What should focal therapy be compared to and how does it compare?

In a recently published randomized trial of a new kind of focal ablation therapy for prostate cancer that was widely misinterpreted in mainstream media, the authors wrote:

"A pivotal comparative study was therefore necessary, but was challenging to design in a manner that would be acceptable to both patients and clinicians and in which the same primary outcome [histologically confirmed progression of cancer] could be assessed for the intervention and the comparator. We had three options for the comparator: surgery, radiotherapy, or active surveillance. For the first two options, a primary outcome that could be applied to both the experimental group and the control group proved difficult to find. Surgery (radical prostatectomy) would not be suitable for a biopsy-based outcome because there would be no prostate from which to take a biopsy. Radiotherapy would be amenable to a protocol-required biopsy, but the histological outcome would be confounded by the necessary neoadjuvant and adjuvant androgen suppression that constitutes the standard of care. Therefore, active surveillance was the only comparator that could reasonably be used over the intended time frame [2 years] of the study.

This is an odd statement, indeed. They rejected surgery as a comparator because salvage treatment is usually given before it is possible to obtain histological (biopsy) confirmation of spread to the prostate bed. This is reasonable. They rejected comparison to radiation because it is difficult to interpret a biopsy on tissue in which the cancer has been shrunk by androgen deprivation. However, all patients were low-risk patients who would almost never receive neoadjuvant or adjuvant androgen deprivation along with their radiotherapy, at least not in the US. Perhaps this is or was standard of care in Europe. That left them with active surveillance as a comparator, but the kind of active surveillance and patient selection for it bears closer examination.

Active surveillance as practiced at the time (2011-2013) in those European centers of excellence was different in some important respects from active surveillance as currently practiced in US centers of excellence. In the US, a confirmatory multiparametric MRI (mpMRI) is often given within a year of the first biopsy, and biopsy cores are obtained from any suspicious areas. The authors state that their study began before this practice became prevalent in Europe. In spite of that, all patients who received focal ablation were given an mpMRI before therapy, while none of the men on active surveillance received it. Certainly, many of the men in the active surveillance cohort had undiagnosed higher grade cancer, and should not have continued on active surveillance. It is impossible to say that any of the cancers progressed in the 2 years on active surveillance, or whether they were simply reclassified because the two repeat biopsies found the cancer that was always there, and which might have been found earlier had the received an mpMRI as the ablation cohort did.

The authors further state:

"The European Medicines Agency agreed that we could reasonably exclude very low-risk patients. Therefore, lower and upper thresholds of risk (defined by Gleason score and tumour burden) were set, below and above which men were excluded.

So "very low risk" prostate cancer patients, who make up most of the patients in active surveillance programs in the US, and all of them in some programs (e.g., Johns Hopkins), were excluded. Focal therapy is compared here to higher risk active surveillance patients than is typical in the US.

Patient selection was also atypical in that no more than 3 positive cores were allowed, and the length of cancer in any one core had to be between 3mm and 5mm. Men with very small (<25 cc and very large (>70 cc) prostates were excluded.

Progression was deemed to have occurred if any of several criteria were met:

1. Gleason pattern≥4
2. > 3 positive cores
3. Cancer core length > 5 mm
4. PSA>10 in 3 consecutive measurements
5. stage T3 discovered

Only the first 3 had a significant effect. It should again be emphasized that many active surveillance programs now recommend radical treatment if a biopsy shows predominant Gleason pattern 4. Under such programs, many, if not most, in their active surveillance cohort would not be deemed to have progressed. This is especially true when mpMRIs are used early to rule out predominant pattern 4.

The procedure

The kind of focal therapy used here (called TOOKAD soluble vascular photodynamic therapy) involves treating the patient under general anesthesia with an intravenous injection of a photosensitizing chemical, called padeliporfin. Optical fibers were inserted transperineally with one end at the tumor to be ablated and the other end attached to a near-infrared laser that delivered an energy dose of 200 J/cm. I believe the authors err when they characterize this as "non-thermal." The operation took about 2 hours, and patients stayed overnight in the hospital. The catheter was removed the next day.

