Is once ever enough?

When Jeff Demanes at the California Endocurietherapy Center, then in Oakland, CA, started doing high dose rate brachytherapy (HDRBT) as a monotherapy (i.e., without any additional external beam therapy or hormone therapy), he arbitrarily chose a treatment schedule of 42 Gy delivered in 6 treatments or fractions. The first 3 fractions were given in one overnight hospital stay after a single insertion of the catheters, which stayed in place for all 3 fractions. Then the whole process was repeated a week later. At the same time, Alvaro Martinez, then at William Beaumont Hospital in Detroit, MI, arbitrarily chose 38 Gy in 4 fractions (twice a day for two days). Although the biologically effective dose (BED) is somewhat higher for the 4-fraction schedule, they had equally excellent oncological and quality-of-life outcomes. This established that prostate cancer responded to fewer larger doses (hypofractionation) -- an intrinsic quality of the cancer, called a low alpha/beta ratio.

Over the years, alternative treatment schedules that might be more convenient for patients were tried. Last year, we saw that 27 Gy delivered in 2 fractions afforded equivalent outcomes to a high fraction schedule (see this link). Several new studies show that HDRBT can be delivered in just a single fraction without causing any extra side effects for the patient. A single fraction translates to a much lower cost treatment, with the added convenience of no prolonged hospital stays, less time under anesthesia, and quicker recuperation. It also means that a patient can travel to a central location for a one-day treatment with no costs incurred for hotels, and without taking a week off from work.

Morton et al. at Sunnybrook Cancer Center in Toronto randomized 170 low- and intermediate-risk patients to either the one- or two-dose schedule. With median follow-up of 20 months, they reported:

• Acute grade 2 urinary toxicity: 51%; grade 3 in one patient
• No significant difference between the 1- and 2-dose schedule
• Acute grade 2 rectal toxicity: 1%
• Chronic grade 2 urinary toxicity: 31%; grade 3 in one patient 
• No significant difference between the 1- and 2-dose schedule
• Chronic grade 2 rectal toxicity: none
• There was no grade 3 rectal toxicity.
• Grade 2 ED rates were 29% for the 2-fraction arm, 11.5% for the single fraction arm.
• Sexual domain scores on the EPIC questionnaire declined by twice as much in the 2-fraction arm.

(note: physician-reported toxicities may be higher when patients are probed about specific issues using the EPIC questionnaire.)

(Update 11/16/2017) In an update, 8 of the 87 (9%) of the patients treated with a single fraction were found to have a local recurrence, and 7 of those 8 patients still had cancer in exactly the same place that was treated initially, and it was more aggressive than the initial Gleason score. Close inspection of the treatment plan showed that the dose received in that place was very high. While the authors conclude that the dose needed to be even higher, I believe it is more likely that the degree of fractionation was inadequate for the reasons explained below (cancer cells in the "S-phase" of mitosis and hypoxia).

(Update 9/15/2020) In a longer-term update of the same trial, a third suffered biochemical failure within 5 years, and 78% were biopsy-confirmed local failures. They also held a trial among 60 patients who received a single fraction of HDR brachytherapy but with a focal boost of at least 23 Gy to the largest prostate tumor. Those patients fared no better.

(Update 3/12/2021) Gomez-Itturiaga et al. reported the results of 44 low and intermediate-risk patients treated with a single 19 Gy fraction of HDR brachytherapy. After 4 years of median f/u, 14 patients (32%) experienced biochemical relapse, and 11 were confirmed to have relapsed in the dominant lesion. 

Hoskin et al. at Mt. Vernon Hospital, Middlesex, UK treated 165 patients: 115 with the 2-dose schedule, 24 with a single 19 Gy dose, and 26 with a single 20 Gy dose.

• At two weeks after treatment, severe prostate/urinary symptoms were higher among those who received the 20 Gy dose.
• Acute catheter use was higher among those getting a single dose (21% and 29% for 19 Gy and 20 Gy, respectively) compared to those receiving the split dose (3%)
• By 12 weeks after treatment, all scores were at baseline or better.
• Acute grade 3 urinary symptoms occurred in about 9% of patients.

Update: Hoskin et al. updated their study:

• 4-year biochemical recurrence-free survival was no different for the single fraction group (94%)
• Late term serious side effects were 2% urinary and none for rectal

Prada et al. reported on 40 low- and intermediate risk patients treated in Spain with a single 19 Gy fraction. They also all received a hyaluronic acid rectal spacer. With 19 months of median follow-up:

• There was no acute or chronic grade 2 or higher urinary or rectal toxicity
• Biochemical control at 32 months was 100% for low risk patients, and 88% for intermediate risk patients.

In an update on 60 patients, they reported that 6-year biochemical control was only 66%.

