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.