Retreatment was allowed if the 12-month biopsy indicated residual cancer. It's important to keep this in mind when looking at the oncological outcomes. 32% received another treatment on the contralateral side. 6% received retreatment after 12 months. There is no analysis provided showing the toxicity among men who received multiple treatments compared to those who only received a single treatment.

Oncological outcomes

After 2 years of follow-up among the men who received up to two treatments of the focal photodynamic therapy (PDT):

• 28% progressed, mostly with higher Gleason grade
• 58% progressed or were reclassified in their active surveillance cohort
• 51% had a positive biopsy
• 86% had a positive biopsy in their active surveillance cohort

The European PRIAS study of active surveillance found that only 23% had progressed within 2 years, which was even less than the 28% progression rate found here with focal treatment, but PRIAS comprised patients who were very low risk only. In the Klotz study of low-risk patients, 30% progressed in 5 years - about the same as progressed in 2 years here with focal therapy. (See this link.)

Since this is only with 24 months of follow-up, we can conclude that 30% were able to avoid radical treatment for 2 extra years. (Update 6/2018: Even after 4 years of follow-up, the difference was maintained at about 30%). But if the active surveillance group had been initialized with mpMRI detection, it's not clear that this benefit would persist.

It's also worth noting that 52% had no evidence of disease in one active surveillance study on a confirmatory biopsy (see this link), similar to what was seen here with focal treatment. The apparent remission rate was about 40% even using mpMRI-targeted biopsy (see this link). These are much higher than the apparent remission rate of 14% in this active surveillance cohort, again calling into question how active surveillance was defined here. With treatment with Proscar or Avodart, the apparent remission rate has been found to be 54% (see this link), which is equal to that observed here with focal therapy. Could the same rate of apparent remissions be achieved simply by taking a pill?

Morbidity

Side effects of treatment, while seldom serious enough to warrant intervention other than re-catheterization for a period of time, did occur. One in three patients suffered some kind of toxicity from the treatment. Most were low grade (grade 1 or 2) and transient. The ones that occurred significantly more in the treated cohort were (cumulative incidence within 2 years):

• Erectile dysfunction 38%
• Blood in urine 29%
• Painful urination 26%
• Urinary retention 17%
• Perineal pain 16%
• Urinary urgency 11%
• Urinary tract infection 11%
• Urinary incontinence 10%
• Urinary frequency 10%
• Ejaculation failure 8%
• Prostatitis 6%
• Inguinal hernia 4%
• Rectal hemorrhage 4%

There was one case of anaphylactic shock due to the anesthesia. Three men had urinary retention serious enough to require surgical intervention.

Would these men have been better off with radical therapy? We can look at these results side-by-side with some toxicity outcomes of SBRT treatment. The table below shows the highest incidence of side effects reported by both studies. I chose this Georgetown study because they gave 2-year outcomes and because they included Grade 1 toxicity - often only grade 2 or higher toxicity is reported. As with focal therapy, almost all of the side effects were mild (grade 1) and acute, occurring within the first month of treatment, and returning to baseline within 2 years. Potency retention was 79% at 2 years. Similar to focal ablation, only 1% had any serious (grade 3) toxicity. However, none were life-threatening.

In the SBRT study, there were no biochemical failures in the first two years among the low risk and intermediate risk patients in the study. This compares to 51% with evidence of disease, and 28% with higher risk prostate cancer already in the first 2 years for the focal therapy, even with retreatment in some.

It should be clear to patients that the benefits of focal therapy depends on what it is compared to. This analysis should also alert patients to be wary of media hype. For a discussion of the unresolved issues in focal ablation, see this link.

(update 2/2020) FDA Rejects TOOKAD for low-risk prostate cancer

The FDA oncologic drugs advisory committee rejected Steba Biotech's new drug marketing application. The decision may be revisited after Steba presents the results of a longer-running trial expected in 2025. In a Medpage interview, Patrick Walsh, on the committee, said:

"I think most of these patients [treated with TOOKAD] won't be told that at 2 years half of the men will still have cancer and in 28% it will be progressing."

