Better cancer control with radiation vs. surgery in high-risk patients

Researchers at the University of Alabama at Birmingham assigned high-risk patients to receive either external beam radiation therapy with androgen deprivation therapy (RT+ADT) or to receive surgery (RP) with or without adjuvant/salvage radiation. RT+ADT was the clear winner. It’s not a randomized trial, and it is small and retrospective, but it’s worthy of note nonetheless.

Baker et al. reported on 121 patients treated between 2001 and 2014 who were diagnosed with Gleason scores ≥8 (on either biopsy or pathology). 71 patients received RT+ADT according to the following protocol:

• ·      75-77 Gy in 40-42 fractions or 70 Gy in 28 fractions
• ·      All received pelvic lymph node radiation
• ·      Almost all (96%) received ADT for 24 months
• ·      1 patient received adjuvant docetaxel

50 patients who had life expectancies ≥ 10 years, no serious comorbidities, and whose prostate were considered resectable, were offered radical prostatectomy instead of radiation. All patients were seen by both a urologist and a radiation oncologist. Of the 50 RP patients:

• ·      76% also had pelvic lymph node dissection
• o   8±6 lymph nodes were sampled
• o   18% had positive lymph nodes
• ·      88% had adverse pathology: positive margins, seminal vesicle invasion, or extraprostatic extension
• ·      74% were stage T3 at pathology (vs. 4% pre-RP)
• ·      84% were GS≥8 at pathology (vs. 63% pre-RP)
• ·      44% received adjuvant radiation
• ·      24% received salvage radiation
• ·      Those with positive lymph nodes received salvage pelvic radiation
• ·      1 patient received adjuvant docetaxel

After average followup of 74 months for those who originally received RT+ADT and 60 months for those who originally received RP, the 5-year biochemical failure rate was:

• ·      7% for those originally receiving RT+ADT
• ·      42% for those originally receiving RP

The 5-year detection of distant metastases was:

• ·      2% for those originally receiving RT+ADT
• ·      8% for those originally receiving RP

The 5-year use of salvage (permanent) ADT was:

• ·      8% for those originally receiving RT+ADT
• ·      34% for those originally receiving RP

While the researchers did not report on toxicities, it is safe to say that those who received original RP suffered worse toxicities. This is true not only because surgery carries greater risk of incontinence and impotence, but also because 68% of those who originally received surgery received radiation on top of that, and half of those men received ADT with their adjuvant/salvage radiation. Adjuvant/salvage radiation has a worse toxicity profile compared to primary radiation.

The results in favor of initial radiation therapy are particularly impressive because radiation patients in this study had more progressed disease at the time of treatment. They had higher Gleason scores, higher stage, and higher risk of lymph node involvement. They were also considerably older. The results are all the more impressive because the amount of radiation given was low by today’s best practice standards, and because combination therapies of external beam radiation with a brachytherapy boost to the prostate have been proven superior to external beam monotherapy in randomized clinical trials. If anything, the selection bias and treatments in this study should have favored those who were initially surgically treated.

On the other hand, it’s been demonstrated that the limited pelvic lymph node dissection of the surgery patients given in this study is often inadequate to detect the full extent of involvement. They note that they have recently changed their protocol to include extended pelvic lymph node dissection (ePLND) on high-risk RP patients. Sometimes ePLND not only detects the extent of involvement, but may also clear the area of cancer without the need of salvage nodal radiation.  Two additional caveats are that the difference in definitions of biochemical failure and the two years of ADT may affect relative outcomes. However, it is hard to imagine that the long-term effects would enough to change conclusions given the magnitude of the difference.

While this is not the large-scale prospective randomized trial of RT vs. RP that we would like to see, the large variance in outcomes should be considered by anyone trying to decide between radiation and surgery for a high-risk diagnosis.

Safety limits of SBRT dose escalation

In a recent commentary, we saw that the lack of a standard of care for SBRT dose escalation may put patients at risk when dose limits are pushed beyond what is customarily considered effective and safe. Hannan et al. have now published their efficacy findings. Further details of the IRB-approved clinical trial specs are available here.

