Vessel-sparing IMRT spares erectile function


While either nerve-sparing surgery or radiation can cause erectile dysfunction, the probability for that for any given patient is always worse after surgery. The recent ProtecT randomized clinical trial removed any doubt of that, if there ever really was any. While nerve-sparing surgery was introduced by Walsh in 1982, there has been no similar breakthrough in IMRT radiation delivery — until now.

Effects of treatments on erectile apparatus

The mechanism of erectile function is complex, involving the brain, hormones, neurotransmitters, enzymes, and nitric oxide, just to mention a few vital components. Nerve impulses must travel from the brain, through the spine, along the nerve fibers that surround the prostate, and then along its length down to the corpus cavernosa (the spongy tissue inside the penis from the penile bulb to the glans). Surgery, even nerve-sparing surgery, usually disrupts the signal that must innervate the penis. “Nerve sparing” is not an all-or-nothing technique. If the cancer has grown out into the neurovascular bundles, only some of the nerves may be spared. Take away too little, and the cancer is not cured; take away too much, and permanent erectile dysfunction is assured. Sometimes surgeons send frozen slices of tissue for pathological analysis before deciding how much to remove.

When radiation causes erectile dysfunction, the mechanism is very different. Nerves are relatively impervious to radiation; however, blood vessels and other endothelial tissue may be affected. The blood that supplies the penis comes to it through the “pudendal arteries” that flow downwards on either side of the prostate (in the “neurovascular bundle”). The blood enters the penis at the penile bulb (the part that extends inside the pelvis) and engorges the tissue of the corpus cavernosa. Radiation may cause an inflammatory reaction in the linings of the blood vessels and in the tissue of the corpus cavernosa. Over a period of months, the inflammation may result in scar tissue that restricts blood flow, and the impedes the ability of the spongy tissue of the corpus cavernosa to expand and contract elastically.

For years, there has been somewhat conflicting evidence about whether radiation’s effect on erectile dysfunction can be mitigated by reducing the dose to the penile bulb (see this link). Consequently, radiation oncologists set a dose constraint for the penile bulb, but that was not a full solution. Many radiation oncologists have wondered whether the dose to the pudendal arteries and to the other parts of the corpus cavernosa could be restricted to preserve erectile function without sacrificing oncological effectiveness. Innovations in MRI-based planning and super-precise (sub-millimeter) beam delivery have enabled that.

Vessel-sparing IMRT

Spratt et al. at the University of Michigan conducted a clinical trial on 135 patients treated between 2001 to 2009 to see whether “vessel sparing” IMRT could better preserve erectile function while achieving equal cancer control. As others have, they used a T2 MRI to delineate the contours of the penile bulb and corpus cavernosa. Their innovation was to use contrast-enhanced MRI angiography to delineate the pudendal arteries that run near the prostate apex. The MRI images were fused with CT scan images and dose goals were set based on those. Intermediate- and high-risk patients were treated with low-dose-rate brachytherapy (seed) boost therapy before they received IMRT; low-risk patients received IMRT alone. A treatment margin of 1 cm was set for patients receiving IMRT only. It was lowered to 0.5 cm for those receiving brachy boost therapy.

Key patient and treatment characteristics included:

  • Age = 63 (median)
  • Baseline erectile function: IIEF score ≥ 16 (mild or no ED)
  • Risk level: low, 39 percent; intermediate, 53 percent; high, 9 percent
  • Gleason score: 3 + 3 = 6, 44 percent; 3 + 4 = 7, 33 percent; 4 + 3 = 7, 13 percent; 8 to 10, -9 percent
  • Treatment: IMRT alone, 39 percent; brachy boost, 61 percent
  • Dose: IMRT, 75.6 to 79.2 Gy; brachy boost, 110 Gy I-125 seeds + 45 Gy IMRT
  • Pelvic dose: 45 Gy (high-risk only)
  • 6-month ADT: yes, 33 percent; no, 67 percent