Hypofractionated radiation therapy using IMRT has a clear advantage

I was reticent to write about hypofractionation yet again after writing about it so often in the last year. See this link for my latest summary. In a sea of randomized trials demonstrating that hypofractionated radiation therapy (i.e., it is delivered in fewer treatments or fractions) was no worse in cancer control or in toxicity to conventionally fractionated (40-44 treatments), there was one study, the Dutch HYPRO study, where the toxicity was a bit worse. At the time (see this link), I speculated that that was because they included an older radiation technique called 3D-CRT rather than the IMRT technology that is now prevalent in the US. A new study from MD Anderson suggests that may indeed be the case.

Hoffman et al. presented the patient-reported outcomes of 173 men with localized prostate cancer who were treated at M.D. Anderson in Houston. They were randomized to receive either:

1. 75.6 Gy in 42 fractions (conventional fractionation) via IMRT
2. 72 Gy in 30 fractions (hypofractionation) via IMRT

The men filled out questionnaires at baseline, and at 2, 3, 4, & 5 years after treatment. Patients were probed on their urinary, rectal and sexual status. Patient-reported outcomes on validated questionnaires is a more reliable source of toxicity data because it does not rely on the patient volunteering information to the doctor or the doctor assessing or recording that information. Analysis of the two groups showed that:

• there was no difference with regard to rectal issues (urgency, control, frequency, or bleeding).
• there was no difference with regard to urinary issues (pain, blood in urine, waking to urinate at night, or leakage)
• there was no difference with regard to sexual issues (erections firm enough for intercourse)
• there were no differences at 2, 3, 4, or 5 years.

This should dispel any concerns that completing IMRT in less time may be more toxic. Just as with all forms of radiation, the technology has improved greatly over the years. In the hands of an experienced and careful radiation oncologist, there is no reason that external beam therapy cannot be completed in less time and at lower cost.

Combining Androgen Deprivation Therapy (ADT) and Salvage Radiation Therapy (SRT) improves outcomes

For the first time, a randomized clinical trial  (GETUG-AFU 16) proves that adding a short course of ADT to SRT improves the progression-free survival over SRT alone. This confirms the implications of several earlier studies, and is not especially surprising. Many radiation oncologists already integrate ADT into their SRT treatments of selected patients.

Carrie et al. (updated 5/2019) conducted a multi-institutional study in France on 743 patients with the following characteristics:

• ·      Randomized for SRT between 2006 and 2010
• ·      All had undetectable PSA post-prostatectomy
• ·      PSA≥0.2 ng/ml and <2 ng/ml at study entry
• ·      Stage pT2 (54%) or pT3 (46%)
• ·      Positive margins (51%)
• ·      Seminal Vesicle Involvement (SVI) (13%)
• ·      No positive lymph nodes or signs of progressive disease
• ·      PSA doubling time> 6 months (74%)
• ·      Gleason 7-10 (76%)
• ·      Median age – 67 years
•     Low Risk = Gleason 7, negative margins, PSADT>8 months and no SVI
•     High Risk= all others

The treatment consisted of:

• ·      External beam RT: 66 Gy to prostate bed ± pelvic lymph node radiation
• ·      369 patients received 6 months of goserelin, 374 received no hormone therapy

After a median of 112 months of follow up, the results were:

10-year  progression-free survival was 46% lower without ADT (HR=0.54)

• HR=0.47 among low risk patients     
• HR=0.56 among high-risk patients

     10-year metastasis-free survival was 75% with ADT,  69% without ADT (HR=0.73)

      Acute toxicities: 89% with ADT, 79% without ADT

·      No difference in Grade 3 acute toxicities

·      No difference in late toxicities

Based on this, the authors conclude, “RT+HT could be considered as the standard in this situation.” The authors are of course privy to data we have not yet seen. It behooves us to further explore this rich source of information, to the extent that the sample size permits, to help determine which patients are most likely to benefit from the combined modality. There may be some with, say, low Gleason score, Stage pT2, small positive margins, and low, slowly rising PSA levels who do not need ADT, or may even be safely watched. Others, with evidence of systemic micrometastases may benefit from even more extensive ADT (see below).

