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 brachy (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: Low - 39%, Intermediate - 53%, High -9%
• Gleason score: 3+3 - 44%, 3+4 - 33%, 4+3 - 13%, 8-10 - 9%
• Treatment: IMRT alone - 39%, brachy boost - 61%
• Dose: IMRT - 75.6-79.2 Gy, brachy boost - 110 Gy I-125 seeds + 45 Gy IMRT
• Pelvic dose: 45 Gy (high risk only)
• 6-month ADT: yes -33%, no - 67%

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 percent of men who had erections firm enough for intercourse 2 years after treatment were:

• 78% if they had vessel-sparing IMRT
• 42% if they had conventional IMRT
• 24% 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%, 44%
• IIEF score ≥16 (no or mild ED): 100%, 70%, 67%
• High/very high confidence in getting and keeping an erection: 63%, 40%, 33%
• Potent without aids: 80%, 45%, 35%
• Potent with aids: 20%, 41%, 53%
• Impotent: 0%, 14%, 12%

As we've seen in other studies, most of the radiation-induced ED will show up within the first two years, and probably within 9 months of treatment. This was shown for 3D-CRT in the ProtecT clinical trial,  for brachytherapy, for SBRT,  and 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%
• Intermediate risk: 100%
• High risk: 98%

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

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

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 2-3 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.