Avoiding radiation damage to salivary glands with Ac-225-PSMA-617 therapy

As we await the results of the VISION trial of Lu-177-PSMA-617, research continues into improving radiopharmeuticals. Ac-177-PSMA-617, which is more lethal to cancer cells within a more limited distance, is one of several promising alternatives (see this link).

One of the serious side effects of the experimental Ac-225-PSMA-617 therapy is radiation damage to salivary glands. "Xerostomia" (dry mouth) also occurs with Lu-177-PSMA-617 therapy, but it is usually transient and less severe, although it does increase with the number of treatments. Sathkegke et al. reported occurrence in 85% of South African patients treated with Ac-225-PSMA-617, but no one stopped treatment entirely because of it. Kratchowil et al. reported occurrence of xerostomia in Heidelberg, Germany so severe in 4 of 40 treated patients that treatment had to be discontinued. Feuerrecker at al reported that all their treated German patients suffered from xerostomia; it was so severe as to curtail treatment in 6 of 26 patients.

Acute, low-grade xerostomia is caused by the temporary irritative inflammatory effects of the radiopharmaceutical on salivary tissue. Lasting damage may result from radioablation of the saliva-producing cells and the nerves that innervate them, and their replacement with and obstruction of the ducts with mucus and scar tissue. Loss of saliva can make chewing and swallowing almost impossible, leading to choking and vomiting. Digestion is impaired, and the ability to taste food may be lost. Saliva has antimicrobial properties, so its loss can lead to tooth decay, gum disease, and oral thrush. Speaking can become difficult.  It can feel like burning, and interfere with sleep. Humans normally produce about a liter of saliva each day.

Some simple therapies (local cooling with ice, Vitamin C, lemon juice, and PMPA) have been found to be ineffective. Taïeb et al. report that treatment with botulinum toxin, Vitamin E and MnBuOE may be more successful, but that regeneration of salivary glands with stem cells or genetic modification may ultimately be necessary. Riley et al. found very low quality of evidence that amifostine, pilocarpine, palifermin, biperidine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin) may be useful. Nail et al. found sublingual atropine reduced salivary uptake in mice. More benefit may be accomplished with some of the following strategies:

Sialendoscopy

Rathke et al. reported the successful use of sialendoscopy in 11 patients. Sialendoscopy is a kind of endoscopic procedure involving the insertion of a thin probe into the salivary glands. It dilates the openings that have closed due to inflammation. They irrigated the glands with saline and prednisolone. It only worked when done immediately.

Pre-treatment with PSMA-11

PSMA-11 is the small molecule ligand used with Ga-68-PSMA-11. Taken without the radiotracer, it attaches to the salivary tissue, where it can block further uptake by the PSMA-617 ligand. Kalidindi et al. found that in mice, pretreatment with 1000 picomoles blocked uptake of Lu-177-PSMA-617 in the salivary glands and kidneys; but uptake, while reduced, was still at therapeutic levels in tumor tissue. This finding would have to be replicated in clinical trials.

Use only when there is significant PSMA-avidity

Damage to normal, healthy tissue increases when there is insufficient PSMA-avid tumor tissue to attach to. Gaertner et al. found that across 135 patients, uptake by normal tissues of the salivary glands, tear ducts, kidneys, and other vital organs was significantly reduced in men with high tumor load. Gafita et al. and Burgard et al. confirmed this "tumor sink" effect. While it is true for many pharmaceuticals that earlier use is more effective and less toxic, there is a balance to be struck between the tumor-killing effect and toxicity for the PSMA-targeted radiopharmaceuticals. We have seen that such treatment can be too late as well, when new metastases lose PSMA-avidity (see this link). It may be a good idea to reduce dose for low tumor volume.

Mix Lu-177-PSMA-617 and Ac-225-PSMA-617

A cocktail of the two may increase the cancer-killing power of Lu-177-PSMA-617 while decreasing the toxicity of Ac-225-PSMA-617. Khreish et al. reported that only 5 of 20 patients given the cocktail reported mild xerostomia.

Use a PSMA antibody

PSMA-617 and PSMA-11 are small molecules that have been found to attach to the PSMA molecule on the surface of prostate cancer cells. They are not as specific as other ligands. Scott Tagawa is exploring the use of a PSMA antibody, called J591 in two clinical trials (this one and this one), that may be more specific than the small molecules. In a previous clinical trial, there were no reports of xerostomia.  The clinical trial of Th-227 targeting PSMA uses a highly specific antibody.

