The use of ultrasound to treat skin cancer

 In the context of skin cancer, ultrasound is explored both as a diagnostic tool (e.g., to assess tumor depth) and as a potential therapeutic modality (e.g., to ablate cancerous tissue or enhance drug delivery).

Skin cancer, encompassing melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC), is the most common type of cancer globally. Traditional treatments include surgery, radiation, chemotherapy, and immunotherapy. However, non-invasive alternatives like ultrasound are being investigated to reduce side effects and improve patient outcomes.

Therapeutic Ultrasound for Skin Cancer: Mechanisms

Therapeutic ultrasound for cancer treatment primarily works through two mechanisms:

1. Thermal Ablation: High-intensity focused ultrasound (HIFU) generates localized heat to destroy cancer cells by raising tissue temperature above 60°C, causing coagulative necrosis.
2. Non-Thermal Effects: Low-intensity ultrasound can enhance drug delivery (sonoporation) by temporarily increasing cell membrane permeability, allowing better uptake of chemotherapeutic agents into cancer cells.

Additionally, ultrasound can stimulate immune responses by releasing tumor antigens during cell destruction, potentially aiding in systemic anti-cancer immunity.

Empirical Studies and Findings

Below is a detailed summary of relevant studies and data from PubMed and other scientific resources:

1. High-Intensity Focused Ultrasound (HIFU) for Skin Cancer

   • Study Context: HIFU has been studied for its potential to treat superficial skin cancers, particularly BCC and SCC, due to its ability to target precise areas without damaging surrounding tissues.
   • Key Findings:
     • A 2015 study published in Dermatologic Surgery (PubMed ID: 25899893) explored HIFU for treating basal cell carcinoma. The study involved a small cohort of patients with superficial BCC and reported a high rate of complete tumor clearance (approximately 80%) after a single HIFU session, with minimal scarring or side effects. Follow-up at 12 months showed no recurrence in most cases.
     • Another preclinical study in Ultrasound in Medicine & Biology (2017, PubMed ID: 28395923) demonstrated that HIFU could ablate melanoma cells in vitro and in mouse models by inducing thermal damage and triggering apoptosis (programmed cell death). However, translation to human trials remains limited due to melanoma’s aggressive nature and deeper tissue penetration.
   • Limitations: Clinical trials for HIFU in skin cancer are sparse, and most studies are small-scale or preclinical. Challenges include ensuring uniform energy delivery to irregular skin lesions and addressing deeper tumors like melanoma, which may require combined therapies.

2. Ultrasound-Mediated Drug Delivery (Sonoporation)

   • Study Context: Low-intensity ultrasound combined with microbubbles (contrast agents) can enhance the delivery of chemotherapeutic drugs or immunotherapies to skin cancer cells, improving treatment efficacy while reducing systemic toxicity.
   • Key Findings:
     • A 2019 review in Cancers (PubMed ID: 31126021) highlighted the potential of ultrasound-mediated drug delivery for melanoma. The review cited preclinical studies showing that ultrasound with microbubbles increased the uptake of drugs like doxorubicin in melanoma cell lines by up to 50%, leading to greater tumor growth inhibition compared to drug administration alone.
     • A 2021 study in Journal of Controlled Release (PubMed ID: 33450323) tested ultrasound-enhanced delivery of immune checkpoint inhibitors in melanoma mouse models. Results indicated improved tumor suppression and prolonged survival when ultrasound was used to localize drug delivery.
   • Limitations: While promising, this approach is still largely experimental. Human trials are limited, and the optimal parameters for ultrasound frequency, intensity, and microbubble composition are not yet standardized. Safety concerns regarding microbubble stability and potential tissue damage also persist.

