Basal cell carcinoma (BCC) is the most common form of skin cancer worldwide, with the majority of cases being amenable to simple therapeutic interventions. However, a subset of patients presents with locally advanced BCC (laBCC), which poses significant therapeutic challenges due to tumor size, location, and potential for functional and cosmetic morbidity. This review examines recent advances in the management of laBCC, with a particular focus on two promising approaches: Talimogene Laherparepvec (TVEC) as a neoadjuvant therapy and definitive radiation therapy. Recent data from phase II clinical trials demonstrate that TVEC, a genetically modified oncolytic herpes simplex virus, can significantly reduce tumor size and even achieve complete pathological regression in some patients with laBCC. Meanwhile, multi-institutional data on definitive radiation therapy show high rates of locoregional control in patients with unresectable or functionally challenging laBCC. This paper reviews the evidence for both approaches, explores their respective advantages and limitations, and considers their place in the evolving treatment landscape for laBCC, which increasingly emphasizes multidisciplinary care. The emerging data suggest that these modalities, alone or in combination with other treatments, may provide effective alternatives to extensive surgery for patients with laBCC, potentially reducing functional and cosmetic morbidity while maintaining oncologic efficacy.
Basal cell carcinoma (BCC) is the most prevalent form of skin cancer, accounting for approximately 80% of all non-melanoma skin cancers (Krishna et al., 2022). While the majority of BCCs are small, indolent, and readily amenable to surgical excision or local destructive techniques, a subset presents as locally advanced disease, defined by size (≥4 cm), depth of invasion, anatomic location, or recurrence despite prior therapy (Kim et al., 2024). These locally advanced basal cell carcinomas (laBCCs) present unique therapeutic challenges, especially when located in cosmetically and functionally sensitive areas such as the face, where extensive surgery may result in significant disfigurement or functional impairment (Koyfman et al., 2025).
Historically, wide local excision has been the standard of care for laBCC, often necessitating complex reconstruction with skin grafts or flaps (Vidimos et al., 2025). However, this approach may be associated with considerable morbidity, particularly for elderly patients or those with tumors in aesthetically sensitive areas. The limitations of surgery have prompted investigations into alternative or complementary therapeutic modalities, including systemic therapies targeting the Hedgehog signaling pathway, radiation therapy, and more recently, immunotherapeutic approaches (Höller et al., 2025).
In recent years, two approaches have emerged as particularly promising for the management of laBCC: (1) Talimogene Laherparepvec (TVEC), a genetically modified oncolytic herpes simplex virus, used as neoadjuvant therapy before planned surgical excision; and (2) definitive radiation therapy for unresectable tumors or cases where surgery would result in excessive morbidity. Both approaches aim to achieve local control while minimizing functional and cosmetic sequelae.
This review examines the current evidence for TVEC and definitive radiation therapy in the management of laBCC, with a focus on recent clinical trials and multi-institutional studies. Additionally, it explores the role of these modalities within the broader context of multidisciplinary care for patients with laBCC and identifies areas for future research and clinical development.
Basal cell carcinoma arises from the basal layer of the epidermis and its appendages. The majority of BCCs are driven by aberrant activation of the Hedgehog signaling pathway, frequently through loss-of-function mutations in the tumor suppressor gene PTCH1 or gain-of-function mutations in the SMO gene (Atwood et al., 2021). This pathway plays a critical role in embryonic development and is normally suppressed in adult tissues. Its inappropriate activation leads to uncontrolled proliferation of basal cells and tumor formation.
Chronic ultraviolet (UV) radiation exposure is the primary environmental risk factor for BCC development, with approximately 80% of cases occurring in chronically sun-exposed areas such as the face and neck (Medical University of Vienna, 2025). The cumulative DNA damage induced by UV radiation contributes to the genetic alterations driving BCC pathogenesis.
Locally advanced BCCs typically result from neglected primary tumors or recurrent disease after prior treatment. They may exhibit aggressive behavior characterized by local tissue destruction, invasion of deeper structures including cartilage and bone, and perineural spread (Koyfman et al., 2025). Unlike metastatic BCC, which is rare (occurring in less than 0.1% of cases), laBCC presents challenges primarily related to local tumor control and functional preservation rather than systemic disease management.