Use a non-PSMA-targeted ligand

Another strategy is to forgo the PSMA target entirely. Ac-225 has been attached to an antibody that very specifically targets hK2 (one of the 4 prostate cancer proteins detected by the 4KScore test). It has entered a clinical trial.

Beware of MSG and other supplements

Harsini et al. conducted a small clinical trial where patients were randomized to take tomato juice with and without monosodium glutamate (MSG). Glutamate is a known heavy-metal chelator. Each patient had two double-blinded PSMA PET scans -- one with MSG; the other without MSG. MSG did reduce the uptake of PSMA into the salivary glands and the kidneys. Unfortunately, it also blocked the uptake of PSMA into tumor tissue. Armstrong et al. reported a similar trial where patients could swish MSG in their mouths or ingest it. Each patient had Ga-68-PSMA-11 PET scans with and without MSG. Swishing had no effect. Oral ingestion reduced uptake in salivary glands and in tumors. Patients getting PSMA theranostics should avoid MSG and Chinese food.

Because the PSMA-targeted radiopharmaceuticals are very loosely held together (chelated) by a coordination complex, it is easily reversed by other heavy metals (like iron, cobalt, vanadium, etc. supplements) or other chelates or chelators (like those frequently found in multi-mineral tablets). Curcumin, a popular supplement, has been found to be a chelator. Use of such supplements may increase the toxicity of these radiopharmaceuticals, or render them ineffective. Antioxidants and free radical absorbers may interfere with the DNA damage that radiopharmaceuticals are trying to achieve. To be safe, and to maximize their effectiveness, patients should avoid all supplements during therapy.

Dose Painting: simultaneous integrated boost (SIB) to the dominant intraprostatic lesion (DIL)

Two technologies have come together to allow for a new kind of radiation treatment known as simultaneous integrated boost (SIB), or, more informally, “dose painting.” The two technologies are: 

1. improved imaging by multiparametric MRIs that can more precisely locate tumors within the prostate, and 
2. improved external beam technology that can deliver doses with submillimeter accuracy. 

Dose painting can be achieved with brachytherapy as well. But just because it can be done, doesn’t mean it should be done. That is, the following two questions must be answered:

1. Is there any benefit in terms of oncological outcomes?
2. Is there any increase in treatment toxicity attributable to it?

The arguments for dose painting include:

• There is often a dominant intraprostatic lesion (DIL) or index tumor. There is some evidence that cancer spreads via clones from it. Because such tumors are often large and high grade, some think that the index tumor may be relatively radioresistant, perhaps because of hypoxia or cancer stem cells. Therefore, a higher dose of radiation may be necessary to kill its cancer cells.
• By concentrating the radiation’s killing power at the DIL, it may be possible to reduce the radiation dose where it is less needed, and thus spare organs at risk (e.g., bladder and rectum).

The arguments against dose painting include:

• The index tumor hypothesis is far from proven. In fact, prostate cancer is multifocal in about 80% of men. Reducing the dose elsewhere is risky because cancer cells may survive and propagate.
• If the dose needed to kill the cancer cells is inadequate, why not increase the dose throughout the prostate to a dose that is adequate? With today’s pinpoint technology, the clinical target volume (the prostate) can be defined with sub-millimeter accuracy and near-perfect shaping.
• Using mpMRI to precisely delineate the DIL may miss much of it. In fact, a study at UCLA found that tumors delineated by mpMRI missed 80% of the tumor's actual volume.
• While mpMRI is good at finding large high-grade tumors, sometimes the highest grade tumor is not large, and mpMRI cannot locate it.
• Intense foci of radiation may increase the probability of normal tissue complications, including damage to the urethra, bladder neck, sphincter, rectum and bowel.

With all these pros and cons in mind, the FLAME randomized clinical trial was instituted to determine whether dose painting is effective and safe in real-world application. Kerkmeijer et al. reported the results of 571 patients treated at 4 institutions in Belgium and the Netherlands from 2009 to 2015. Patients were:

• Predominantly (85%) high risk
• Adjuvant ADT was given to 65% for a median of 18 months.
• Received hypofractionated radiation to the prostate: 77 Gy in 35 treatments, which is biologically equivalent to 82 Gy in 41 treatments.
• Half received a SIB to the DIL as well: 95 Gy in 35 treatments, which is biologically equivalent to 116 Gy in 58 treatments.
• The boost dose was reduced sometimes to meet very tight dose constraints on organs at risk.