Potency preservation

During a median follow-up of 8.7 years, patients filled out questionnaires and doctors evaluated their erectile function at 2 years and 5 years. They were also queried about their use of erectile medicines and aids. Their responses were matched to the results of the PROSTQA study, matched for age, baseline potency, and other sexual risk factors. The percentages of men who had erections firm enough for intercourse 2 years after treatment were:

  • 78 percent if they had vessel-sparing IMRT
  • 42 percent if they had conventional IMRT
  • 24 percent if they had nerve-sparing prostatectomy

Other measures of erectile function at baseline, 2 years, and 5 years included:

  • No sexual aid use: 88, 47, and 44 percent
  • IIEF score ≥ 16 (no or mild ED): 100, 70, and 67 percent
  • High/very high confidence in getting and keeping an erection: 63, 40, and 33 percent
  • Potent without aids: 80, 45, and 35 percent
  • Potent with aids: 20, 41, and 53 percent
  • Impotent: 0, 14, and 12 percent

As we’ve seen in other studies, most of the radiation-induced ED will show up within the first 2 years, and probably within 9 months of treatment. This was shown for 3D-CRT in the ProtecT clinical trial,  for brachytherapy, for SBRT, and for EBRT. Perhaps the authors will make an attempt to separate the effect of patient aging in a future analysis. The University of Michigan should be able to accomplish this using their age-adjusted sexual domain EPIC scores.

It’s worth noting that potency preservation was no different for those who had the brachy boost or IMRT only. It was better for younger men, men with higher baseline performance, and those who did not have adjuvant ADT.

Oncological outcomes

At 5 years, the biochemical recurrence-free survival for each risk group was:

  • Low risk: 100 percent
  • Intermediate risk: 100 percent
  • High risk: 98 percent

At 10 years, the biochemical recurrence-free survival for each risk group was:

  • Low risk: 100 percent
  • Intermediate risk: 89 percent
  • High risk: 88 percent

One could not ask for better outcomes!

Conclusion

It appears that vessel-sparing IMRT is a vast improvement over conventionally targeted IMRT in terms of preservation of erectile function, and based on this, should be adopted as standard practice for all patients who might benefit. Interestingly, potency preservation is similar to that reported for SBRT (see this link) and for high-dose-rate brachytherapy (see this link). That is not at all surprising because both of those therapies use much narrower margins than those used for IMRT, typically 2 to 3 mm vs. 10 mm for IMRT, and the biologically effective dose to the vascular tissue of the pudendal arteries are lower. With SBRT, intra-fractional motion is tracked, thus avoiding dose to nearby structures. With HDR brachytherapy, the gland is immobilized with catheters that prevent doses to the nearby vessels and organs. Hopefully, equally excellent results can be achieved with hypofractionated IMRT, but that remains to be proved in future trials. With salvage IMRT, the entire prostate bed is treated, so I do not know if radiation to the pudendal arteries can be similarly avoided.

Anyone planning on having IMRT should forward a copy of this study to his radiation oncologist, and ask to discuss it at their next meeting. Of course, for men who are low risk, active surveillance will cause no erectile dysfunction and no loss of ejaculate.

Editorial note: This commentary was written by Allen Edel for the “New” Prostate Cancer InfoLink.

8 Responses

  1. If nerve-sparing RP has the worst ED outcomes, is there any hope for guys who have had salvage RT also? Any stats on those lucky fellas? 😥

    Also, I thought I read that RT resulted in worse ED as years passed; not true?

    Finally, I was startled to see that 88% of high-risk guys were still alive at 10 years! Is this the same regardless of type of treatment and stage?

    Bob

  2. It would be intriguing to see these results compared with those of proton beam radiation therapy (PBRT), which also is highly targeted with very minimal collateral radiation or damage. I’m 6 years out from PBRT and have never been better in the “performance” department. It’s one of the primary reasons I went with PBRT in the first instance.

  3. Bob:

    Guys who have had salvage radiation get increased risk from both therapies — nerves and blood vessels may be affected.

    I discussed ED over time in the article above. You may want to re-read that paragraph.