Between 2006 and 2011, the researchers at several institutions conducted a dose escalation trial utilizing SBRT on 91 men treated for low and intermediate risk prostate cancer. Among those men:

• ·      64% were intermediate risk, defined as:

o   Either GS 6 and PSA between 10 and 20 ng/ml , or

o   GS 7 with PSA≤ 15 ng/ml and clinical stage ≤ T2b

• ·      36% were low risk by the NCCN definition.

All patients received 5 treatments or fractions. The first 15 patients were treated with 45 Gy, the next 15 with 47.5 Gy, the next 15 with 50 Gy. Because that last group did not exhibit their predefined “maximally tolerated dose” in the short term, an additional 47 patients also received the 50 Gy dose.

The cancer control was excellent. At 5 years after treatment:

• ·      98.6% were free from biochemical failure
• ·      100% were free from metastases
• ·      None had died of prostate cancer
• ·      Overall survival was 89.7%

Toxicity was another matter. There were no reports of serious acute urinary toxicity. However, late-term urinary toxicity of grade 3 or greater was reported in 5.5% of patients. For the purposes of their analysis, acute toxicities were those observed within 9 months of treatment, and late-term toxicities were those observed between 9 and 18 months.

Rectal toxicity was reported in detail earlier by Kim et al. and merit a closer look:

• ·      Among those who received 45 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   No acute grade 2 toxicity was observed.

o   Late-term grade 2 toxicity was observed in 1 patient (of 15).

• ·      Among those who received 47.5 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   Acute grade 2 toxicity was observed in 4 of 15 patients (27%)

o   Late-term grade 2 toxicity was observed in 5 of 15 patients (33%).

• ·      Among the 61 patients who received 50 Gy there was:

o   One case of serious (grade 3) acute toxicity and one case of life-threatening (grade 4) acute toxicity.

o   3 cases (5%) of serious (grade 3) late-term toxicity and 2 cases (3%) of life-threatening (grade 4) late-term toxicity.

o   2 of the patients developed rectourethral fistulae, and 5 required diverting colostomies.

We note that even at the lowest dose level given in this trial (45 Gy), they were delivering much more than the customary SBRT dose of 36.25 Gy. Because this study began with such a high dose, it did not succeed in its objective of finding an optimal dose. It did, however, find the dose that created dose-limiting toxicity. At 50 Gy, they were delivering a dose that is bioequivalent to more than twice the customary and safe IMRT dose (80 Gy in 40 fractions). This is especially troubling when we realize that 36% were low-risk patients who might have delayed treatment with active surveillance.

There are many aspects of this study that are hard to understand. It’s hard to understand why they didn’t start at a more reasonable dose level. Dr. Alan Katz reported excellent cancer control with extremely low toxicity using only 35 Gy (see this link). With the sharp increase in acute grade 2 toxicities at 47.5 Gy, it’s hard to understand why the researchers did not pull the plug before patients were seriously harmed. It’s also hard to understand how the internal review board (IRB) did not question the ethics of this study.

(Update 2/6/2019) In a small (n=26) prospective dose-finding study of 40 Gy (n=9), 45 Gy (n=10) and 50 Gy (n=7) among low and intermediate risk patients, Potters et al. reported freedom from biochemical failure of 92%, 100% and 100% respectively with 67 months of follow-up. There were no Grade 3 toxicities, and toxicity was about equal in all groups. Quality of life returned to baseline in all groups within 2 years.

We have observed (see this link) that there is a lot more to SBRT safety than simply setting the prescribed dose. Careful planning, image guidance and accurate delivery are equally important. In the right hands, SBRT is among the safest and most effective of all radiation therapies, with excellent convenience and relatively low cost. In fact, I chose it for myself.

Is there an optimal treatment schedule for high dose rate brachytherapy?

Protocols for high dose rate brachytherapy (HDR-BT) monotherapy vary. In recent years, practitioners have adopted various schedules for patient and physician convenience. Jawad et al. reported on the HDR-BT experience at William Beaumont Hospital. They treated 494 favorable risk patients using three different treatment schedules. Their definition of “favorable risk” was a Gleason score ≤7 and stage≤T2b and PSA≤15 ng/ml. The 3 treatment schedules they utilized, the number of patients who received each, and the relative biologically effective dose  (BED) were as follows:

1. 38 Gy in 4 fractions (n=319) – 1.29 relative BED 
2. 24 Gy in 2 fractions (n=79) – 1.00 relative BED 
3. 27 Gy in 2 fractions (n=96) – 1.25 relative BED

Dose schedules #1 and #3 delivered much higher relative dose compared to dose schedule #2. The questions addressed by the study are whether the higher dose is justified by greater cancer control, and whether dose increased at the expense of increased side effects.

