Monday, November 26, 2018

Can surgery+radiation+ADT provide equal outcomes to brachy boost therapy +ADT in high risk men?

As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10 year metastasis-free survival and 10 year prostate cancer specific survival (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

  • 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
    • 88 received adjuvant EBRT
    • 49 received adjuvant ADT
    • 50 received both (called MaxRP)
    • Median ADT duration - 8.6 months in 49 men with negative lymph nodes
    • Median ADT duration - 14.5 months in 39 men with positive lymph nodes
  • 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
    • Median ADT duration - 6 months
After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:
  • 2.8 times greater for any RP (statistically significant)
  • 0.5 times less for RP+adjuvant EBRT (not statistically significant)
  • 3.2 times greater for RP+adjuvant ADT (statistically significant)
  • 1.3 times greater for MaxRP (not statistically significant)
The 5-year PCSM was:
  • 2% for MaxRT
  • 22% for any RP (significantly higher than MaxRT)
  • 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
  • 27% for RP+adjuvant ADT (significantly higher than MaxRT)
  • 10% for MaxRP (not significantly different from MaxRT)
They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study
Tilki
Kishan
Sample size
BBT: 80
RP+EBRT: 88
RP+ADT: 49
RP+EBRT+ADT: 50
BBT: 436
RP+EBRT: 272
RP+ADT: 175
ADT duration (median)
BBT: 6 months
RP (N1): 14.5 mos.
RP (N0): 8.6 mos.
BBT: 12 months
RP (% N1)
44%
17%
5-year % PCSM
RP (any): 22%
BBT: 2%
RP (any): 12%
BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:
RP+ADT: 3.2
RP+EBRT: 0.5 (not sig.)
RP+ADT: 3.2
RP+EBRT: 2.0


We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.






Tuesday, October 30, 2018

Newest radiopharmaceutical: Th-227-PSMA-antibody

Bayer has announced a new clinical trial of the latest entry in the race for radiopharmaceuticals to treat prostate cancer, joining Lu-177-PSMA-617, Ac-225-PSMA-617, and I-131-MIP-1095. They are trying Thorium-227 attached to a PSMA antibody.

Thorium-227, like Ac-225, is an alpha-particle emitter. Alpha emitters are very powerful, but very short range, only killing cells that are 2 to 10 cells away from the cancer cell it attaches to. This may limit its toxicity, but may require higher doses for larger, more widespread tumors.  Beta emitters, like Lu-177, are less powerful, but the beta particle penetrates to a much greater depth, affecting about 125 cells. Researchers at the University of Heidelberg are experimenting with mixtures of the two.

The other part of the equation is the ligand that the radioactive atom is attached to and that attaches to the PSMA protein on the prostate cancer cell. Ligands include PSMA-617, PSMA-I&T, MIP-1095, and J591. Ligands may be small molecules, antibodies, or "minibodies." Bayer is using a proprietary antibody-type ligand that they developed for the purpose. Ligands that are more specific for PSMA have less toxicity.

On the other side of the ligand molecule, it must bind very tightly to the radioactive element. If it doesn't, the radioactive element might be released into systemic circulation where it can damage healthy cells. Heavy metals, like thorium, are attached relatively weakly by a process called "chelation," but some chelators are stronger than others. Researchers have so far been unsuccessful in developing a stable chelate for Ra-223 (the main ingredient in Xofigo, which is also manufactured by Bayer) to a PSMA ligand. However, Th-227 decays into Ra-223, so it is unknown if the thorium chelate will continue to hold as it decays. However, Bayer has already begun two clinical trials for Th-227 chelated to an antibody for non-Hodgkin's lymphoma since 2015, and for ovarian cancer and mesothelioma since April, which have not been terminated for excess toxicity. There is every reason to hope that the chelation complex they devised for the PSMA-antibody ligand holds up in biological systems.

This is a dose-finding (Phase 1) clinical trial among 108 patients with metastatic castration-resistant prostate cancer. They list 4 locations that will be recruiting: Memorial Sloan Kettering in NYC, as well as locations in the UK, Finland, and Sweden.

Wednesday, October 24, 2018

SBRT has excellent outcomes for intermediate risk patients

Stereotactic Body Radiation Therapy (SBRT, or sometimes SABR or SHARP or CyberKnife) has had excellent 7-year outcomes in an update of the consortium study. Amar Kishan presented the results of his analysis at the ASTRO meeting today.