Timing of the initiation of SRT is an issue in this study. SRT was delayed until there was a confirmed indication of biochemical recurrence (PSA≥0.2 ng/ml). However, three randomized clinical trials published after this study started have confirmed the benefit in biochemical control of beginning radiation much sooner in PSA progression. It is unclear whether ADT would have been as beneficial or necessary at all had therapy begun when PSA reached 0.03 ng/ml on an ultrasensitive test.

Several randomized clinical trials have demonstrated a benefit to adding ADT to RT for first-line treatment of advanced prostate cancer. There have been several retrospective analyses that hinted that ADT could enhance the effectiveness of SRT as well. Cortés-González et al. in Sweden reported a 4-year biochemical no evidence of disease of 63% among men treated with 3 months of hormone therapy before SRT. Choo et al. in Toronto reported a 7-year freedom from relapse rate of 79% among men treated with 2 years of ADT after SRT. Pai et al. in Vancouver reported 5-year biochemical disease-free survival of 80% if they had adjuvant radiation with ADT pre-treatment, but 67% without the pre-treatment; and 62% if they had salvage radiation with ADT pre-treatment, but only 27% without the pre-treatment.

An earlier randomized clinical trial (RTOG 9601) proved that 2 years of anti-androgen therapy with bicalutamide improved the 7-yr freedom from progression to 57% compared to 40% for SRT alone. Incidence of metastases was also significantly reduced, and toxicity was about the same, except for an increase in gynecomastia and liver toxicity. Howard Sandler added this comment:

"So, in my view, 9601 endorses ADT or bicalutamide for men with elevated PSAs after surgery, but most rad oncs have a PSA threshold: if the PSA is low, then RT alone, if the PSA is high, RT+ADT. There is variation in this threshold. My own personal threshold is 0.5 ng/mL."

Further evidence for the systemic effect of ADT came from a retrospective study by Soto et al. at the University of Michigan. They reported that concurrent ADT was beneficial only among those who had been originally diagnosed as high risk (the group most likely to evince micrometastases).

Among the factors yet to be learned are the optimum duration and timing of the added ADT. In a retrospective study, Jackson et al. at the University of Michigan reported 5-year incidence of distant metastases was 6% if they received more than 12 months of additional ADT after SRT, but 23% if they received less than 12 months of additional ADT. In fact, every month of ADT was associated with a 10% reduction in biochemical failure, distant metastases, and mortality.

(Update 3/21/2019) Fossati et al. identified 3 risk factors that determined optimal duration of adjuvant ADT with salvage RT:

• Stage ≥ pT3b
• Gleason score ≥ 8
• PSA≥ 0.5 ng/ml

Men with 2 or 3 risk factors benefited from up to 3 years of adjuvant ADT; men with 1 of the 3 benefited from up to 12 months of ADT; men with no risk factors did not benefit from adjuvant ADT.

This study raises many important questions about the use of ADT with SRT:

• ·      Is it beneficial when radiation doses above 70 Gy are used, or with hypofractionated SRT?
• ·      Is it beneficial when started sooner?
• ·      What are the effects of adding ADT on long-term sexual function?
• ·      Are there subsets of patients who are more likely to benefit than others?
• ·      Are there biochemical markers (e.g., Decipher™ or CellSearch™) that may be used to identify patients more likely to benefit?
• ·      Should ADT be started neoadjuvantly (before SRT)? Should ADT be used concurrently and adjuvantly?
• ·      Is the optimum duration of ADT use related to the patient’s pathological findings – pre-treatment PSA, Gleason score, stage, and positive margins?
• ·      Would outcomes improve with the expansion of the treatment field to include pelvic lymph nodes, and in which patients?
• ·      Would outcomes improve through the detection and boosted treatment of metastases identified using multiparametric MRIs or PET scans?
• ·      Would immune enhancement (e.g., Provenge, Leukine, Yervoy, Keytruda) improve outcomes?
• ·      Would outcomes improve still further with adjuvant docetaxel, as demonstrated recently by RTOG 0621?
• ·      Would stronger forms of androgen deprivation (e.g., Zytiga or Xtandi) improve outcomes?

