Saturday, August 27, 2016

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 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 sessions 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 session. 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?

(Update May 2023)   Peterson et al. reported the toxicity results of the RADICALS-RT trial. Patients getting salvage radiation were not randomized but received either 66 Gy in 33 fractions (417 patients) or 52.5 Gy in 20 fractions (217 patients).
  • In the first 2 years, Grade 1 or 2 cystitis was reported more often in the 66GY/33fx (30%) than in the 52.5Gy/20fx group (20%)
  • After 2 years, Grade 1 or 2 cystitis was reported more often in the 66GY/33fx (16%) than in the 52.5Gy/20fx group (9%) - not statistically different
  • All other toxicities were similar

(Update January 2020) Chin et al. retrospectively reviewed 112 patients treated post-prostatectomy in the UK. They were treated with 52.5 Gy in 20 fractions.  With 10 years of follow-up they reported:
  • 51% were free of biochemical failure.
    • 68% if treated when PSA≤ 0.2 ng/ml
    • 49% if treated when PSA> 0.2 ng/ml
  • 16% had distant metastases
  • 11% died of prostate cancer
  • 75% overall survival
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%
  • Acute urinary toxicity: Grade 2: 6%, Grade 3: 1%
  • Acute rectal toxicity: Grade 2: 14%, Grade 3: 0
  • Late-term urinary toxicity: Grade 2: 15%, Grade 3: 0
  • Late-term rectal toxicity:Grade 2: 4%, Grade 3:0
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%
  • Acute urinary or rectal toxicity, Grade 2 or higher: 20%
  • Late-term urinary or rectal toxicity, Grade 2 or higher: 6%
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:
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% 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% of the patients is far out of line from what they'd expect from conventional 70 Gy salvage IMRT I also hope that using such extreme parameters does not discourage future studies.

A more reasonable clinical trial is at the University of Southern California (USC). They are randomly assigning patients to salvage treatment with 5, 10 or 15 SBRT treatments over 1-3 weeks. 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.

A trial at UCLA is discussed in detail here.

None of these clinical trials mentions the type of equipment, image guidance system, or whether neoadjuvant/concurrent/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.

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