Can salvage radiation therapy be safely and effectively completed in less time?

Salvage or adjuvant external beam radiation therapy for prostate cancer is usually a protracted affair, more so since we learned that a total dose of about 64 Gy to 70 Gy was needed to be effective in the salvage setting. At the typical rate of 1.8 Gy to 2.0 Gy per treatment, it takes approximately 35 treatments over the course of 7 weeks to complete. This is very costly and extremely time consuming. Can it be accomplished in less time without adding side effects or rendering it less effective?

Using fewer treatments for radiation therapy is called hypofractionation. Stereotactic body radiation therapy or SBRT is on the fastest end of the hypofractionation spectrum. It is accomplished in a blazingly fast five treatments. With its pinpoint accuracy, many radiation oncologists are using it for primary treatment at doses up to 8 Gy per treatment. But that is also its drawback for salvage therapy – it may be too accurate. Because we don’t know exactly where in the prostate bed the cancer may be hiding, IMRT or 3D-CRT – radiation technologies with less abruptly ending margins – have been traditionally preferred. There has also been some concern that blasting the anastomosis (the place where the urethra has been cut and re-attached, and where most recurrences occur) with high intensity X-rays may be too much for the fragile tissue.

There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:

  • The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
  • Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid some of this. It is an open question as to whether this can be done with the entire prostate bed the way it is with the prostate in place. This becomes an important consideration only at higher dose rates.
  • It is unknown whether those late-responding tissues will suffer increased damage from the higher dose rates after longer follow-up.
  • As mentioned, the scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
  • The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
  • None of the studies (below) mention the effect on erectile function, which is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.

Ohri et al. at Thomas Jefferson University in Philadelphia developed a mathematical model based on known radiobiological parameters to help determine ways in which salvage radiation therapy can be optimized. Among other findings, they showed that moderate hypofractionation – increasing the dose to 2.5 Gy per treatment in each of 26 treatments – gave only modest improvements. However, increasing the dose to 6.5 Gy in each of 5 treatments increased the probability of tumor control while decreasing expected urinary and rectal toxicity – a win/win! But would this happen in real life?

Kruser et al. at the University of Wisconsin treated 108 consecutive patients with a moderately hypofractionated schedule – 2.5 Gy per treatment in each of 26 treatments. After 4 years of follow-up, they found:

  • Freedom from biochemical failure: 67 percent
  • Acute urinary toxicity: Grade 2: 6 percent, Grade 3: 1 percent
  • Acute rectal toxicity: Grade 2: 14 percent, Grade 3: 0 percent
  • Late-term urinary toxicity: Grade 2: 15 percent, Grade 3: 0 percent
  • Late-term rectal toxicity: Grade 2: 4 percent, Grade 3: 0 percent

These toxicities are nearly identical to those found by Goenka et al. at Memorial Sloan-Kettering Cancer Center using the traditional dosing schedule. The freedom from biochemical failure rate is also similar to other studies using 70 Gy across 7 weeks (e.g., Shelan et al.).

Now, a group at Sunnybrook in Toronto (Gladwish et al.) report possibly even better results using a hypofractionation schedule of 3 Gy per treatment in each of just 17 treatments. After a median of 2 years of follow-up, they found:

  • Freedom from biochemical failure: 83 percent
  • Acute urinary or rectal toxicity, Grade 2 or higher: 20 percent
  • Late-term urinary or rectal toxicity, Grade 2 or higher: 6 percent

None of these were randomized clinical trials, so the results across studies are not strictly comparable. However, they do tell us that in well-selected patients treated at centers of excellence, that hypofractionation can reduce treatment times with acceptable safety and efficacy.

Can this be taken further?

Ohri et al. conclude that:

More aggressive hypofractionation, using a regimen of 6.5 Gy × 5, however, provided significant improvements in both tumor control and expected toxicity. … Based on our findings, careful clinical study of more aggressive hypofractionated schedules may be warranted.

There are a couple of such clinical trials that have taken them up on their challenge. One of them (NCT01923506) is currently enrolling patients at the City of Hope in Los Angeles. There are some peculiarities in this trial. They are treating with doses as high as 45 Gy across 5 treatments to the prostate bed – higher than anyone uses on the whole prostate for primary SBRT! And they are setting a goal of up to 33 percent of patients experiencing dose-limiting toxicity. I am surprised that their ethics board approved this. I hope the patients are informed that a toxic dose of Grade 3 or higher among 33 percent of the patients (TD33) is far out of line from what they’d expect from conventional 70 Gy salvage IMRT. I hope that using such extreme parameters does not discourage future studies.

The other clinical trial is at the University of Virginia (NCT01868386). They are looking only at moderate hypofractionation schedules ranging from 2.5 Gy in each of 26 treatments to 4.26 Gy in each of 10 treatments.

Neither study mentions the type of equipment, image guidance system, or whether neoadjuvant, concurrent, or adjuvant ADT is allowed.