The consortium consisted of

1 Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA
2 Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA
3 Flushing Radiation Oncology Services, Flushing, NY, USA
4 21st Century Oncology, Fort Myers, FL, USA
5 Department of Radiation Oncology, Georgetown University, Washington, DC., USA
6 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
7 Division of Genesis Healthcare Partners Inc., CyberKnife Centers of San Diego Inc., San Diego, CA, USA
8 Swedish Radiosurgery Center, Seattle, WA, USA.
9 Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON,
Canada.
10 Section of Radiation Oncology, Virginia Mason Medical Center, Seattle, WA, USA
11 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
12 Department of Radiation Oncology, University of Michigan
13 Scripps Health, 11025 North Torrey Pines Road, La Jolla, CA, USA
14 Virginia Hospital Center, 1701 N. George Mason Dr, Arlington, VA, USA

The meta-analysis covers 2,142 low (n=1,185) and intermediate-risk men treated with SBRT between 2003 and 2012. Intermediate risk men were further subdivided into "favorable intermediate risk" (n=692) and "unfavorable intermediate risk" (n=265) per the NCCN definition.

After a median follow-up of 6.9 years, the 7-year biochemical recurrence-free survival was:

  • low risk: 95.5%
  • favorable intermediate risk: 91.4%
  • unfavorable intermediate risk: 85.1%
  • all intermediate risk: 89.8%

Low risk patients and some of the favorable intermediate risk patients would probably be diverted to active surveillance today. The 7-year intermediate risk biochemical recurrence-free survival compares favorably with (note: this is not a randomized comparison, which is the only valid way of comparing):

  • Surgery: favorable intermediate risk (PSA=6.0, T1c, GS 3+4, 33% cancerous cores): 81% (mean of 5 and 10-yr Progression-free survival) (1)
  • Surgery: unfavorable intermediate risk (PSA=6.0, T1c, GS 4+3, 67% cancerous cores): 53% (mean of 5 and 10-yr Progression-free survival) (1)
  • Hypofractionated IMRT (5 year):  85% (2)
  • Conventional IMRT (5 year): 85% (2)
  • Low dose rate brachytherapy: favorable intermediate risk (avg of 5 and 10-yr): 85% (3)
  • Low dose rate brachytherapy: unfavorable intermediate risk (5-year): 81% (3)
  • Brachy boost therapy: unfavorable intermediate risk (10 year): 92% (4)

7-year metastasis-free survival was:

  • low risk: 99.9%
  • favorable intermediate risk: 98.3%
  • unfavorable intermediate risk: 97.0%
  • all intermediate risk: 98.0%

There were no prostate cancer-related deaths.

Use of ADT and higher doses (doses ranged from 33 Gy to 40 Gy in 4 or 5 treatments) did not affect recurrence.

Acute (within 3 months of treatment) toxicity was low:

  • Urinary toxicity Grade 2: 8.8% Grade 3: 0.6%
  • Rectal toxicity Grade 2: 3.2% Grade 3: 0.1%

Late-term cumulative toxicity was low:

  • Urinary toxicity Grade 2: 9.4% Grade 3+: 2.1%
  • Rectal toxicity Grade 2: 3.9% Grade 3+: 0.4%


Late-term grade 3 or greater urinary toxicity of 2.1% compares favorably to other radiation monotherapies reported in other studies. For example:

  • Low dose rate brachytherapy: 7.6% (5)
  • High dose rate brachytherapy (3 fractions):11% (6)
  • Hypofractionated IMRT (70 Gy/28 fx): 3.5% (7)
  • Conventionally fractionated IMRT: 2.3% (7)
  • Brachy boost therapy: 19% (8)


Late-term grade 3 or greater rectal toxicity of 0.4% compares favorably to other radiation monotherapies reported in other studies. For example:

  • Low dose rate brachytherapy: 0.8% (5)
  • High dose rate brachytherapy (3 fractions):1% (6)
  • Hypofractionated IMRT (70 Gy/28 fx): 4.1% (7)
  • Conventionally IMRT: 2.6% (7)
  • Brachy boost therapy: 9% (8)

This 7-year analysis on a large group of patients from multiple sites, should make intermediate risk patients comfortable in choosing SBRT, especially if they are favorable intermediate risk. For patients who are unfavorable intermediate risk, brachy boost therapy affords incomparable oncological control, but at the risk of much higher late term urinary and rectal toxicity.