Locally advanced BCCs typically present as large (≥4 cm), ulcerated lesions with rolled borders. Depending on the location, they may invade adjacent structures such as the orbit, nasal cavity, or ear canal, potentially causing functional impairment (Vidimos et al., 2025). Perineural invasion, which occurs in approximately 5-10% of cases, may manifest as pain, paresthesia, or motor deficits along the distribution of the affected nerve (Koyfman et al., 2025).
Diagnosis is established through skin biopsy, typically a punch or incisional biopsy to sample an adequate depth of tissue. Histopathological examination reveals characteristic features of BCC, including basaloid cells with peripheral palisading, retraction artifact, and a mucinous stroma. Various histological subtypes exist, with infiltrative, morpheaform, and basosquamous subtypes generally considered more aggressive (Kim et al., 2023).
For laBCC, comprehensive imaging is essential to delineate the extent of disease and guide treatment planning. Magnetic resonance imaging (MRI) is particularly valuable for assessing soft tissue involvement and perineural spread, while computed tomography (CT) may better visualize bone invasion. High-frequency ultrasonography can provide detailed information about tumor thickness and depth, aiding surgical planning (Koyfman et al., 2025).
Before discussing the emerging roles of TVEC and definitive radiation therapy, it is important to review the established approaches to laBCC management, which form the foundation upon which newer strategies are built.
Surgery remains the gold standard for most BCCs, with several techniques employed depending on tumor characteristics and location:
While surgery offers high cure rates, laBCC often presents in locations where complete excision with adequate margins may result in significant functional or cosmetic morbidity. Additionally, some patients may be poor surgical candidates due to advanced age, comorbidities, or tumor characteristics (Koyfman et al., 2025).
The discovery of the central role of Hedgehog pathway dysregulation in BCC pathogenesis led to the development of targeted therapies, specifically Hedgehog pathway inhibitors (HPIs):
While HPIs have revolutionized the management of inoperable laBCC, their use is limited by significant side effects, including muscle spasms, taste disturbance, alopecia, and weight loss, which lead to treatment discontinuation in up to 30% of patients. Additionally, tumor resistance typically develops within 6-12 months of therapy initiation (Koyfman et al., 2025).
Radiation therapy has historically been used as a definitive treatment for BCC in patients unsuitable for surgery or as adjuvant therapy after incomplete resection. Conventional approaches include:
Traditional approaches to radiation therapy were limited by concerns about cosmetic outcomes, particularly late radiation toxicity, and technical challenges in treating complex, three-dimensional targets (Koyfman et al., 2025).
Talimogene Laherparepvec (TVEC) represents a novel approach to cancer therapy as an oncolytic virus immunotherapy. TVEC is a genetically modified herpes simplex virus type 1 (HSV-1) designed to selectively replicate within tumor cells while sparing normal tissues (Ressler et al., 2025). Two key genetic modifications underlie its therapeutic activity:
When injected directly into tumor tissue (intralesional administration), TVEC selectively infects and replicates within tumor cells, leading to:
This dual mechanism—direct oncolysis plus immune activation—distinguishes TVEC from conventional therapies and provides a rationale for its investigation in laBCC (Höller et al., 2025).
Until recently, TVEC was approved only for the treatment of unresectable melanoma, based on the phase III OPTiM trial, which demonstrated improved durable response rates compared to GM-CSF alone. However, new evidence suggests efficacy in laBCC as well.
The most significant contribution to this evidence comes from the NeoBCC trial, a phase II study conducted by researchers from the Medical University of Vienna and University Hospital Vienna. This trial investigated TVEC as neoadjuvant therapy for laBCC with the primary goal of reducing tumor size prior to planned surgical excision (Ressler et al., 2025; Medical University of Vienna, 2025).
The NeoBCC trial enrolled 18 patients with laBCC who, due to tumor size and location, would have required complex surgical closure with a flap or skin graft. Key inclusion criteria included:
Patients received six intralesional injections of TVEC over a 13-week period prior to planned surgical resection (Ressler et al., 2025).
The results of the NeoBCC trial demonstrated remarkable efficacy:
These findings are particularly significant given the challenges of treating laBCC in functionally and cosmetically sensitive areas, where extensive surgery may result in disfigurement or functional impairment.