Siddiqui et al. treated 68 low and intermediate-risk patients at William Beaumont Hospital with a single dose of 19 Gy using HDRBT. With median follow-up of 3.9 years, the outcomes were as follows:

• Acute grade 2 urinary toxicity: 12.1%
• Acute grade 2 rectal toxicity: none
• Chronic grade 2 urinary toxicity: 14.7%
• Chronic grade 2 rectal toxicity: 3%
• There was no grade 3 toxicity.
• They did not report ED rates.
• 5-year disease-free survival: 77%
• 5-year biopsy-proven local failure:19%

The authors conclude:

Higher than expected rates of biochemical and local failure, however, raise concerns regarding the adequacy of this dose. Additional investigation to define the optimal single-fraction HDR brachytherapy dose is warranted, and single-fraction treatment should not currently be offered outside the context of a clinical trial.

(Update 11/23/2019) Barnes et al. reported the outcomes of a single 19 Gy fraction on 28 patients who were primary low-risk (14), and favorable intermediate-risk (10). After 2 years of median follow-up:

• 3-yr biochemical failure-free survival was 81%
• Acute grade 2 urinary toxicity=18%; grade 3 urinary=4% (1 case)
• Late-term grade 2 urinary toxicity= 18%; none grade 3
• No grade 2 or higher rectal toxicity, acute or late-tern

In addition to patient convenience, there is another reason that toxicity may be lower with a single dose: every time the patient moves between fractions, the catheters are dislocated into a slightly different position. Such movement puts radiation in areas that were not part of the pre-treatment simulation, so that organs at risk (e.g., bladder, rectum, and urethra) may receive a higher dose than planned. Use of fiducials and cone-beam CT between each fraction can mitigate this effect.

The sexual side effects deserve closer scrutiny; but otherwise, so far, so good. So why not just treat all patients with one dose of 19 Gy? For that matter, why not do that with SBRT? That would only entail a single painless, anesthesia-less short treatment - one and done, why not?

Radiobiological reasons for fractionation

The big outstanding question is whether cancer control will be as good with a single dose. At 10 years after treatment, Demanes reported biochemical control of 99% among low-risk patients, and 95% among intermediate-risk patients using his 6-fraction regimen. Most of the above studies of single-fraction HDRBT had only had very short follow-up. The longest follow-up was the Prada et al. update, which showed that after 6 years, biochemical control was only 66%.  However, the 4-year Hoskin et al. update showed biochemical control at 94%. It's unclear why those two studies would be so different. The William Beaumont Hospital trial of single dose HDRBT already had 7% biochemical failures at 3 years, and the Washington University study found a 19% failure rate at  3 years. Is this just patient selection, or does it reflect a failure of the treatment?

It's worth reviewing the reasons why fractionated radiation can fail; it's called the 5 R's of radiobiology: repopulation, repair, redistribution, re-oxygenation, and radioresistance.

Repopulation doesn't apply when cancer is slow-growing as prostate tumors are. It is a consideration for rapidly growing tumors, like head and neck cancers. In such cancers, ablation of some tumor tissue may actually speed up the growth of the rest. Very frequent treatments (hyperfractionation) is needed in such cases.

Repair refers to the fact that the cancer that was not lethally damaged can re-grow between treatments and even during treatments. This may be a problem for low dose rate brachytherapy because the prolonged damage may be sublethal. Some researchers in Sweden recently questioned whether the relatively long CyberKnife treatments (which may take an hour per fraction) may allow for some to occur during each treatment. (This concern would not apply to SBRT delivered on other platforms or to HDRBT.)

Redistribution refers to cell cycles that cancer cells go through as they duplicate their DNA and divide in a process called mitosis. One phase of the cell cycle, called the S-phase, is where DNA repair and replication occurs. Cells are less sensitive to the lethal effects of radiation during the S phase, and some portion of cancer cells are in the S-phase at any given moment. Fractionation increases the odds that cancer cells will not be in the S-phase across all the times radiation hits them. With a single dose, the odds of some cells being in a radioresistant phase are higher.

Re-oxygenation refers to the fact that oxygen is required for radiation to kill cancer cells. Tumors are relatively hypoxic (low oxygen environments) compared to healthy tissue, because their blood supply is often malformed and leaky. This means that cancer cells in the center of a large tumor may lack the oxygen needed for radiation to kill them. With each fraction, the radiation kills the cells at the surface of the tumor that may have a better blood supply. And with repeated fractions, layers of surface cells are stripped away until the tumor is gone. A single dose may not be optimal when the index tumor is large.

Radioresistance means that some kinds of cells, particularly those that don't replicate quickly, like nerves and muscle, are inherently less subject to lethal radiation damage. Like many slow-growing tissues, prostate cancer is known to be radioresistant. That's why dose escalation has been necessary to cure it. 19 Gy in a single dose actually exceeds the biologically effective dose of 42 Gy in 6 fractions, so it is probably more than enough to overcome any radioresistance.

It may not be feasible to deliver 19 Gy in one fraction to every patient. Because of variations in individual pelvic anatomy, visceral fat and prostate size, a large single dose may violate the dose constraints for organs at risk.

It will be a few more years before the above clinical trials have matured enough to tell us whether the single dose treatment is adequate for the job. Until then, it is prudent to use a fractionated treatment schedule.