After 5.5 years median followup for schedule #1, 3.5 years for schedule #2, and 2.5 years for schedule #3, the toxicity outcomes were as follows:

• No difference in clinical outcomes (cancer control) among the 3 treatment schedules.
• Acute (appearing in less than 6 months) and chronic (appearing 6 months or more after treatment) grade ≥2 genitourinary (GU) and gastrointestinal (GI) side effects were similar for all treatment schedules.
• Grade 2 acute GU toxicities:

o   Frequency/urgency: 14%

o   Dysuria (painful urination): 6%

o   Retention: 7%

o   Incontinence: 1.5%

o   Hematuria (blood in urine): 1.5%

• ·      Grade 2 chronic GU toxicities:

o   Frequency/urgency: 20%

o   Dysuria (painful urination): 7%

o   Retention: 4% (Urethral stricture: 2%)

o   Incontinence: 2%

o   Hematuria (blood in urine): 7%

• ·      There was minimal grade 3 GU toxicity
• ·      Grade 2 acute GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: <1%

o   Rectal bleeding: 0%

o   Proctitis: <1%

• ·      Grade 2 chronic GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: 0.5%

o   Rectal bleeding: 2%

o   Proctitis: 1%

• ·      No Grade 3 or higher GI toxicity
• ·      Time to maximal appearance of symptoms was similar across treatment schedules
• ·      They did not report ED rates, which are typically low for HDR-BT.

Given the equivalence of cancer control and toxicity with treatment schedule, and the lack of any effect due to increasing the biologically equivalent dose, there seems to be little basis, other than cost and convenience, for choosing among these treatment schedules, at least with the available follow-up reported here.

Aspects of treatment scheduling that affect the convenience of HDR-BT are the number of implantations of the catheters, and the time frame in which the fractions are delivered.  William Beaumont Hospital uses a single implantation of catheters for all treatment schedules. Schedule #1 involves a longer (overnight) hospital stay because they wait for several hours between fractions for healthy tissue to recover. It also means that anesthesia must be administered over a longer period.

The California Endocurietherapy Center at UCLA has typically used a different protocol. They deliver 42 Gy in 6 fractions, with 3 fractions delivered one week and 3 fractions delivered a week later. This involves 2 overnight hospital stays, with anesthesia each time. Recently, they added a protocol where they deliver 27 Gy in 2 fractions (similar to schedule #3), but those fractions are still inserted a week apart. While this is certainly a cost reduction for the patient, who can now be treated as an outpatient, the patient is inconvenienced by having to go through the full procedure twice. It is a convenience for the treatment team that no longer has to attend the patient over an extended timeframe.

The William Beaumont Hospital experience demonstrates that HDR-BT treatment schedules can be constructed so as to lower costs and increase convenience for patients and doctors, without sacrificing cancer control or quality of life.

Dose-escalated radiation therapy doesn’t impact survival within ten years

Zaorsky et al. conducted a meta-analysis of 12 randomized clinical trials covering data on 6884 patients treated with external beam radiation at various dose levels. Their goal was to determine whether increasing the delivered biologically effective dose made a difference in 5 or 10 year metastasis-free survival, prostate cancer specific survival, or overall survival.

They found that dose-escalated radiation had the following effects:

• ·      10-year freedom from biochemical failure improved by 9.6% in low-risk men.
• ·      10-year freedom from biochemical failure improved by 7.2% in intermediate-risk men.
• ·      There was no corresponding improvement in metastasis-free survival, prostate cancer specific survival, or overall survival out to 10 years.
• ·      Dose escalation was not correlated with increases in acute toxicities.
• ·      Late-term gastrointestinal toxicities increased in patients treated with 3D-CRT.
• ·      Late-term toxicities were lower among patients treated with IMRT despite higher dose levels.

