Quality of life after three different first-line radiation therapies for localized disease: Part 3


This is the third and last of three reports discussing a recent, detailed paper by Evans et al. The first (Part 1) was published on Tuesday, August 25, and Part 2 on Wednesday, August 26.

PART 3. DISCUSSION AND CONCLUSIONS

In this section, we will make an attempt to explain the findings of the study and draw whatever conclusions we can from them.

We have seen a very consistent pattern across all the measures of QOL and in all of the domains: LDRBT patients did worst, SBRT patients did best, and IMRT patients were in between. Why should that be? Let’s examine a few hypotheses:

Patient selection/non-random

This was not a randomized comparative trial, so it is possible that the LDRBT patients selected were, for some reason, more prone to the damaging effects of radiation. This argument is weakened by the fact that they were 5 years younger, and their urinal, rectal, and erectile function at baseline were better than in the other two groups.

Better practitioners not represented

Some of the top LDRBT practitioners like Peter Grimm, Michael Zelefsky, Brian Moran, and Gregory Merrick, to name a few, were not represented here. This study only shows the LDRBT QOL outcomes at one institution, albeit an excellent one, the Cleveland Clinic. One could also argue in the other direction that some of the most experienced SBRT practitioners, like Christopher King, Alan Katz, and Debra Freeman, were not represented here. Their results might have increased comparative favorability of the SBRT results still further. However, the results do seem to be comparable to those reported by Katz and the eight-institution consortium.

Time of treatment

IMRT and LDRBT results were based on best practice in 2003-2006, while SBRT was based on patients treated in 2007-2011. There were technological improvements in both modalities since then that might make their outcomes more comparable to SBRT. As radiation technology continues to evolve, it becomes problematic to choose among them based on past performance.

Hypofractionation spares healthy tissue

Hypofractionation (SBRT or HDRBT) — radiation applied in fewer treatments (or fractions) — has been found to kill cancer cells more efficiently than normal fractionation (IMRT) or continuous fractionation (LDRBT). Because prostate cancer is especially susceptible to hypofractionation (technically, we say it has a low alpha/beta ratio of about 1.5), and because healthy nearby early-responding tissues are less susceptible (they have a higher alpha/beta ratio of about 10), healthy tissues are better spared by it.

A convenient measure for comparing the dose seen by nearby healthy tissues is something called the biologically effective dose (BED). We can compute, for each modality, the maximum BED experienced by nearby early-responding tissues that are responsible for acute side effects. With SBRT (7.5 Gy × 5 fractions), the BED to those tissues is 30 percent less than the dose from IMRT (1.8 Gy × 44 fractions). For LDRBT (144 Gy I-125 Rx dose), the maximum BED to those tissues is 56 percent greater than the dose from IMRT.  Making comparisons based solely on BED is problematic because LDRBT radiation is extremely short range, so a lower proportion of the bladder and rectum surface may be exposed to that maximum dose.

Dose constraints

Radiation oncologists set strict dose constraints for the bladder, urethra, rectum, and sometimes to the penile bulb, limiting the volume of those organs that receive potentially toxic doses. However, there is only so much that doses can be limited if they are to effectively kill the cancer in the prostate. I don’t know what dose constraints were set for the three modalities examined in this study. We can only assume that they used best practices.

Imaging

The imaging of the pelvic organs both in planning and in the application of radiation makes a large difference in toxicity. This is where SBRT shines. SBRT commonly uses a fused image of a CT and MRI with fiducials or transponders in place for planning. This helps to precisely predetermine, down to less than a millimeter, where all the beams will be directed. These practices can be used with IMRT as well. However, with IMRT, the images are aligned only once per session, whereas with SBRT, the images are aligned continually throughout the session. We recently saw how disastrous SBRT could be without intra-fractional motion tracking. LDRBT seed placement is commonly accomplished under ultrasound image guidance, using computerized intra-operative planning. The ultrasound can help the doctor see where the needles are going, but it can’t see the seeds well. Even stranded seeds tend to move, the prostate is moved by each needle insertion, and the prostate swells throughout the procedure, so that it is impossible to know where their final position will be. An image is obtained about a month later, after the swelling subsides, to check for major discrepancies in seed positions and to give an after-the-fact reading of the doses absorbed by organs at risk.