There are a couple of randomized clinical trials that will help answer more of the outstanding questions. RADICALS-RT includes arms that are getting no ADT, short-term ADT, and long-term ADT. RTOG 0534 includes arms that are getting SRT with no ADT, short-term ADT, and short-term ADT with pelvic lymph node radiation.

GETUG-AFU 16 represents an important advance in our knowledge of the interaction of short-term ADT with salvage radiation. However, before subjecting every man getting salvage radiation to ADT, we have to learn which patients are most likely to benefit, and the optimum treatment protocol.

Hypofractionated radiation therapy for localized prostate cancer: an update

In the past year, we have reviewed several major randomized clinical trials comparing hypofractionated radiation therapy to conventionally fractionated radiation therapy for primary treatment. To recap:

The CHHiP Study (reviewed here and published here) proved that 60 Gy delivered in 20 fractions was not inferior to 74 Gy in 37 fractions in terms of cancer control, patient-reported toxicity, or physician-reported toxicity.

The Fox Chase trial (reviewed here), which focused on men with intermediate and high-risk prostate cancer, proved that 70.2 Gy delivered in 26 fractions was not inferior to 76 Gy in 38 fractions. All functional outcomes (urinary, bowel, and sexual) were similar in the long term.

RTOG 0415 (reviewed here), which focused on men with low-risk prostate cancer, proved that 70 Gy delivered in 28 fractions was not inferior to 73.8 Gy in 41 fractions in terms of cancer control, rectal or urinary toxicity.

Finally, the HYPRO trial, which enrolled predominantly (>70 percent) high-risk patients and some intermediate risk patients,’ previously published its toxicity analysis (reviewed here). They have now released their findings about cancer control (available here). Patients assigned to hypofractionation received 64.6 Gy in 19 fractions; conventional fractionation was 78 Gy in 39 fractions. Radiation was delivered using 3D-CRT rather than IMRT. After 60 months median follow-up, they report:

• ·      Treatment failure occurred in 20 percent of the patients receiving hypofractionated radiation vs. 22 percent of those who received conventional fractionation. No significant difference.
• ·      5-year relapse-free survival was 80.5 percent among the hypofractionated radiation patients vs. 77.1 percent among the conventionally fractionated radiation patients. No significant difference.

They conclude:

“Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer.”

It’s difficult to understand their reticence to adopt hypofractionation as the new standard of care, and W. Robert Lee (in an accompanying editorial) explains the apparent discrepancy. He notes that the HYPRO trial set a goal of raising the relapse-free survival by 10 points, from 70 percent to 80 percent using hypofractionation. While it achieved over 80 percent control, it was not a difference of 10 points. Therefore, they could not prove that the hypofractionated protocol was superior. The other trials only attempted to prove that hypofractionation was not inferior, which they did.

Patients, who are not as concerned with the statistical niceties of the distinction between inferiority studies and superiority studies, have reason to rejoice over these results. Collectively, these studies mean that the treatments can be done as effectively and with about the same toxicity as the typical 9-week IMRT schedule.

It’s worth mentioning that hypofractionation is gaining acceptance for other kinds of cancer as well, such as breast cancer. Extreme hypofractionation, such as SBRT, has been used effectively and with low toxicity in prostate and other cancers, but has not yet been proven in a randomized clinical trial.

There are some appropriate cautions: hypofractionation can be very safe if the radiation oncologist is using the latest fast and accurate linear accelerators that are designed to deliver the higher doses. State-of-the-art image guidance, using such tools as fiducials, radio transmitters, and cone-beam CT imaging, is equally important. And nothing is more important than an experienced radiation oncologist who takes meticulous care to optimize the treatment plan with respect to dose constraints for organs at  risk.

This is a hard sell to many radiation oncologists in private practice because it hits them in the pocketbook. On the other hand, if they don't get on board, they will be left in the dust. Some patients may nevertheless opt for the more conventional treatment, but there is no reason that the hypofractionation option should not be discussed.