade 0 and Grade 1.

Table 1: Toxicity of shorter vs. protracted SBRT schedule

	11 day arm % of patients	29 day arm % of patients
Acute rectal toxicity
Grade 0/1	82	89
Grade 2	18	11
Grade 3	0	0
MCIC	90	75
Acute urinary toxicity
Grade 0/1	67	63
Grade 2	32	34
Grade 3	1	3
MCIC	96	75
Late rectal toxicity Grade 3	0	0
Late urinary toxicity Grade 3	1 patient	0

The study found :

·        Severe (Grade 3) toxicity was extremely rare

·        Acute toxicity was low (mostly, under Grade 2) in both arms.

·        Acute Grade 2 rectal toxicity was higher in the 11-day arm.

·        Acute Grade 2 urinary toxicity was not statistically different between arms.

·        MCICs, urinary and rectal, were lower (better) in the 29-day arm.

·        There were no differences between the two arms in sexual or hormonal effects.

·        So far, late toxicity has been low and not significantly different in both arms.

Although the authors defined MCIC to detect short-term decline in urinary and rectal function, King et al. (2013) found that those effects soon subsided, and there was a return to baseline function.

Grade 2 acute rectal symptoms were much higher in the 11-day Canadian arm compared to similar treatments at other institutions. This may be attributable to the higher dose used in the Canadian study. Acute Grade 2 urinary symptoms were significantly higher than the Katz study, but comparable to the Georgetown experience. Katz and Georgetown used lower doses (35/36.5 Gy vs. 40 Gy) and tighter treatment margins (2 mm vs. 5 mm) compared to the Canadian study.

Table 2: Toxicity reported in different SBRT studies: Canada, Katz, Georgetown

	Canada 11 day arm (40 Gy) % of patients	Katz (35 Gy) % of patients	Georgetown (35/36.25 Gy) % of patients
Acute rectal toxicity			(at one month)
Grade 0/1	82	96	95
Grade 2	18	4	5
Grade 3	0	0	0
MCIC	90
Acute urinary toxicity			(at one month)
Grade 0/1	67	96	64
Grade 2	32	4	35
Grade 3	1	0	0
MCIC	96
Late rectal toxicity Grade 3	0	0	0
Late urinary toxicity Grade 3	1 patient	0	0

Although spreading out treatments across 29 days instead of 11 days appears to reduce acute rectal toxicity, toxicity is nonetheless low grade. It is possible that small reductions in dose, or tighter treatment margins, may be made without sacrificing oncological control, and may be a better solution than spreading out the treatment intervals. Concerns about convenience may outweigh concerns about low-grade rectal toxicity for the patient, and such decisions are best left to a shared decision between patient and doctor.