I know many patients will be eager to use a shorter, more intense treatment schedule for salvage radiation therapy based on the encouraging results of SBRT for primary radiation therapy, and the two trials of moderate salvage hypofractionation so far. I am hopeful that clinical trials will confirm their safety and benefit.

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

6 Responses

  1. In reading and appreciating the importance of this article, your sitemaster thinks it is important to understand that the prostate bed (properly known as the prostate “fossa”) is usually the primary target for adjuvant or salvage radiation therapy.

    When there are definitive indications or strong suspicions that cancer recurrence may be occurring locally within the pelvis but at a distance from the prostate fossa (e.g., inclusive of the prostate lymph nodes or elsewhere), then, even though the prostate fossa is commonly included in the total target area to be radiated, the size and extent of the radiation field may further affect the exact dose of radiation to be administered to specific tissues, as may the use of neoadjuvvant and/or adjuvant androgen deprivation therapy (ADT).

    The use and applicability of this type of wide-field radiation therapy and exactly what dose of radiation is applicable to any particular tissue are still very controversial — as are the dose and the timing of neoadjuvant and/or adjuvant ADT in these patients.

  2. Wouldn’t proton therapy which is radiation but even more focused to a pencil beam along with 3D MRI imaging and biopsy results give the best results. Theoretically it should; however, long-term results don’t seem to support this. I wonder what the unaccounted factors are?

    Ron Rosen, MD

  3. Ron,

    I think one problem for proton salvage RT is the same as for SBRT salvage — it is too precise. With salvage, it is desirable to cover a wider field because the precise location within the prostate fossa is undetermined, and micrometastases can be anywhere. It’s the same reason that when proton therapy is used to treat higher risk patients, the prostate is the target for the proton boost, while photons (IMRT) are used for the wider field.

    If what you have in mind is focal salvage — locating and treating a tumor within the fossa and nothing else — there are a couple of emerging technologies that may make that possible. Even multi-parametric 3-T MRI in the most capable hands can’t locate tumors smaller than about 4 mm in length. However, there is a new generation of PET radio-indicators that couple a positron emitter (like 68Ga) with an anti-PSMA antibody. They are highly specific to prostate cancer. When that is used with the new simultaneous PET/MRI scanner, it may be able to find much smaller foci of cancer cells. Potentially, those foci can be precisely eliminated with SBRT, protons, or carbon ions. The University of Heidelberg has been experimenting with this, and has one of two carbon-ion therapy devices in the world. Carbon ions don’t suffer from the same scattering effects that protons exhibit, and may turn out to be ideally suited for the job.

  4. Again, excellent review of a very relevant research topic. As a patient with sRT in his possible future, I am finding more and more reasons to follow this blog.

    RT technology has evolved much in recent years, with very precise techniques such as IGRT and now SBRT. The increase in accuracy always seems to be used to justify increasing the dose, making RT more lethal to cancer cells with the same level of side effects. A commendable goal, but I can’t help but think some patients at low risk of progression might prefer a lower dose if it comes with less risk of side effects. If 60 Gy was found effective in major historical studies using older 3D conformal and IMRT methods, why does everyone now feel 70 Gy is necessary? After all, we are still shooting blind for the most part.

    SBRT is effective for primary treatment when fiducials are used in the prostate gland to help beam localization, but after primary treatment imaging does not generally delineate a target until it may be too late for a complete cure.

    If my anastamosis is going to be damaged by radiation, to the point where I require repeat catheterization, trips to the ER, multiple dilations, etc., what have I gained when the cancer may not even be in the target area? I hope the studies shed light on this but I would be very cautious about offering myself as a guinea pig here.

  5. Archie,

    You make some very important points. These are large issues you raise, and ones I hope to more fully explore in future posts.

    The problem with 60 Gy is that it wasn’t found to be especially effective. There were several salvage dose escalation studies that show that doses below 70 Gy are on the steep part of the dose-response curve. That means that raising the dose gives a lot of “bang for the buck” in terms of cancer control compared to toxicity. Beyond 70 Gy, the S-shaped curve flattens out, so we get increased toxicity for very little extra cancer control at higher doses.

    Image guidance (IGRT) is used for salvage therapy as well as primary therapy. Sometimes ROs will implant fiducials in the prostate bed, although many just line up the pelvic bones, which are rigid. IGRT techniques become especially important with hypofractionated dose rates.

    The reason the prostate fossa is the target for salvage is because it’s almost always the first stop on the way out of the prostate for the cancer cells. As we’ve learned from biopsy studies, most of the time the cancerous tissue is in the area of the anastomosis — the prostate doesn’t always come away cleanly when the surgeon is trying to spare the bladder neck, the urethral sphincter, and the neurovascular bundles. When there is a positive surgical margin or it is found to be stage T3, we know there is going to be some cancer in the fossa.

  6. Thank you for your thoughtful response. I apologize that my comments were a bit broader than the original topic. I do look forward to your future posts on these issues.

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