After 6 years of follow-up:

• 5-year biochemical disease-free survival (bDFS) was 92% for those that received the SIB and 85% for those who didn't, a significant difference.
• Both biochemical failures and clinical recurrences were cut in half by the SIB
• In the limited follow-up period, there weren't enough distant metastases or deaths to detect a significant difference.
• There were no significant differences in Grade 2 or Grade 3 urinary or rectal  toxicity,
• As previously reported, late-term Grade 2 or greater toxicity was 10% for rectal, 27% for urinary with no significant differences.
• There was no late-term Grade 3 rectal toxicity, and minimal late-term Grade 3 urinary toxicity in either arm.
• There were no significant differences in patient-reported quality of life for urinary, rectal or sexual outcomes.

Because oncological results were as good as brachy boost therapy, the current gold standard for treating high-risk patients, and late-term urinary toxicity was minimal, hypofractionated IMRT with SIB is poised to become the new standard of care for high-risk patients. Longer follow-up will determine whether the results hold up.

(update 9/21/22) Tree et al. reported the results of the DELINEATE trial in 256 men treated at Royal Marsden in the UK. Patients had intermediate (43%) or high-risk (57%) PCa. All had DILs detected via MRI. All received ADT. They were randomized to one of 3 cohorts:

1. 74 Gy in 37 treatments to prostate+seminal vesicles + 82 Gy SIB to DIL
2. 60 Gy in  20 treatments to prostate+seminal vesicles + 67 Gy SIB to DIL
3. (high-risk only)same as Cohort A + 60 Gy to pelvic lymph nodes

After more than 5 years of follow-up:

• Gastrointestinal toxicity grade 2 or more: 13% Cohort A, 15% Cohort B, 21% Cohort C
• Urinary toxicity grade 2 or more: 13% Cohort A, 18% Cohort B, 18% Cohort C
• Freedom from biochemical failure: 98% Cohort A, 97% Cohort B, 95% Cohort C

Excellent results from SIB to DIL, even in high-risk patients. Moderate toxicity.

There are some opportunities for improving results for patients even further.

• SBRT with SIB: As we've seen extreme hypofractionation may provide more lasting results with equally good toxicity. Whole gland treatment with as high as 47.5 Gy in 5 fractions did not incur any excess toxicity in trials (see this link). 
• Tumor detection and delineation with PSMA PET/CT scan: a small comparative study showed that PSMA PET/CT had superior sensitivity and positive predictive value compared to mpMRI. More importantly, it can eliminate patients who would not benefit from localized treatment because of occult metastases.
• Genomics to detect radio-resistant tumors and radiation sensitivity
• Imaging to detect hypoxic tumors (e.g., BOLD MRI, FAZA PET, or MISO PET)

SBRT for High-Risk Patients

As we have seen, SBRT is a preferred therapy for low and intermediate-risk patients (see this link). It is effective, safe, convenient, and relatively inexpensive. However, its use for high-risk patients remains controversial.

Amar Kishan has accumulated data from 8 institutions that have used SBRT for 344 high-risk patients. They were treated as follows:

• They received from 35 Gy-40 Gy in 5 treatments (7-8 Gy per treatment)
• 72% received adjuvant ADT for a median of 9 months
• 19% received elective nodal radiation

After a median follow-up of 49.5 months:

• 4-year biochemical recurrence-free survival  (bRFS)was 82%
• Higher dose, longer ADT, and nodal radiation were associated with better bRFS
• 4-year metastasis-free survival was 89%
• Late grade 3 GU toxicity was 2.3%
• Late grade 3 GI toxicity was 0.9%
• Toxicity was associated with dose and ADT use

Although the results of different prospective trials aren't comparable, the following table gives an idea of 4-6 year outcomes of prospective trials of high-risk patients using various therapies.