Tuesday, October 23, 2018

Whole pelvic salvage radiation + short-term ADT improves oncological results

We didn't expect to see this for another two years, but they hit their recruitment goal early and were able to provide 5-year results. Alan Pollack, the lead investigator, presented the preliminary findings of NRG Oncology/RTOG 0534 (or SPPORT) trial at the ASTRO meeting, and in Medpage Today. It proved that salvage whole pelvic radiation (sWPRT) with short term ADT  (STADT) is superior to either prostate-bed only salvage radiation (PBRT) or prostate-bed only salvage radiation with short term ADT.

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:
  1. sWPRT+STADT
  2. PBRT + STADT
  3. PBRT
  • ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
  • Radiation dose to the prostate was 64.8-70.2 Gy at 1.8 Gy per fraction.
  • Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
  • The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion
The oncological results were:
  • 5-year freedom from progression (biochemical or clinical) was 89% for sWPRT+STADT, 83% for PBRT+STADT, and 72% for PBRT (all significantly different). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
  • 8-year incidence of metastases was 25 for sWPRT+STADT (HR=0.52), 38 for PBRT+STADT (HR=0.64), and 45 for PBRT (sWPRT+STADT was significantly better than the other two)

The reported toxicity results were:
  • GI grade 2 or higher: 7% for sWPRT+STADT vs. 2% for PBRT
  • Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT
  • Bone marrow grade 3: 2.6% for sWPRT+STADT vs. 0.5% for PBRT
  • Late term bone marrow grade 2 or higher was 4% for sWPRT+STADT

There were some caveats. The researchers found that the benefit of salvage whole pelvic treatment and ADT was not maintained in men with very low PSA. There are further analyses expected based on patient risk characteristics and genomic biomarkers. We previously saw in a retrospective study that prostatectomy Gleason score had a significant influence. With better PET scans now, we can have more assurance that whole pelvic radiation is necessary. But at very low PSA (<0.2), even our best PET scans may not find the cancer. Also, it may be that long-term ADT may improve results even further, and that dose escalation may improve results. While this changes the standard of care for many men with persistent PSA and recurrences after prostatectomy, the patient and his radiation oncologist still must rely on judgment.



Monday, October 15, 2018

Low Dose Rate Brachytherapy Monotherapy at the Mayo Clinic

The Mayo Clinic reported the 10-year oncological results on 974 consecutive low and intermediate risk patients treated with low dose rate brachytherapy (I-125 seeds) monotherapy from 1998 to 2013.

Patients were treated as follows:

  • 90% of the prostate received 159 Gy (median dose) of 1-125 seeds
  • 26% received some ADT (mainly to shrink the prostate)


Patient characteristics (number (%)) were as follows:

  • Gleason 6: 783 (80%)
  • Gleason 3+4 :153 (16%)
  • Gleason 4+3:  38 (4%)
  • Stage T 2b or 2c: 24 (2.5%)
  • PSA ≥ 10: 93 (10%)
  • Low risk: 693 (71%)
  • Intermediate risk: 281 (29%)


While they did not routinely collect data on the percent of positive biopsy cores, they did define an "unfavorable intermediate risk" cohort as having Gleason 4+3 or multiple intermediate risk factors.

With median follow-up of 6 years, there were only 45 cases of biochemical failure, and 10 deaths from any cause. The 10-year biochemical recurrence-free survival was:

  • 85% overall
  • 90% among low risk men
  • 74% among intermediate risk men


The following hazard ratios were significant on multivariate analysis:

  • Gleason score 4+3: 7.0
  • Use of ADT: 0.3
  • PSA (per unit increase): 1.17
  • Unfavorable intermediate risk : 3.75


Predominant Gleason pattern 4 also affected the rate of distant metastases and prostate cancer-specific survival. Use of ADT did not. Local recurrence was only 2%.

Radiation dose was consistently escalated, so the effect of dose differences failed to meet statistical significance. Patient selection has changed over the years. Low risk men are routinely steered towards active surveillance. Multiparametric MRI is now used to stage intermediate risk candidates in order to find those where cancer is likely to have escaped the prostate capsule or penetrated the seminal vesicles -- those patients may be offered multimodal radiation with both external beam therapy and a brachy boost. While use of monotherapy was rare among those with GS 4+3, it is probably much rarer today. Monotherapy seems to be sufficient in favorable intermediate risk men.

This study had similar results to those reported by Cleveland Clinic (see this link). It also affirms that monotherapy is all that's needed for favorable intermediate risk (see this link), and that brachy boost therapy is needed for unfavorable risk patients (see this link). These are reflected in current guidelines (see this link). The use of ADT beyond cytoreduction does not seem to be necessary, at least in high risk men receiving brachy boost therapy (see this link). This study did not address the toxicity of brachytherapy, which should be discussed with one's brachytherapist.

With thanks to Brian Davis for allowing me to read the full text of his study.

Friday, October 12, 2018

ASTRO, ASCO, & AUA strongly endorse a shortened course of IMRT for primary therapy

It will come as no surprise to my readers that moderately hypofractionated IMRT (first-line radiation delivered in 20-26 treatments or fractions instead of the conventional 40-44 fractions) received strong endorsement from all of the major US organizations of physicians who treat prostate cancer. The American Society for Radiation Oncology (ASTRO), in collaboration with the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) issued the new guidelines, which are also supported by the Society of Urologic Oncology (SUO), European Society for Radiotherapy & Oncology (ESTRO), and Royal Australian and New Zealand College of Radiologists.

A hypofractionation task force issued the new evidence-based guidelines. They divided their guidelines into two parts: (1) moderately hypofractionated IMRT (20-26 fractions); (2) ultrahypofractionated IMRT (4-5 fractions), usually called SBRT, SABR, SHARP, or CyberKnife (I will refer to it as SBRT). They strongly support moderate hypofractionation. They conditionally support SBRT, because of the moderate degree of evidence published by their cut-off date of March 31, 2017. They may revisit those guidelines after further review.

The following guidelines were strongly endorsed based on high quality evidence with strong consensus:

1A: Low risk men who refuse active surveillance should be offered moderately hypofractionated IMRT.

1B: Intermediate risk men should be offered moderately hypofractionated IMRT.

1C: High risk men should be offered moderately hypofractionated IMRT.

1D: Moderate hypofractionation should be offered regardless of patient age, comorbidity, anatomy, or urinary function. However, physicians should discuss the limited follow-up beyond five years for most existing RCTs evaluating moderate hypofractionation. *

1E: Men should be counseled about the small increased risk of acute gastrointestinal (GI) toxicity with moderate hypofractionation. Moderately hypofractionated EBRT has a similar risk of acute and late genitourinary (GU) and late GI toxicity compared to conventionally fractionated EBRT. However, physicians should discuss the limited follow-up beyond five years for most existing RCTs evaluating moderate hypofractionation.*

The following guidelines were strongly endorsed based on moderate quality evidence with strong consensus:

7A: Image guidance (e.g., fiducials, transponders, cone beam CT, etc.) should be used for both moderate hypofractionation and SBRT.†

8A: 3D-CRT should not be used with hypofractionation.§

The following guidelines were conditionally endorsed based on moderate quality evidence with strong consensus:

2A: 60 Gy in 20 fractions or 70 Gy in 28 fractions are suggested for moderate hypofractionation.

2B: No variation in treatment regimen by patient age, comorbidity, anatomy, or urinary function.

3A: Low risk men who refuse active surveillance should be offered SBRT

4A: The SBRT dose for low and intermediate risk men should be 35 Gy - 36.25 Gy in 5 fractions.**

4B: SBRT doses of 36.25 Gy in 5 fractions should not be exceeded outside of a clinical trial or registry.**

5A: At least two dose-volume constraint points for rectum and bladder should be used for moderate hypofractionation or SBRT: one at the high-dose end (near the total dose prescribed) and one in the mid-dose range (near the midpoint of the total dose).


The following guidelines were conditionally endorsed based on low quality evidence with strong consensus:

3B: Intermediate risk men should be offered SBRT, but should be encouraged to do so in a clinical trial or registry.**

3C: High risk men should be not be offered SBRT outside of a clinical trial or registry.

4C: Daily SBRT treatment is not recommended due to increased risk of toxicity.

5B: Normal dose/volume constraints used in the reference study should be adhered to for both moderate hypofractionation and SBRT


The following guideline was strongly endorsed based on low quality evidence with strong consensus:

6A: Planned target volume definition of the reference study should be adhered to for both moderately hypofractionated IMRT and SBRT.††


* While most of the hypofractionation trials did not report beyond 5 years of follow-up (see Table at this link), some did. The Archangeli et al. trial reported survival outcomes out to ten years. (I believe the guideline authors erred about this.) M.D. Anderson published an eight-year update after the close of the task force review. As we saw in our review of RTOG 0126, survival does not become a useful endpoint for perhaps 15-20 years for men with localized prostate cancer, and surrogate endpoints, such as 5-year recurrence-free survival or metastasis-free survival must be used instead. Kishan et al. proposed that for ultrahypofractionated regimens, 3-year PSA may be an excellent surrogate endpoint. The ProtecT clinical trial showed that adverse effects of radiation almost always show up in the first two years.

† For the disaster that can ensue when fiducials are not used with SBRT, see this link. The guidelines should state that intra-fractional motion tracking should be used with SBRT.

§ In the recently presented (not published in time for these guidelines) randomized clinical trial of ulrahypofractionated RT vs conventionally fractionated RT, they did use 3D-CRT in both arms. There was no difference in 5-year biochemical recurrence-free survival or 6-year toxicity.

** In a large, multi-institutional clinical trial (too late to make it into these guidelines), Meier et al. reported excellent 5-year oncological and toxicity outcomes using 40 Gy in 5 fractions. In SBRT dose escalation trials, both Zimmerman at UT Southwestern (reported here) and Zelefsky at MSKCC (I've heard from his patients) found that 45 Gy in 5 fractions gave excellent oncological and toxicity outcomes. The task force neglected the fact that prescribed doses are reported differently by different ROs. Alan Katz, for example, reports a prescribed dose of 35 Gy to the planned target volume (the prostate plus the margin around it), but the clinical target volume (the prostate itself) gets about 38 Gy, while the margin gets considerably less.

†† Smaller margins are possible when fiducials are used for intra-fractional tracking. Tighter margins cause less toxicity to organs at risk.

Sadly, the effect of hypofractionation on erectile function was seldom reported and was not part of the task force's analysis.

It is worth noting that conventionally fractionated IMRT became the standard of care without any comparative clinical trials. The longest running single institution dose-escalated IMRT trial (at MSKCC) had 10 years of follow-up on a small sample size (n=170). By contrast, Alan Katz is expected to report 10-year SBRT outcomes this year on 515 patients. The task force is holding SBRT to a higher standard that by this time next year, it should have the published results to meet.

While the task force endorsed moderate hypofractionation, we will have to see whether radiation oncologists (ROs) follow their guidelines. Because ROs are reimbursed by the number of fractions they give, they will be understandably reluctant to reduce the number of fractions. It remains to be seen whether insurance companies will enforce a limit. It is a clear benefit to the patient in terms of convenience and cost.

Thursday, October 11, 2018

I-131-MIP-1095 will enter a phase 2 randomized clinical trial

As I reported last year, a new radiopharmaceutical has entered the pack. I-131-MIP-1095, a powerful beta-particle emitter attached to a PSMA-targeted ligand, will enter a multicenter phase 2 randomized clinical trial. Progenics®, the manufacturer, put out a press release, which can be read here.

They will be testing a combination of I-131-MIP-1095 with enzalutamide (Xtandi) in patients who are metastatic, castration resistant, have not yet had chemotherapy, and who have become resistant to Zytiga. It is hoped that Xtandi will radiosensitize the cancer to the radiopharmaceutical with a resultant PSA decrease.

120 evaluable patients will be recruited; half will get the radiopharmaceutical + Xtandi, half will get Xtandi alone. All patients will be screened using DCFPyL PET/CT to assure that their metastases are PSMA-avid. The primary endpoint - the percent who have greater than 50% PSA reduction - will be collected for a year. Secondary endpoints - radiographic response, progression-free survival, and overall survival - will be reported at the end of two years.

The other two major radiopharmaceuticals in clinical trials are Lu-177-PSMA-617 and Ac-225-PSMA-617. Lu-177-PSMA-617 has entered phase 3 randomized clinical trials in the US with about 30 test sites expected. So far, recruiting has begun in Omaha NE, Albuquerque NM, Kettering OH and Houston TX and at UCLA, Tulane, Mayo, and Indiana University. There are also various phase 1 and 2 clinical trials in the US and internationally.

I recently reported about the very promising outcomes of Ac-225-PSMA-617 in Germany. Patients report that they are combining Ac-225-PSMA-617 and Lu-177-PSMA-617 to get the advantages of each. Weill Cornell in NYC is investigating Ac-225-J591 in a phase 1 trial.