The abstract makes no mention of dose-escalated radiation treatment of high-risk men. We discussed some conflicting  survival data on higher risk patients in a previous commentary (see this link). As we saw, even at the higher risk levels, ten years follow-up was not long enough to detect difference in survival due to dose escalation.

The authors conclude:

“Thus, freedom from biochemical failure is a poor surrogate of overall patient outcomes for trials of RT.”

This is an unwarranted conclusion from the data presented in the abstract. We discussed the issue of surrogate endpoints (like freedom from biochemical failure) and length of follow-up in a previous commentary (see this link). For a newly diagnosed intermediate-risk man, the time frame for development of distant metastases could easily be upwards of 10 years, and a lot longer for low-risk men. The only valid conclusion one can draw from their analysis is that 10 years is too short a time frame to detect any effect of dose escalation on metastasis-free survival, prostate cancer survival or overall survival in these risk groups. Their analysis makes the argument for using surrogate endpoints, rather than against them. Given the long natural history of prostate cancer progression in these risk groups, how else can we gauge the impact of dose escalation within a practical followup timeframe?

The other interesting conclusion is that dose escalation, when delivered with IMRT technology, had no impact on acute or late-term toxicities. This argues for IMRT-delivered dose escalation: since it did not increase toxicity risk, and may increase long-term cancer control, there is no reason not to use it. This holds true even among low risk men who, for whatever reason, have elected not to engage in active surveillance. It also holds true for men with fewer than ten years of life expectancy who, for whatever reason, have elected not to engage in watchful waiting.

Salvage whole-gland cryoablation after radiation therapy failure

At the 17^th International European Association of Urology Meeting, Joseph Chin of the University of Western Ontario presented his analysis of outcomes of 157 patients treated with whole-gland salvage cryotherapy after primary radiotherapy failure between 1995 and 2004. After a median followup of 117 months:

• ·      10-year overall survival was 76%
• ·      10-year metastasis-free survival was 74%.
• ·      Median biochemical disease-free survival was 56 months.
• ·      10-year biochemical disease-free survival was 34%.
• ·      15-year biochemical disease-free survival was 23%.
• ·      Of the 179 complications, 22 (12%) were serious.

While more than 3 in 4 men had a biochemical recurrence after salvage cryotherapy, it’s not at all clear whether any salvage therapy on this group of patients could have increased survival any better or with fewer complications. As far as I’m aware, this is the longest followup that has been reported in a salvage cryotherapy study, but, paradoxically, its greatest strength is also its greatest weakness. Many of the men treated in this study were selected for salvage treatment before we had advanced imaging techniques that might have identified small distant metastases in many of them. Also, cryotherapy has benefitted from technological advances that have reduced morbidity considerably.

There are many outstanding questions:

• ·      How should patients be selected for salvage therapy after radiation?
• ·      Can we use advanced imaging to eliminate those patients in whom distant metastases have already occurred?
• ·      Did the salvage therapy delay progression?
• ·      Is there a survival advantage to salvage whole-gland cryoablation vs. focal or hemi-gland cryoablation?
• ·      Is there an advantage in terms of treatment morbidity to salvage whole-gland cryoablation vs. focal or hemi-gland cryoablation?
• ·      How does salvage cryo compare to other ablative salvage therapies, salvage radiotherapies, or salvage surgery after radiation failure?

Why toxicity was higher with hypofractionation in Dutch trial

Aluwini et al. have published the toxicity outcomes of a randomized clinical trial (HYPRO) designed to test whether a hypofractionated external beam (EBRT) regimen compared to conventional fractionation. They will report on the oncological outcomes at a later date.

Between 2007 and 2010, 782 intermediate and high-risk patients were treated at 4 Dutch centers. About half were treated with the hypofractionated regimen, half with conventional dosing as follows:

• ·      Hypofractionation: 19 fractions of 3.4 Gy each
• ·      Conventional fractionation: 39 fractions of 2.0 Gy each
• ·      The relative biologically effective dose is 16% higher for the hypofractionated regimen.
• ·      Both groups were treated with conformal EBRT (3D-CRT and IMRT).