Late-term effects

This study tracked patients for 2 years, which is long enough for most of the late-term side effects to show up. However, some will inevitably show up even later. Some tissues, particularly some in the bowel, are “late responding” to radiation damage. Late responding tissues are relatively more sensitive to the concentrated radiation of SBRT (they have an alpha/beta ratio of 3-5), so it is possible that SBRT’s advantage will decrease with longer follow up.

Conclusions

Although one can quibble over methodological issues in comparing the modalities, SBRT certainly provides excellent quality of life to treated patients. SBRT also is the most convenient of the treatments, requiring only five short visits, no intrusive procedures (other than fiducial placement), and no anesthesia. LDRBT is the winner on cost of treatment, with a $17,000 median Medicare reimbursement, followed by SBRT ($22,000) and IMRT ($31,000). However, a full cost analysis should also include the costs of managing the side effects of treatment, which seem to be much lower for SBRT and higher for LDRBT. Based on the findings of this study, and approximately equivalent oncological control for the three modalities in favorable risk patients, it is hard to justify IMRT. Availability,however, is an issue: IMRT is available everywhere, while there is less access to excellent practitioners of SBRT (usually as CyberKnife®) and LDRBT. Some insurance still will not cover SBRT, although that is less often a barrier now.

An oft-heard argument against SBRT is that there’s not enough long-term data. SBRT is the youngest of the three modalities, used against prostate cancer since 2003. The longest-running SBRT study, has 7 years of follow up on 515 patients. For comparison, robotic prostatectomy has been used since 2000, and has never been proven superior to open surgery in a randomized comparative trial. IMRT, likewise, has never been evaluated in a comparative randomized trial, and, in its current form, using dose escalation and precision IGRT techniques, was only begun in the mid-1990s. The longest-running IMRT study, at Memorial Sloan-Kettering Cancer Center, has 10 years of follow up on 170 patients. LDRBT has been used, in some form, for over 100 years. However, in its modern form with dose escalation and intra-operative planning methods, there are no studies older than 15 years that have any decisional value. I have often bemoaned the problem of “irrelevance” in long-term clinical studies: by the time we get the results, technology and practice have changed so much that the results have become irrelevant in making decisions among the best available therapies.

While this study raises the hypothesis that SBRT may be superior to IMRT and LDRBT, it is prudent for the patient to keep them all in his consideration set — at least until the results of randomized comparative trials become available. This study should influence patients and clinicians to give serious consideration to SBRT.

Later this year, we will have the early results from Sweden of a randomized clinical trial of SBRT versus IMRT in intermediate-risk patients. There are several more comparative trials that are scheduled for completion in the coming years. If they confirm the results of this study, it will be difficult to justify IMRT as first-line therapy. Unfortunately, as far as I know, there are none planned comparing SBRT and LDRBT. There are few institutions that offer both modalities (Memorial Sloan-Kettering Cancer Center is an exception), so randomization would be problematic.

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel, who was treated with SBRT in 2010.

19 Responses

  1. Excellent summary. Could you clarify the cost of IMRT? The recent post on PBRT stated cost as $19,000 versus $31,000 for IMRT in your summary.

  2. John:

    The cost for any type of radiation therapy varies vastly from place to place around the country. The only way you can get a truly accurate cost is by finding out what your individual insurance provider is reimbursing for a specific treatment at a specific institution.

  3. I pulled the median $31,000 figure for primary therapy from this source. I think the median $19,000 figure may reflect Medicare reimbursement across all uses of IMRT, which would include such lower cost uses as salvage radiation and palliative radiation.

  4. Thanks. This is helpful. Medicare reimbursement is almost the same for IMRT and PRBT.

  5. Daniel Hamstra, the corresponding author, had the following response:

    “It was hard to break out in all the analyses we did. In addition, the editors made us put more than half of the data in the supplemental data. But I don’t think it is a good idea to put out there that SBRT is better for sexual function and LDR is worse. I really don’t think we have that good of a handle on it. Are you able to access the full supplemental data?