The NeoBCC trial reported that TVEC therapy was generally well-tolerated. The most common adverse events were consistent with the known safety profile of TVEC in melanoma, including:
No treatment-related serious adverse events were reported, and all patients completed the planned course of therapy (Ressler et al., 2025).
Beyond the clinical outcomes, the NeoBCC trial provided insights into the immunological effects of TVEC therapy in laBCC. Comprehensive analyses conducted in collaboration with the St. Anna Children's Hospital demonstrated:
These findings support the proposed mechanism of action of TVEC as both a direct oncolytic agent and an immunotherapy, capable of converting immunologically "cold" tumors to "hot" tumors more susceptible to immune-mediated clearance.
While radiation therapy has been used for decades in the management of BCC, recent advances in technology and delivery techniques have substantially improved its efficacy and tolerability for laBCC:
These advances have dramatically reduced side effects and expanded the role of radiation therapy in managing complex laBCC cases (Koyfman et al., 2025).
A significant contribution to the evidence supporting definitive radiation therapy for laBCC comes from a recent multi-institutional study conducted by Cleveland Clinic Foundation, the University of Pennsylvania Health System, and Brigham and Women's Hospital (Koyfman et al., 2025).
This retrospective study identified 680 patients with laBCC treated between 2005 and 2021, of whom 140 received definitive radiation therapy. For this study, "locally advanced" was defined as tumors that were:
The study population included 101 patients treated with radiation at initial diagnosis and 39 with recurrent disease after prior therapy. Most patients (70.4%) were treated with electron-based radiation plans, with dose fractionation regimens ranging from hypofractionated (30-35 Gy in five fractions over two weeks) to conventional fractionation (60-70 Gy in 30-35 fractions over 6-7 weeks) (Koyfman et al., 2025).
The results demonstrated high efficacy of definitive radiation therapy:
These findings represent one of the largest contemporary studies demonstrating the efficacy of definitive radiation therapy for laBCC and provide valuable prognostic information for treatment selection and patient counseling.
Definitive radiation therapy offers several advantages for patients with laBCC:
However, limitations should also be acknowledged:
The management of laBCC increasingly emphasizes a multidisciplinary approach, bringing together expertise from multiple specialties to optimize treatment strategies. This approach is particularly valuable given the expanding therapeutic options and the complex decision-making required for patients with challenging tumors (Vidimos et al., 2025).
Key specialists involved typically include:
Institutional models, such as that employed at Cleveland Clinic, demonstrate the value of multidisciplinary tumor boards specifically focused on non-melanoma skin cancer. These forums facilitate:
The expanding therapeutic armamentarium for laBCC necessitates careful consideration of treatment selection and sequencing, guided by:
For many patients with laBCC, combination approaches may offer the best chance for optimal oncologic and functional outcomes. Emerging paradigms include:
The multidisciplinary approach also addresses important barriers to optimal care for patients with laBCC:
The management of laBCC continues to evolve, with several important ongoing investigations:
Advances in tumor molecular profiling and immune monitoring may provide valuable tools for treatment selection and response assessment:
Several emerging therapies show promise for future management of laBCC:
The management of locally advanced basal cell carcinoma has evolved significantly in recent years, with emerging evidence supporting the efficacy of both Talimogene Laherparepvec as neoadjuvant therapy and definitive radiation therapy as alternatives or complements to extensive surgery. The phase II NeoBCC trial demonstrated that TVEC can achieve substantial tumor shrinkage, facilitating less extensive surgery, and even complete pathological responses in some patients. Similarly, multi-institutional data on definitive radiation therapy show high rates of locoregional control and disease-specific survival in carefully selected patients with laBCC.
These advances highlight the importance of a multidisciplinary approach to laBCC, considering the full spectrum of available therapies and their optimal sequencing. While surgery remains a cornerstone of treatment for many patients, the availability of effective alternatives provides opportunities to tailor therapy to individual tumor and patient characteristics, potentially reducing functional and cosmetic morbidity while maintaining oncologic efficacy.
Looking ahead, ongoing clinical trials and translational research promise to further refine treatment selection and develop novel therapeutic approaches for this challenging disease. The integration of molecular profiling, immune monitoring, and novel targeted therapies may usher in a new era of precision medicine for patients with laBCC, improving outcomes and quality of life.
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