    It does not say that 88% were alive; it says that 88% were free from biochemical recurrence after 10 years. The high-risk patients in this trial were all treated with brachy boost therapy with 6 months of ADT, and whole pelvic radiation.

  4. Robert-

    Sometimes we are fortunate and sometimes we are disappointed that group statistics like these never predict for the individual. We looked at a large 5-year PBRT study last year (see this link), The two studies used different measures of sexual QOL; this study used IEFF5 scores, while the PBRT study used EPIC scores. They are highly correlated but not exact. The sexual QOL scores for vessel-sparing IMRT declined by about 14% by 5 years, while the sexual QOL scores reported for PBRT declined by 29% by 4 years (excluding those who had ADT). So it seems that this vessel-sparing technique was markedly better at preserving erectile function. Perhaps PBRT may be able to take advantage of this vessel-sparing technique as well.

  5. Alan:

    How do the 5- and 10-year outcomes for men with high and intermediate risk compare to other treatment modes, and other studies? bRFS rates of 98% and 88% in high-risk men strike me as high for just 6 months ADT.

    I certainly do not know the numbers from comparative studies like you do. … What are your thoughts?

  6. Rick,

    Keep in mind that this was a highly selected group of men based on the requirements of this particular clinical trial. The men were selected for good baseline erectile function, and were therefore younger (median age 63 vs. about 70 in most radiation studies). Younger men often have less progressed disease.

    With that caveat, the oncological outcomes were not out of line with other data we’ve seen on brachy boost therapy. In the ASCENDE-RT study (see this link), the 9-year bRFS was 83% for high-risk, and 94% for intermediate-risk men. They had 12 months of ADT. So, very similar.

    Using HDR brachy boost therapy, MSKCC and Guix et al. reported similarly high bRFS rates.

    Taking pains to rule out distant metastases, whole pelvic treatment, some use of ADT, and sufficient dosage all seem to be important in achieving oncological results like this. I think that using the new PET scans to inform patient selection will improve outcomes. I know that UCLA is now offering the Ga-68-PSMA-11 PET/CT to high-risk patients (for $2,650).

  7. Thanks Alan. … These results warm my heart personally, since this was my protocol — albeit with a lot more ADT.

    Just one comment. To my mind there is a big difference between 6 and 12 months of ADT. My own anecdotal experience has seen greater recurrence in high-risk men if they do not endure a minimum of 12 months of ADT initially. There have been several studies comparing neoadjuvant time frames for ADT … 4 vs 28, 6 vs 36, 18 vs 36 etc; I am not aware of any studies for high-risk men using a 12-month threshold, so this observation has no evidential backing.

  8. Well, DART 01/05 showed there was an advantage among high-risk men of 28 months of adjuvant ADT compared to 6 months. But the advantage with brachy boost therapy is less clear. To some extent, higher dose seems to diminish the need for ADT. There has never been a randomized study comparing ADT and no ADT with boost therapy that I’m aware of. The problem with trying to use retrospective studies to determine this is that there is often a reason (higher risk characteristics) that some patients are given longer duration of ADT.

    Demanes believed that adjuvant ADT conferred no additional advantage when used with HDR-BT (see this link), and as we saw in a previous commentary, the study with the lowest utilization of adjuvant ADT in high-risk patients (Zamboglou et al., at 60 percent) actually had the best oncological outcomes.

    Similarly, Alan Katz found that adjuvant ADT did not improve outcomes among high-risk patients treated with SBRT (which also has a high biologically effective dose), and Chris King makes 9 months of ADT optional in his SBRT high-risk protocol. It’s possible that there is an as yet undiscovered quality about extreme hypofractionation that obviates the need for adjuvant ADT, or it may just be the higher biologically effective dose. Men to be treated with LDR-BT are sometimes given a longer duration of ADT pre-treatment in order to shrink their prostates — we do know that seeds are more effective on smaller prostates.

    Until we have data from a randomized clinical trial, adjuvant ADT duration is a matter of judgment. From what I’ve seen, most use either 6 months or 12 months, starting 2 months before radiation.

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