    “I don’t think the conclusion or concern that LDR leads to worse sexual decline is an accurate one. The main reason SBRT looks better for sexual function is that they were the oldest group and had the worst sexual function to begin with. Fundamentally, if sexual function is bad, the EPIC instrument does a poor job of documenting it getting much worse. So, the multivariate analysis of sexual function at 2 years indicated that the only variables significant for decline in sexual function were:

    Baseline sexual function (with a large effect size)
    Baseline physical function (with a somewhat smaller effect size)
    With borderline associations with baseline mental health and age.

    “Age and baseline function are highly inter-related which is likely why age was less prognostic.

    “I would not conclude that LDR was worse. In fact the analysis previously reported using the PROSTQA data (below) found that age was very important as was baseline function. It then built prognostic models based upon differing treatment techniques etc. and found not huge differences between IMRT and LDR.

    “Prediction of erectile function following treatment for prostate cancer.”

    Alemozaffar M, Regan MM, Cooperberg MR, Wei JT, Michalski JM, Sandler HM, Hembroff L, Sadetsky N, Saigal CS, Litwin MS, Klein E, Kibel AS, Hamstra DA, Pisters LL, Kuban DA, Kaplan ID, Wood DP, Ciezki J, Dunn RL, Carroll PR, Sanda MG.

    JAMA. 2011 Sep 21;306(11):1205-14. doi: 10.1001/jama.2011.1333.
    http://jama.jamanetwork.com/article.aspx?articleid=1104401

  6. I wrote back:

    “Thank you for explaining that. I did not have access to all the supplemental data. I will append all your comments. You are quite right that age only seemed to be less prognostic in multivariate analysis because it’s interrelated with baseline function. My guess is that the problem of covariance also affects changes over time. Age-adjusted baseline sexual function and age-adjusted EPIC scores over time might obviate the problem. My guess is that treatment effects might turn out to be independently significant in the age-adjusted changes.

    “I don’t know if you saw the analysis from BC:
    “Half of long-term erectile function (EF) loss after brachytherapy (BT) is due to aging”
    https://prostatecancerinfolink.net/2015/02/23/half-of-long-term-erectile-function-ef-loss-after-brachytherapy-bt-is-due-to-aging/

    “I hear what you’re saying that the older men in the external beam cohorts had less relative deterioration because they were already so low. Yet the Massachusetts Male Aging Study (used in their analysis) seems to show the opposite — the relative deterioration in sexual function in 70-year-old men is actually much greater than for 65-year-old men.

    “In the BC study, they noticed the same temporal pattern that you did — the deterioration in sexual function after BT occurred quite early. I don’t know why the temporal pattern should differ from external beam, but it certainly seems to. Perhaps future follow-up studies will elucidate this phenomenon.”

  7. Cost of IMRT for an advanced case

    Hi John, Sitemaster and Allen,

    In March and April of 2013 in Northern Virginia I had 78 Gy of TomoTherapy (IMRT) radiation, including a pelvic boost of 46 Gy, in 39 sessions. The cost of the treatments was just over $100,000. The center no longer has a TomoTherapy machine, partly because upkeep proved burdensome.

    My treatments were very much at the upper end of the range of cost that I have heard about for IMRT radiation.

    I am highly pleased with the results for my case that was so challenging at the outset in 1999. So far, my PSA has not exceeded 0.02 and is currently < 0.02 (just a tad lower than my first-ever PSA of 113.6 in 1999). I ceased supportive ADT in April 2014. I have also been pleased with the side effect profile, though romance has definitely taken a hit, perhaps due to age, perhaps to nearly a decade and a half of intermittent ADT, perhaps to the radiation, or more likely due to a combination of these factors.

  8. Thanks for a Fine Series of Articles

    Hi Allen,

    Well done, and thank you!

    I’ve read all three pieces carefully as well as some of the linked information. Here are some thoughts.

    Re SBRT (few, generally 5 sessions) as a viable modality: You have presented a good case based on follow-up that is still fairly limited (that that 72-month — a.k.a. “seven year” — study is encouraging). I really look forward to multi-institution results with 5 years of median follow-up. The Bauman results indicate that SBRT is still investigational.

