PSMA-targeted radioligand therapy (RLT) has revolutionized the treatment landscape for advanced prostate cancer by delivering radioactive isotopes directly to malignant cells expressing PSMA. Particularly, the tandem use of alpha-emitter ^225Ac-PSMA and beta-emitter ^177Lu-PSMA has demonstrated remarkable anti-tumor efficacy. However, an unfortunate consequence of this targeted therapy is the inadvertent radiation exposure and consequent damage to non-target tissues such as the salivary glands. Such toxicity manifests as xerostomia or chronic dry mouth, severely diminishing quality of life and potentially forcing patients to discontinue otherwise effective therapies.

Historically, attempts to mitigate salivary gland damage using methods such as applying cold packs, external cooling, or single-agent anticholinergic drugs have yielded limited success. The paramount challenge lies in selectively protecting the salivary glands without compromising the accumulation of radioligands in tumor tissues. Against this backdrop, the recent study from the National University of Singapore offers a beacon of hope through a dual-modality prophylactic intervention that harnesses the complementary pharmacological effects of Botox and scopolamine.

Botulinum toxin, a neurotoxic protein widely known for its neuromuscular blockade properties, is administered via ultrasound-guided injections into the major salivary glands – specifically the parotid and submandibular glands – on alternate sides of the body. By inhibiting acetylcholine release at the presynaptic neuromuscular junction, Botox effectively reduces salivary gland secretory activity and blood flow, likely diminishing the retention and uptake of PSMA-targeted radioligands in these tissues. Complementing this, transdermal scopolamine patches applied behind the ears serve as a systemic anticholinergic agent, further curbing parasympathetic stimulation and potentially enhancing glandular protection.

The study enrolled fourteen patients with metastatic castration-resistant prostate cancer scheduled for combined ^225Ac- and ^177Lu-PSMA RLT. Botox injections were administered three to four weeks prior to the initiation of therapy, allowing sufficient time for the neurotoxin to exert its effects on glandular function. Scopolamine patches were applied three days before treatment and maintained until two hours post-therapy. Molecular imaging assessments, including pre- and post-treatment PSMA PET/CT scans and SPECT/CT, quantitatively evaluated changes in radioligand uptake within the salivary glands.

Results revealed a significant and clinically meaningful reduction in PSMA tracer accumulation in treated salivary glands. Notably, Botox-injected parotid glands exhibited an average 30% decrease in radioligand uptake when compared to the contralateral untreated glands. Similarly, treated submandibular glands demonstrated a 17% reduction relative to their untreated counterparts. Importantly, despite this protective effect on non-target tissue, tumor uptake of PSMA radioligands remained unaffected, underscoring the therapeutic selectivity of the intervention.

Patients tolerated the combined Botox and scopolamine regimen remarkably well, with only mild localized injection discomfort reported and no serious systemic adverse events. Crucially, no participants discontinued radioligand therapy owing to xerostomia, suggesting a substantial improvement in treatment adherence and overall quality of life. This safety profile is particularly encouraging given that both Botox and scopolamine are already FDA-approved agents with well-characterized mechanisms of action and established clinical use in other settings.

The implications of these findings are far-reaching. Addressing salivary gland toxicity not only alleviates a debilitating side effect but also holds potential to broaden the therapeutic index of PSMA-targeted radiopharmaceuticals, especially those employing potent alpha emitters like ^225Ac. By mitigating dose-limiting toxicity, clinicians may be empowered to deliver higher or more frequent therapeutic doses, potentially enhancing oncologic outcomes without compromising patient well-being.

Dr. Jingjing Zhang, assistant professor at the Theranostics Centre of Excellence, emphasized the translational impact of the study: "Our approach leverages readily available, FDA-approved medications to pioneer a protective strategy against radiation-induced salivary gland damage. This innovation could rapidly be adopted in clinical centers equipped to perform PSMA radioligand therapy, thereby enhancing patient care on a global scale."

Mechanistically, the synergy between Botox’s local neuromuscular blockade and the systemic parasympathetic inhibition by scopolamine likely orchestrates a multifaceted reduction in salivary gland perfusion, secretion, and consequent PSMA radioligand uptake. This dual blockade represents a significant advancement over prior monotherapies or physical cooling methods that failed to achieve meaningful glandular protection.

Further research is warranted to optimize dosing, timing, and delivery parameters of this combined intervention, as well as to evaluate long-term outcomes and potential effects on salivary gland function recovery. Nonetheless, these promising early results chart a clear path forward toward integrating neurotoxin and anticholinergic agents into standard care protocols for patients undergoing PSMA-targeted therapies.

In conclusion, this innovative protective strategy opens new avenues to improve the therapeutic ratio of radioligand therapy in advanced prostate cancer. By proactively safeguarding salivary glands from radiation damage, the combined use of botulinum toxin and scopolamine holds great promise to enhance patient quality of life, maintain adherence to life-extending treatments, and ultimately improve clinical outcomes in this challenging oncologic arena.

Subject of Research: Protective strategies against salivary gland toxicity during PSMA-targeted radioligand therapy in metastatic prostate cancer patients.

Article Title: Botulinum Toxin Plus Scopalamine as a Protective Strategy Against Salivary Gland Toxicity in Patients Treated with 225Ac- and 177Lu- PSMA-Targeted Radioligand Therapy (TANDEM PSMA-RLT).

News Publication Date: 2025

Web References:
https://jnm.snmjournals.org/content/66/supplement_1/251452

Image Credits:
Images created by Tianzhi Zhao, Jingjing Zhang, et al., National University of Singapore, Singapore / Richard P. Baum et al., Curanosticum Wiesbaden-Frankfurt, Wiesbaden, Germany.

Keywords:
Personalized medicine, side effects, medical treatments, prostate cancer

The program, known as the Geriatric Assessment-Guided Intervention-Supportive Care (GAIN-S), integrates a multidisciplinary approach encompassing personalized fitness regimens, nutritional counseling, psychiatric support, and psychosocial assistance. Delivered entirely via telehealth modalities, GAIN-S offers an innovative model that dismantles traditional barriers, such as travel burden and limited local expertise, often faced by elderly patients scattered across remote or underserved territories. This carefully orchestrated regimen was scrutinized in a rigorously designed randomized clinical trial involving 77 participants aged 65 years and older, all receiving treatment for metastatic solid tumors in Brazil from mid-2022 to mid-2023.

The trial’s choice of Brazil as a testing ground was both strategic and poignant. With healthcare infrastructure concentrated predominantly in major urban centers, a vast swath of the population endures limited access to specialized oncology and geriatric care. The study’s reliance on urban-based care providers, who delivered interventions remotely, allowed for a direct examination of telehealth’s capacity to equalize access and elevate care standards across socioeconomically and geographically disparate regions. Results at the three-month evaluation point revealed significant improvements across vital outcome measures, including enhanced physical function, mood stabilization, deeper illness comprehension, and overall quality of life.

One of the critical technical pillars underpinning this success was the utilization of encrypted, secure messaging platforms—in this case, WhatsApp—to schedule appointments and obtain informed consent. By employing end-to-end encryption and ephemeral messaging features, the team ensured patient confidentiality and data security, addressing a pervasive concern in digital health interventions. This operational detail underscores the essential convergence of technological innovation with clinical expertise, enabling scalable and privacy-conscious telehealth solutions.

Senior author Dr. William Dale, MD, PhD of City of Hope, emphasized the transformative potential of such telehealth programs, stating that bringing expert care directly into patients’ homes circumvents the logistic and financial barriers that so often compromise treatment adherence and outcomes. This decentralized method not only enhances equity but also optimizes the allocation of specialized resources, ensuring that providers’ expertise can reach far-flung populations without necessitating physical relocation of either party. The implications extend beyond cancer care to broader chronic disease management paradigms.

Lead author Dr. Cristiane Decat Bergerot, PhD, of Oncoclinicas&Co in Sao Paulo, reinforced the notion that integrating supportive care early in the cancer care trajectory is essential. Early intervention via remote platforms fosters improved communication channels between patients, families, and healthcare teams, setting the stage for more effective symptom management, emotional support, and personalized treatment planning. Such timely engagement is especially critical in geriatric oncology, where comorbidities and frailty complicate clinical decision-making.

Commenting on the study, independent expert Dr. Martine Extermann, MD, PhD, from Moffitt Cancer Center, highlighted the broader clinical significance of GAIN-S within the framework of Comprehensive Geriatric Assessment and Management (CGAM). CGAM, a well-established evidence-based standard compensating for the heterogeneity of aging cancer patients, traditionally remained confined to large academic institutions due to resource demands. This trial compellingly demonstrates that telehealth modalities can democratize CGAM’s benefits, facilitating its adoption in community settings and emerging economies alike, thereby expanding its global reach.

Furthermore, the randomized controlled design fortifies the evidence base underpinning telehealth interventions in geriatric oncology, outperforming prior observational or pilot investigations. The methodological rigor and clear outcome improvements make a compelling case for policy makers and healthcare systems to recalibrate resource allocation strategies, incorporating telehealth-supported supportive care as an integral component of oncologic treatment frameworks targeting older adults.

This study also shines a spotlight on the technological and infrastructural prerequisites necessary for widespread telehealth implementation. Reliable internet connectivity, user-friendly digital platforms, and secure communication channels must coalesce seamlessly with clinical workflows to realize the full potential of remote care. The deployment in Brazil, a middle-income country with diverse connectivity landscapes, offers real-world insights into overcoming such logistical challenges and tailoring solutions to local contexts.

In addition to clinical and technical factors, the social dimensions of telehealth interventions receive due consideration. The ease with which older patients adapted to remote interactions, the psychological relief afforded by reduced travel requirements, and the enhanced caregiver involvement collectively underscore telehealth’s holistic benefits. Importantly, these factors contribute to improved adherence, satisfaction, and ultimately, better health trajectories.

The implications of this research ripple beyond national boundaries. As the global population ages and cancer incidence rises disproportionately among older adults, scalable, equitable care strategies are urgently required. The GAIN-S program exemplifies such innovation, representing a beacon for international oncology communities eager to adopt sustainable, patient-centered telehealth frameworks that reconcile clinical excellence with accessibility.

To access the full details of the GAIN-S randomized clinical trial, alongside an expert commentary by Dr. Extermann, readers are encouraged to consult the June 2025 issue of JNCCN via JNCCN.org. This research not only advances scientific understanding but also sets a precedent for harnessing technology to meet the nuanced challenges of geriatric cancer care in a digitally connected world.

Subject of Research: People

Article Title: Telehealth Geriatric Assessment and Supportive Care Intervention (GAIN-S) Program: A Randomized Clinical Trial

News Publication Date: 11-Jun-2025

Web References:

• JNCCN
• Telehealth GAIN-S Study
• The Last Word Commentary

Image Credits: NCCN

Keywords: Cancer, Carcinoma, Cancer research, Cancer treatments, Oncology, Aging populations, Gerontology, Older adults, Economic geography, Underdeveloped areas, Telecommunications