After a median followup of 60 months, the 3-year late-term toxicity outcomes were as follows:

• ·      Genitourinary toxicity, grade 2 or higher: 41% among the hypofractionated group vs. 39% for conventional fractionated.

o   Hazard ratio: 1.16 (Non-inferiority threshold: 1.11)

• ·      Genitourinary toxicity, grade 3 or higher: 19% among the hypofractionated group vs. 13% for conventional fractionated.

• ·      Gastrointestinal toxicity, grade 2 or higher: 22% among the hypofractionated group vs. 18% for conventional fractionated.

o   Hazard ratio: 1.19 (Non-inferiority threshold: 1.13)

• ·      Gastrointestinal toxicity, grade 3 or higher: 3% among the hypofractionated group vs. 3% for conventional fractionated.

Because the toxicity difference slightly exceeded the pre-established thresholds, the authors conclude that the hypofractionated regimen was not non-inferior to the conventionally fractionated regimen in terms of late term toxicity.

Because the hypofractionated regimen was a higher biologically effective dose, we might expect toxicity to be somewhat higher. Several recent major trials showed that hypofractionated IMRT was non-inferior to conventional fractionation in terms of both oncological control and late-term toxicity (see this link and this one, and this one). The lesson we learn from this study is that hypofractionation carries increased risk of toxicity. To avoid that, it is important to use well-planned IMRT or SBRT regimens. 3D-CRT is probably not the optimal platform for such treatment.

Survival slightly higher at high-volume radiation treatment centers

We all know that prostate surgery results are significantly better at high-volume centers (see this link). Unsurprisingly, the same holds true for primary radiation treatment of high-risk patients.

Chen et al. analyzed the National Cancer Database to find data on 19,465 high-risk patients treated at 1,099 facilities between 2004 and 2006 and followed up through 2012. Patient data included age, race, insurance status, comorbidity, clinical stage, Gleason score, type of radiation, use of ADT, type of facility, household income, education level, and location. The 20% highest volume facilities treated half the patients, and that was arbitrarily chosen as the definition of “high volume.” After median 81 months of follow-up, they found:

• ·      High volume facilities treated 223 patients (median)
• ·      Low volume facilities treated 76 patients (median)
• ·      High volume facilities were more likely to be academic hospitals, in a metropolitan area.
• ·      Patients treated at high volume facilities were more likely to have higher Gleason scores, stage T3, and lower PSA. They were also twice as likely to receive brachy boost therapy (17% vs. 8%).
• ·      They adjusted for all patient data in their analysis.

They were only able to retrieve data on overall mortality, not prostate cancer-specific mortality. The key finding was that for every 100 patients treated, mortality risk was reduced by 3%. So, a typical high volume facility treating 223 patients in this time period had 4.4% fewer deaths per patient treated than a typical low volume facility treating 76 patients.

Incidental findings of mortality risk included:

• ·      33% lower risk among patients who received brachy boost therapy
• ·      17% lower risk among patients who received brachytherapy
• ·      Risk increased 5% for every year of age
• ·      30% lower risk among Hispanics compared to Anglos or African-Americans
• ·      40% higher risk among those using Medicaid
• ·      Higher risk among those with <$35,000 income and with less education
• ·      Higher risk among those with more co-morbidities, higher tumor stage, and Gleason score

Unfortunately, there were no available data in this analysis on physician experience.

While the effect of treatment volume is small, it is statistically significant. What is most striking, however, is the overwhelming effect of age, poverty, and other risk factors. There is an important interaction effect as well: brachy boost therapy, which requires the coordination of various specialists, is often only available at high volume centers. As we’ve seen both here and in recent clinical trials, oncological outcomes are significantly improved by the combination therapy.

Higher volume facilities tend to have the best equipment, attract the best doctors and have experienced treatment teams. However, the individual doctor’s experience and abilities is of much greater importance. With brachy boost therapy, it is not necessary that the external beam therapy and the brachytherapy be performed at the same facility, only that the radiation oncologists coordinate their treatments. Often, it is more convenient to travel to an experienced brachytherapist, but to have the time-consuming external beam portion of the treatment done locally. The patient should primarily find the most qualified doctor(s) for his treatment.