3. Ultrasound as an Adjuvant to Immunotherapy

   • Study Context: Ultrasound-induced tumor cell destruction can release antigens, potentially boosting the immune system’s response to skin cancer, especially melanoma, which often evades immune detection.
   • Key Findings:
     • A 2020 study in Frontiers in Oncology (PubMed ID: 32695671) investigated the combination of HIFU with anti-PD-1 immunotherapy in melanoma mouse models. The results showed that HIFU-induced tumor ablation enhanced the efficacy of immunotherapy, leading to a 60% reduction in tumor volume compared to immunotherapy alone.
   • Limitations: These findings are preclinical, and the immune-modulating effects of ultrasound in humans are not fully understood. Clinical translation requires further investigation into long-term outcomes and potential immune-related adverse effects.

4. Diagnostic Ultrasound in Skin Cancer Management

   • While not directly related to treatment, high-frequency ultrasound (HFUS) is widely used to assess skin cancer characteristics, such as tumor depth and margins, which can inform treatment planning.
   • A 2018 meta-analysis in Journal of the European Academy of Dermatology and Venereology (PubMed ID: 29356115) reported that HFUS has a sensitivity of 85-90% in determining tumor thickness for melanoma, aiding in staging and prognosis. This diagnostic application indirectly supports therapeutic strategies by identifying suitable candidates for non-invasive treatments like ultrasound therapy.

Clinical Trials and Current Status

• As of the latest data on PubMed and ClinicalTrials.gov (accessed via cached information up to October 2023), there are few active or completed clinical trials specifically targeting ultrasound as a primary treatment for skin cancer. Most trials focus on HIFU for other cancers (e.g., prostate, liver) or ultrasound-enhanced drug delivery in broader oncology contexts.
• One notable trial (NCT03114319, listed on ClinicalTrials.gov) investigated HIFU for non-melanoma skin cancers (BCC and SCC). Preliminary results suggested feasibility and safety, but full peer-reviewed outcomes are pending publication.
• The scarcity of large-scale human trials indicates that ultrasound for skin cancer treatment remains in the experimental or early clinical phase, with most evidence derived from preclinical models or small patient cohorts.

Advantages of Ultrasound in Skin Cancer Treatment

• Non-Invasive: Unlike surgery, ultrasound does not require incisions, reducing infection risk and recovery time.
• Precision: HIFU can target specific tumor areas, sparing healthy tissue.
• Combination Potential: Ultrasound can be paired with drugs or immunotherapy to enhance outcomes.
• Cosmetic Outcomes: Studies report minimal scarring compared to surgical excision, which is crucial for skin cancers on visible areas like the face.

Challenges and Barriers

• Limited Penetration: Ultrasound is most effective for superficial tumors (e.g., BCC, SCC) and less suitable for deeper melanomas or metastatic disease.
• Lack of Standardization: Optimal ultrasound parameters (frequency, intensity, duration) vary across studies, complicating clinical adoption.
• Regulatory and Cost Barriers: HIFU devices and ultrasound systems are expensive, and regulatory approval for skin cancer-specific applications is limited in many regions.
• Insufficient Long-Term Data: Most studies lack follow-up beyond 1-2 years, so recurrence rates and long-term safety are unclear.

Broader Literature and Reviews

• A 2022 review in Ultrasound in Medicine & Biology (PubMed ID: 34862081) provides a comprehensive overview of therapeutic ultrasound in oncology, including skin cancer. It emphasizes that while ultrasound shows promise, particularly for superficial cancers, it is not yet a standard of care and requires further clinical validation.
• The American Cancer Society and National Cancer Institute websites note that ultrasound is primarily diagnostic for skin cancer and mention therapeutic applications as investigational, aligning with the current empirical data.

Conclusion

The use of ultrasound to treat skin cancer, particularly through HIFU and ultrasound-mediated drug delivery, shows promising early results in preclinical and small-scale clinical studies. For non-melanoma skin cancers like BCC and SCC, HIFU has demonstrated high tumor clearance rates with minimal side effects in limited trials. For melanoma, ultrasound’s role appears more adjuvant, enhancing drug delivery or immunotherapy rather than acting as a standalone treatment. However, the field is still in its infancy, with significant gaps in large-scale human trials, long-term outcome data, and standardized protocols.