Is once ever enough (in prostate radiation therapy)?

When Jeff Demanes at the California Endocurietherapy Center, then in Oakland, CA, started doing high-dose-rate brachytherapy (HDR-BT) 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 six treatments or fractions. The first three fractions were given in one overnight hospital stay after a single insertion of the catheters, which stayed in place for all three 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 four fractions (twice a day for 2 days). Although the biologically effective dose (BED) is somewhat higher for the four-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 (α/β) ratio.

Over the years, alternative treatment schedules that might be more convenient for patients have been tried. Last year, we saw that 27 Gy delivered in two fractions afforded equivalent outcomes to a high fraction schedule (see this link). Several new studies show that HDR-BT 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 of 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 the two-dose schedule. With a median follow-up of 20 months, they reported:

  • Acute grade 2 urinary toxicity: 51 percent; grade 3 in one patient
    • No significant difference between the one- and two-dose schedule
  • Acute grade 2 rectal toxicity: 1 percent
  • Chronic grade 2 urinary toxicity: 31 percent; grade 3 in one patient
    • No significant difference between the one- and two-dose schedule
  • There was no acute or chronic grade 2 or grade 3 rectal toxicity.
  • Grade 2 rates of erectile dysfunction were 29 percent for the two-fraction arm, 11.5 percent for the single fraction arm.
  • Sexual domain scores on the EPIC questionnaire declined by twice as much in the two-fraction arm.

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

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

  • At 2 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 percent and 29 percent for 19 Gy and 20 Gy, respectively) compared to those receiving the split dose (3 percent)
  • By 12 weeks after treatment, all scores were at baseline or better.
  • Acute grade 3 urinary symptoms occurred in about 9 percent of patients.

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 hydrogel 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 percent for low-risk patients, and 88 percent for intermediate-risk patients.

Krauss et al. treated 63 low- and intermediate-risk patients at William Beaumont Hospital with a single dose of 19 Gy using HDR-BT. With median follow-up of 2.9 years, the outcomes were as follows:

  • Acute grade 2 urinary toxicity: 12.1 percent
  • Acute grade 2 rectal toxicity: none
  • Chronic grade 2 urinary toxicity: 10.3 percent
  • Chronic grade 2 rectal toxicity: 3 percent
  • There was no grade 3 toxicity.
  • They did not report ED rates.
  • 3-year biochemical control: 93 percent

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

All of the above studies have only had very short follow-up. 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 percent among low-risk patients, and 95 percent among intermediate-risk patients using his six-fraction regimen. The William Beaumont Hospital trial of single-dose HDRBT already had 7 percent biochemical failures 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 Rs 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 HDR-BT.)

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. A single dose of 19 Gy actually exceeds the biologically effective dose of 42 Gy in six 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.

Editor’s note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.





4 Responses

  1. I thank you for the information. It made me confused a bit, however. If three doses could be given in 1 day, then I don’t see the point in arguing about a difference in length of treatment in a choice between one and two fractions as to convenience for the patient.

    Further, I really believe in simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL). This concept gives a higher dose to the tumor than to the rest of the prostate, as generally the DIL is the lesion that causes the metastases. The SIB concept demands an image-guided treatment.

    Third we have a large study from SKCC where combined treatment with EBRT and BT was found superior to EBRT alone. I do not recall the fractionation but the results were encouraging.

  2. Finn:

    When three doses are given, it involves an overnight hospital stay. They wait 4 hours between fractions and the catheters are kept inside throughout, so the patient has to be numbed. Doctors and nursing staff are kept around. Repeating the procedure three times is a lot more of a bother all around and a lot more costly than just doing it once in a single in-office visit lasting just a few hours.

    SIB to the DIL was not the subject of this commentary, but you may want to read my commentary on it at this link. We’ll have to see if clinical trials prove its value.

    Brachytherapy boost treatment was not the subject of this commentary. It has been covered several times on this site. Use the search bar if you are interested.

  3. A very thought-provoking blog…

    I was wondering: As the time per fraction increases (and the effective (alpha/beta) increases), it seems that the effective “killing power” of the BED decreases. Question: Would raising the applied BED further help compensate for this drop due to longer time per fraction?

    It’s not clear to me that the studies in Allen Edel’s link (above) will be able to specifically separate out this “repair” effect from some of the other “R-effects” discussed in the blog.

  4. T Petrie:

    Alpha/beta does not increase or decrease. It is a property of the tissue in question. It is a parameter that tells us how susceptible that type of cell is to killing by fewer, more intense doses of radiation rather than more, less intense doses. For prostate cancer, the alpha/beta is about 1.5.

    With HDR-BT, the plan calculates “dwell times,” that is, the amount of time the hot Ir-192 seed is paused at a particular place within the prostate. The longer the dwell time, the higher the absorbed dose at that spot.

    You are right that it may be impossible to know which of the “Rs” are responsible for any given failure. It may be possible to prevent some of them to some extent with radio-sensitizing agents, checking cell oxygenation, medicines that increase production of reactive oxygen species, and exercise.

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: