PSMA PET finds more cancer than Axumin

A PSMA PET scan (Ga-68-PSMA-11) detected more sites of cancer than an Axumin PET scan in the same recurrent patients. This prospective clinical trial was  conducted among 50 men at UCLA in 2018. All men had post-prostatectomy PSA from 0.2- 2.0 ng/ml.  The Calais et al. findings are summarized in the following table:

	Ga-68-PSMA-11	Axumin
Detected - % of patients	56%	26%
Prostate bed	14%	18%
Pelvic lymph nodes	38%	8%
Extra-pelvic lesions	16%	0%

The two scans performed equally well at detecting recurrence in the prostate bed, but the PSMA PET scan was able to detect more cancerous pelvic lymph nodes and non-regional metastases. The surprising result is that more recurrences are attributable to pelvic lymph nodes (stage N1) or to extra-pelvic metastases (stage M) than to cancer in the prostate bed. If this is true of all recurrent men, it indicates that salvage whole pelvic radiation is usually preferred over salvage prostate bed radiation. We saw (see this link) that salvage whole pelvic radiation improved progression-free survival compared to salvage prostate bed-only radiation. But in that SPPORT trial, the authors noted that the improvement did not hold up at low PSAs. Even the best PSMA PET/MRI has a tumor size detection limit of about 4 mm. If cancer in the pelvic lymph nodes is still curable, it may be necessary to treat cancer while it is still undetectable.

The detection rate by PSA was as follows, but is based on small numbers of patients in each PSA group. The differences in the detection rates are statistically significant for PSAs over 0.5:

PSA (ng/ml)	Ga-68-PSMA-11	Axumin
0.2-0.5 (n=26)	46%	27%
0.51-1.00 (n=18)	67%	28%
1.01-2.00 (n=6)	67%	17%

The other PSMA-based PET scan, DCFPyL, has completed recruiting.

(update 12/19/20) In a meta-analysis - in different patients - the detection rates were as follows:

PSA (ng/ml)	Ga-68-PSMA-11 n = 3,217 in 38 studies	Axumin n = 482 in 6 studies
0.2-0.5	45%	37%
0.51-1.00	59%	48%
1.01-2.00	80%	62%

The difference for PSAs from 1-2 ng/ml is statistically significant.

FDA has approved the Ga-68-PSMA PET/CT at UCLA and UCSF.

One large "zap" for painful bone metastases is enough

In 2011, the American Society for Radiation Oncology (ASTRO) issued a consensus statement as part of its "Choosing Wisely" campaign that found that 30 Gy in 10 fractions (treatments), 20 Gy in 5 fractions, and 8 Gy in 1 fraction all gave equivalent pain relief. The detailed guidelines are here. They did note, however, that repeat treatments were sometimes necessary. A retrospective study this year at the Mayo Clinic found that local control of prostate cancer bone metastases was much improved (from 47% 3-year local control to 87% 3-year local control) by increasing the radiation single dose from 8 Gy to ≥ 18 Gy. (However, the higher dose did not significantly affect the biochemical failure or distant failure rate.)

Now, Nguyen et al. report the results of the first prospective randomized clinical trial. The trial was conducted at MD Anderson from 2014 to 2018 among 160 people with painful bone metastases from any of a variety of cancer types.

• Half received 12 Gy in a single fraction for ≥ 4 cm bone lesions, or 16 Gy in a single fraction for < 4 cm bone lesions (Single Fraction Cohort - SF)
• Half received 30 Gy in 10 fractions (Multi-Fraction Cohort - MF)
• Treated bone metastases were predominantly non-spinal
• Up to three bone metastases were treated at a time

At all follow-up times (2 weeks, 3 months, 6 months and 9 months):

• Pain palliation (complete+partial) was significantly better among the SF
• At 9 months, pain palliation was 77% for the SF vs 46% for the MF
• In the Single Fraction Cohort, those who got the 16 Gy dose had 3 times better pain palliation vs those who got the 12 Gy dose.
• Local control at 2 years was 100% for SF vs 76% for MF
• Median survival was not significantly different
• No significant differences in toxicity (nausea, vomiting, fatigue, dermatitis, and fracture)
• No significant differences in quality of life

This Phase II study was too small to be definitive, especially for cancer-type subgroups. However, the patient should challenge an radiation oncologist who plans to give more than a single fraction to explain his recommendation. (It is entirely possible the the location of the bone metastasis calls for a lower dose rate.) Moreover, the single fraction dose of 16 Gy or 18 Gy seems optimal for both pain palliation and local control. The patient should not expect this D3alliative treatment to increase survival.

Spine metastases

Spinal metastases may respond to radiation differently from other bone metastases. Ryu et al. reported the results of the NRG Oncology/RTOG 0631 randomized clinical trial. They tried to obtain proof that SBRT (16-18 Gy in one dose) was superior to IMRT in one dose (8 Gy) in terms of pain response. After 3 months, 61% of those treated with IMRT had a significant pain improvement vs 41% of those treated with SBRT. After 1 year, there was no difference in pain scores. After 2 years, there was no difference in spinal fractures or compression. 

There is conflicting data from other institutions. Sprave et al. at Heidelberg reported better pain response at 6 months (but not at 3 months) with SBRT (24 Gy in 1 fraction) vs 3DCRT (30 Gy in 10 fractions). Sahgal et al. in a Canadian/Australian multi-institutional trial, found there was a better pain response with SBRT (24 Gy in 2 fractions) compared to IMRT (20 Gy in 5 fractions). After 3 months, significant pain improvement was 35% for SBRT vs 14% for IMRT.

note: thanks to Valerae Lewis for allowing me to review the full text

How much prednisone is needed with abiraterone?

Abiraterone (Zytiga) inhibits the enzymes necessary for the adrenal glands to produce androgens. The adrenals are the secondary source of androgens after the testicles. Unfortunately, the same enzyme is needed for the adrenals to produce cortisol, so a glucocorticosteroid (in the form of prednisone, dexamethasone, or methylprednisolone) has to be replaced when taking abiraterone. When abiraterone is prescribed for men with metastatic hormone-sensitive prostate cancer, 5 mg once daily (5 mg qd) or sometimes 2.5 mg twice daily (2.5 mg bid) is taken for replacement. When abiraterone is prescribed for men with metastatic castration-resistant prostate cancer, 5 mg twice daily (5 mg bid) is taken with it, because the anticipated duration of taking the steroids is shorter. Recently it was found that switching from prednisone to dexamethasone 0.5 mg once a day (0.5 mg qd) can extend the duration of abiraterone effectiveness (see this link).

The biggest danger of taking too little corticosteroid to replace what is lost is a condition called a "syndrome of secondary mineralocorticoid excess." This occurs because the pituitary gland reacts to the lack of cortisol by producing a hormone called ACTH (this is called "negative feedback"). ACTH increases the production of mineralocorticoids (like aldosterone), hormones that increase blood pressure, lower potassium and cause edema in the limbs.

Cortisol has many functions, including energy production, control of inflammatory response (e.g., preventing arthritis), and preventing allergies and runaway immune response. It also has mental effects, affecting mood and memory formation. Symptoms of too little cortisol may include fatigue, dizziness (especially upon standing), nausea, fever, weight loss, muscle weakness, joint pain, mood changes, and the darkening of regions of the skin.

The danger of taking too much corticosteroid may include insulin resistance, a decrease in lean body mass, increase in fat accumulation, and decrease in bone mineral density. It is also immunosuppressive, and may cause tissue breakdown (catabolism) and gastritis. Adverse effects increase with dose and duration of use.

Glucocorticosteroids have been found to have independent anti-cancer activity (see this link). The effect is short-lived as resistance eventually arises. It is also given to mitigate some of the side effects of chemotherapy like emesis/nausea and peripheral edema.

Attard et al. conducted a randomized clinical trial among men taking 1000 mg/day abiraterone for metastatic castration-resistant prostate cancer at 22 hospitals in 5 countries in 2013-2014.

• 41 received it with prednisone 5mg bid (P5 bid)
• 41 received it with prednisone 5 mg qd (P5 qd)
• 40 received it with prednisone 2.5 mg bid (P2.5 bid)
• 42 received it with dexamethasone 0.5 mg qd (D0.5 qd)

The primary outcome measured was mineralocorticoid excess through 24 weeks of treatment as indicated by elevated blood pressure or a blood test for low potassium (hypokalemia). They also measured serum levels of ACTH, which gets elevated if there is not enough glucocorticoid. For side effects of too much glucocorticoid, they measured insulin resistance, loss of lean body mass, gain of body fat, and loss of bone mineral density. For the benefits, they measured suppression of androgen precursors, the % of patients in whom PSA declined by at least 50%, the duration of radiographic progression-free survival, and the patient-reported change in quality of life.

	P5 bid	P5 qd	P2.5 bid	D0.5 qd
Mineralocorticoid excess	29%	63%	40%	30%
(95% confidence range)	17%-46%	47%-77%	26%-56%	17%-46%
Grade 3 hypertension	7%	22%	13%	7%
Grade 3 hypokalemia	0%	7%	0%	0%
Change in ACTH (pmol/L)	-1.1	9.0	4.0	-1.8
Change in fasting serum insulin (insulin resistance)	Not statistically significant	Not statistically significant	Not statistically significant	significant
Change in lean body mass	-6%	-3%	-6%	Not statistically significant
Change in total body fat	12%	Not statistically significant	Not statistically significant	19%
Change in bone mineral density	Not statistically significant	Not statistically significant	Not statistically significant	-2%
Androgen precursor suppression	-81%	Not statistically significant	Not statistically significant	-88%
PSA declined by ≥ 50%	63%	78%	60%	88%
Radiographic Progression-free survival	18.5 months	15.3 months	12.8 months	26.6 months
Quality of Life change	Not statistically significant	Not statistically significant	Not statistically significant	Not statistically significant

Although sample sizes were not large enough to directly compare the treatments, the data suggest that P5 bid and D0.5 qd do a good job of preventing mineralocorticoid excess, whereas P5 qd does not. P5 bid and D0.5 qd seem to cause body changes. D0.5 qd seems to have superior oncological effectiveness.

There was tremendous individual variation. It seems prudent to start with the prescribed dose (P5 bid) and monitor body changes, or to start at the lower dose (P5 qd) and to monitor blood pressure and potassium levels.

In a retrospective study, Gill et al. found that castration-resistant men at Huntsman Cancer Center who refused prednisone suffered no worse from the syndrome of mineralocorticoid excess when given 50 mg/day Inspra (eplerenone - an aldosterone antagonist) compared to men who used 10 mg/day prednisone. They also lost weight, perhaps water-weight. Patients taking 10 mg/day of prednisone may wish to discuss this alternative.

Evidence for Dose Escalation in Adjuvant/Salvage Radiation

It is well known that prostate cancer is relatively radio-resistant compared to other kinds of cancer. While dose escalation (most recently by increasing the biologically effective dose using hypofractionated dose (more that 2.0 Gy per session) delivery or brachytherapy boost therapy) has become the mainstay in primary radiation therapy, doses delivered for adjuvant or salvage radiation has stayed about 10 Gy lower. Recently, Dr. King's analysis of the dose responsiveness of salvage radiation questioned this supposition (see this link). While his mathematical arguments provide us with intriguing plausibility, only clinical evidence from a randomized clinical trial can change practice.

We now have Level 1 evidence that expanding the adjuvant/salvage treatment field to include the pelvic lymph nodes improves the oncological outcomes in men with higher PSA at the time of salvage radiation.

Link et al. conducted a small, retrospective study among 120 locally advanced (stage T3/4) post-prostatectomy patients at the University of Heidelberg between 2009 and 2017. All were lymph node negative.

• 43 received whole pelvic radiation therapy (WPRT)- 62% received 79.3 Gy to the prostate
• 77 received radiation to the prostate bed only (PBO)- 70% received 79.3 Gy to the prostate
• Biologically equivalent dose (2 Gy) to the prostate was 79.3 Gy ("high dose") if they had positive margins or PET/CT/MRI imaging-detectable prostate bed tumors (62% of patients), 71.4 Gy ("low dose") if they had negative margins (38% of patients).

Median freedom from biochemical failure was:

• longer among those who got the higher dose: 76 months vs 21 months
• longer among those who received WPRT vs PBO: 68 months vs 32 months

There is a lot of overlap in treatments, so it is impossible to tease out the effect that each had on the oncological outcomes. Almost all of those who received the escalated dose also had positive margins - a known factor for predicting success of adjuvant/salvage radiation. Also, almost all men who had adjuvant radiation had positive margins and dose escalation - adjuvant radiation has proven to be more successful than "wait-and-see" in 3 major randomized clinical trials.

Toxicity increased with both dose and size of the treatment field. Grade ≥ 2 toxicity was reported by:

• 3.4% among those who received low dose and PBO
• 12.5% among those who received high dose and PBO
• 15.4% among those who received low dose and WPRT
• 36.7% among those who received high dose and WPRT
• No reports of Grade 3 gastrointestinal toxicity
• 13% Grade 3 urinary toxicity among high dose patients, none among low-dose patients

This is a far cry from the randomized clinical trial we need for practice-changing dose escalation for adjuvant/salvage radiation. However, we can't rule out that there is no oncological benefit to dose escalation. It remains unknown what proportion of these high-risk patients would have done just as well with lower doses and smaller treatment fields. The increase in toxicity with dose and treatment field means that patients ought not jump into this without understanding the risks and discussing them with their radiation oncologists.