	Follow-up	bRFS	BED	ADT (median)	Late GU Toxicity Grade ≥3
SBRT (1)	4 yrs	82%	198-253 Gy	9 mos.	2.3%
Surgery+SRT (2)	5 yrs	78%	154 Gy	6 mos.	8% (3)
HDR-BT (4)	5 yrs	91%	227-252 Gy	6.3 mos.	3-16%
LDR- Brachy Boost (5)	5 yrs	86%	227 Gy	12 mos.	19%
HDR-Brachy Boost (6)	6 yrs	88%	267 Gy	12 mos.	2.5%
IMRT (7)	5 yrs	88%	174 Gy	28 mos.	2.5%

SBRT = stereotactic body radiation therapy,. External beam radiation (EBRT) concentrated in 5 treatments

bRFS= biochemical (PSA) recurrence-free survival

BED= biologically effective dose (comparable effectiveness)

ADT= androgen deprivation therapy used for a limited time to improve outcomes

late GU toxicity ≥3 = serious urinary side effects requiring intervention, occurring more than 3 months after therapy

HDR-BT = high dose rate brachytherapy (temporary implants)

LDR-BT = low dose rate brachytherapy (permanent implants/seeds)

Brachy Boost therapy - External beam radiotherapy (EBRT) with a boost of radiation to the prostate using brachytherapy 

IMRT = intensity-modulated radiation therapy, usually given in about 40 treatments

(1) https://www.redjournal.org/article/S0360-3016(21)00068-7/pdf

(2) https://riskcalc.org/ProstateCancerAfterRadicalProstatectomyNew/ with GS 8

(3) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)00111-X/fulltext

(4) https://www.redjournal.org/article/S0360-3016(11)00552-9/abstract

(5) https://www.redjournal.org/article/S0360-3016(16)33484-8/abstract

(6) https://www.thegreenjournal.com/article/S0167-8140(18)30238-X/fulltext

(7) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)70045-8/fulltext

As we've seen (see this link), brachy boost therapy is the gold standard for long-term recurrence-free survival. At about 5 years, however, all therapies seem to be about equally effective, with biochemical recurrence-free survival in the range of 78-91%. However, they differ markedly in the incidence of serious late-term urinary side effects. For LDR Brachy Boost therapy, the risk of urinary retention is high, while the risk of incontinence and urinary retention is elevated among patients having salvage radiation (SRT). External beam monotherapy, using either IMRT or SBRT, had a low risk of serious late-term urinary side effects (and almost no risk of serious rectal side effects).

IMRT, as a primary therapy for high-risk patients, requires long-term use of ADT to be effective. The DART RADAR trial showed that for high-risk patients, 6 months of adjuvant ADT wasn't nearly enough. Nabid suggests that 18 months of adjuvant ADT may be optimal when paired with IMRT. SBRT seems to be equally effective with less adjuvant ADT, but the optimal duration is yet to be determined.

The question that will only be resolved with longer follow-up is whether the recurrence rates are stable after 4 years, or whether they will deteriorate with longer follow-up. In the ASCENDE-RT trial of brachy boost therapy vs external beam radiation only, biochemical recurrence rates were similar after 5 years. Recurrence increased at a rate of 5% per year among those treated with EBRT alone, but only at a rate of 1% per year if they got the brachy boost. There was similar stability of outcomes when HDR brachytherapy was used. Recurrence after salvage radiation increased from 22% at 5 years to 30% at 10 years. There is every reason to believe that SBRT, which uses biologically effective doses (BED) of radiation similar to brachy boost therapy, will follow a stable recurrence pattern over time, but that remains to be shown.

Ensuring the safety of patients is critical, and high-risk patients are usually treated with wider margins that can affect toxicity. As we saw, SBRT there are many factors that must be considered when giving radiation this intense (see this link).

The first randomized trial (see this link) of radiation delivered in 6 treatments compared to 39 treatments to intermediate to high-risk patients proved that the cancer control and toxicity were similar. Another randomized trial (PACE-B) has already shown that the toxicity is lower with SBRT. An ongoing arm of that trial (PACE-C) is focusing on high-risk patients.

NCCN has included SBRT as a reasonable standard-of-care option for high-risk patients (Table 1 Principles of Radiation Therapy PROS-E 3 of 5 in NCCN Physicians Guidelines 3.2020). Due to the pandemic, an international panel of radiation oncologists is recommending that high-risk patients consider its use (see this link).