    Re sexual function and LDBRT: I suspected that the apparent percentage of sexual problems for brachytherapy was because of the age difference between the cohorts, and I see above that corresponding author Hamstra views it that way too. For many years the doctors I regard as experts in ADT have advised that men of about 70 do not generally register good performance after ADT at that age, and that is credible to me. This parallels the interpretation of results of the three modalities stated by Dr. Hamstra. (The converse for ADT is also arguably true: under age 70, at least some of us regain substantial function during the off-therapy periods.)

    Re bowel toxicity for LDBRT: The figure for 2 years is surprisingly high in view of the nature of LDBRT. ?

  9. Jim,
    I very much disagree that the Bauman results indicate that SBRT is investigational, at least no more than any other therapy. It only acts as a caution that when dealing with heavy doses, one must be meticulous about motion tracking — as most clinicians are. Two years is certainly enough to pick up acute QOL effects. As I said, late term effects may show up later, but they are rare. Dr. Katz will be presenting 9-year results this Fall at the ASTRO conference — which is just 1 year short of the longest series published for IMRT.

    The sexual effects work in the opposite direction from what you suppose. Younger men have more efficient cellular recovery mechanisms after radiation, and, as often shown (e.g., Alemozaffar et al.) have less deterioration in sexual function, not more. No one in this study had ADT.

  10. Allen, I’m replying to your comment of 12:34 pm today.

    Regarding whether SBRT is investigational, there should be a consensus that the acute side effects look good — no issue there. Regarding efficacy and long-term side effects, many of us are just not ready yet to conclude that SBRT has mastered both of those areas, though it well may have — just not proven yet.

    Thanks for the heads up on the Katz results; I’m looking forward to those. Consider that the Uchida team can now make a pretty good case for its particular form of HIFU and supporting technology/special expertise as a worthy therapy for appropriate prostate cancer cases; yet there seems to be no other HIFU team that has yet replicated their approach and results or achieved the same worthy results with a different HIFU therapy. I doubt if anyone would deem HIFU a proven therapy for general use; it’s clearly still investigational. My own impression is that SBRT with just a few sessions (hypofractionation) is going to be proven soon, and I have doubts that that will happen with HIFU. But considering the case for HIFU makes the case for considering these therapies investigational at this point.

    Regarding IMRT, an abundance of studies have been published, and new developments constitute incremental advances in a well-studied field rather than a bold step forward as in SBRT with hypofractionation. Check out the Prostate Cancer Results Study Group graphs/references and this will be evident, though a PubMed check will also make the point. I’m really familiar with these studies as a whole as I looked carefully at them, as well as additional studies, in choosing my radiation therapy in 2012/2013.

    Re sexual side effects: I was making a different point than the ones you correctly note, though I believe mine is the same as the one that researcher Hamstra is making: men around age 70 typically have a considerably lower sexual capability/interest than men about 5 years younger. Therefore, there is less ground to lose in these side effects for the older men — less scope for an effect to happen and be observed. I was citing ADT just as evidence of this age effect around age 70 — not as a comment directly about any of the radiation therapies.

  11. Jim,

    I don’t know whom you purport to speak for when you say “many of us consider it investigational,” but the largest professional organization, ASTRO, certainly does not. With 10-year published results for IMRT and, imminently, 9-year published results (on a much larger sample size) for SBRT, I would be hard pressed to call one “investigational” and one not.

    Randomized comparative studies that “prove” one therapy better than another are rare. IMRT was never proven, nor was robotic surgery. They are just accepted by consensus, having displayed good efficacy and safety in monadic, single-institution trials.

    I do not consider the “Prostate Cancer Results Study Group” to be a good source for information. Close scrutiny reveals they left out many studies that should qualify under their criteria. I consider it no more than a marketing tool for Peter Grimm (it is run from his office). One can do a lot better than that.

  12. Secondary cancer risk ruled out with SBRT delivered in five sessions?

    Hi again Allen,

    One consideration that was important to me in selecting a therapy back in 2012 was the possibility of secondary cancer. That risk seems to be very small with IMRT, and I’m hoping you can reassure us about that with SBRT the risk is also very small.

    A key principal with external beam radiation, now with IMRT, is that all cells in the paths of the rays are damaged to some extent — both cancer cells and healthy cells, but healthy cells are able to recover during the gaps between treatments, typically including days off on weekends. With hypofractionated SBRT the dose per session is several-fold higher, and my recollection is that early on Dr. Christopher King altered his pioneering protocol from treatments on five sequential days to treatments with interventing days off, because of unexpectedly severe acute side effects. My impression is that most doctors now managing hypofractionated SBRT allow at least a day off between the sessions. Can you give us any insight into the potential risk for secondary cancer following SBRT with hypofractionation (a.k.a. for our purpose here as complete radiation dose delivered in five sessions)?

    Perhaps this issue has already been resolved by convincing analysis. However, it is an important issue, and its resolution would help move hypofractionated SBRT beyond investigational status for many of us.

    There was a roughly similar issue when androgen deprivation therapy (ADT, a.k.a. hormonal therapy) was investigational back in the early years of its use. Back then, the oral drug DES was typically available, and it came into wide use because it was strikingly effective in knocking down testosterone, which caused the cancer to retreat. Unfortunately, it took a while for doctors to realize that DES created substantial cardiovascular risks which caused some deaths. After that recognition, other ADT drugs were used that were much safer.

    By the way, my local hospital, INOVA Fairfax, in Northern Virginia (DC metro area) started offering hypofractionated SBRT via CyberKnife about a year or two ago for appropriate patients, though the staff is keeping their minds open about its long term role.

  13. Let me be very clear that any form of treatment that is being covered by Medicare is no longer “investigational”.

  14. Your concerns (and those of whoever else you include in “many of us”) are unfounded. I wrote about secondary cancer risk on this site several months ago.

    The Murray et al. simulation study found that SBRT/SABR had the lowest relative risk of secondary radiation-induced cancers compared to IMRT, 3D-CRT, etc. I rush to add that the risk is quite low across all modalities.

  15. Re “investigational”: Thanks Allen and Sitemaster for resolving that issue for me that SBRT with hypofractionation is no longer investigational. Glad to learn that.

  16. Hi Allen, regarding your comment yesterday: “I do not consider the “Prostate Cancer Results Study Group” to be a good source for information. Close scrutiny reveals they left out many studies that should qualify under their criteria. I consider it no more than a marketing tool for Peter Grimm (it is run from his office). One can do a lot better than that.”

    The Group has a number of criteria for including studies, and they seem reasonable and appropriate for the Group’s purpose of comparing studies. As I understand it, a study has to satisfy all of the criteria to be included, though I did notice a few minor discrepancies such as inclusion of studies that were just short of the “minimum” number of patients in the studies. Here is a link to their formal report, though they are publishing updates informally at Peter Grimm’s web site.

    Here is the sentence re criteria in that abstract: “… Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group)….”

    Do you have any specific studies in mind that satisfied those criteria but were omitted?

    I used the Group’s results, but many of the studies were too old — used older technology such as dosing now known to be inadequate — to be meaningful for my decisions in 2012, and, due to the criteria, they omitted some studies of technology at the leading edge that lacked the minimum/median follow-up of 5 years or the minimum number of patients. I supplemented with additional studies based on PubMed search or following experts. Do you have any suggestions for keeping up with radiation research beyond the Group’s updating results?

  17. Jim,

    This site is the best one I know of for keeping up with the latest and best studies out there. I think the Sitemaster does a heroic job in sorting through an otherwise unmanageable morass of information to find what is important and actionable in them. I am flabbergasted by the sheer volume of his consistently high-quality output. The vast body of reliable information he has amassed is accessible with one click on the search bar. I help him out with some of the radiation-related studies lately.

  18. Hi Allen,

    Regarding your follow-up comment on risk of secondary cancer, thank you for your fine prior article and for this reassuring information, including the exceptionally low risk with hypofractionated SBRT. (I have struggled to keep up with developments here during the past 2 years and had not noticed your article before.)

  19. Amen to that!

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