Definitive Radiation Therapy Effective for Treating Locally Advanced Basal Cell Carcinoma

Definitive radiation therapy offers a high degree of locoregional control in large, locally advanced basal cell carcinomas, according to a recent multi-institutional research study. One hundred and forty tumors were treated with definitive radiation that resulted in a five-year rate of locoregional control of 78%. A high-risk subgroup of patients in whom locoregional recurrence was more common was also identified.

This research represents one of the largest contemporary studies demonstrating the efficacy of definitive radiation therapy for locally advanced basal cell cancer.

Background

Basal cell cancer is usually one of the easiest, most curable cancers. “Most times, basal cell tumors present really small,” says Shlomo Koyfman, MD, study co-author and a radiation oncologist at Cleveland Clinic Cancer Institute. “However, because basal cell cancer is slow growing, it can sneak up on people. There is a population of patients who come in with large basal cell tumors because they’ve delayed coming in due to anxiety about seeing a doctor or because they live far away. If basal cell carcinoma is found early, it’s usually resolved with surgery or surface radiation, but this becomes complicated when the disease is advanced.”

“Patients need to be part of the decision making in their therapy,” says Allison Vidimos, MD, study co-author and a dermatologist at Cleveland Clinic Cancer Institute. “Some patients may benefit from surgery but decline it because it's a major undertaking based on where the tumor is located. We're grateful that this paper shows that radiotherapy can also be a very viable and tolerable treatment option for those patients.”

Study design

Since there has been little data about outcomes in locally advanced basal cell carcinoma, the investigators conducted a retrospective study to determine the impact of definitive radiation therapy and to understand risk factors of recurrence. The study aimed to focus on cases that were unresectable or where surgery would have resulted in extensive disfigurement.

The researchers reviewed data from patients treated with definitive radiation therapy for locally advanced basal cell carcinoma at Cleveland Clinic Foundation, the University of Pennsylvania Health System and Brigham and Women’s Hospital between 2005 and 2021. For this study, “locally advanced” was defined as tumors that were ≥4 cm, required extensive resection, deemed unresectable or would have required upfront radiation therapy or systemic therapy prior to resection.

Initially, 680 cases were identified, 140 of which were treated with definitive radiation therapy (101 patients at initial diagnosis and 39 patients at disease recurrence). Most of the 140 patients (70.4%) were treated with an electron plan with varying dose fractionation regimens ranging from hypo fractionated regimens (30-35 Gy in five fractions delivered over two weeks) as well as conventionally fractionated regimens (60-70Gy in 30-35 fractions, delivered five days per week). The majority of patients (93.5%) were treated with a BED10 of at least 50 Gy. Median follow-up was 22.9 months (1.5-207.

Study outcomes

This study shows that definitive radiation therapy is a safe and effective treatment for patients with locally advanced disease. Five-year Kaplan Meier estimates of locoregional control exceeded 75%.

At the latest follow-up, 26 (18.6%) patients developed a recurrence. Twenty-two of the 26 (84.6%) recurrences were locoregional failures, and four (15.4%) of the recurrences were distant metastases. The median time to recurrence was 25.8 months. For the patients experiencing locoregional failures, one of the 22 (4.5%) patients developed nodal recurrence.

Median survival was 27.1 months (range, 0.2-49.4 months) in the 26 individuals who developed a recurrence following radiation. Seven (26.9%) patients died from basal cell carcinoma. Five-year basal cell carcinoma survival was 85% (95% CI, 74.3%-97.3%), and was similar in patients treated with upfront definitive radiation therapy (82.7%; 95% CI, 67.8%-100%) compared to radiation therapy for a recurrence (86.7%; 95% CI, 72.4%- 100%) (P = .73).

On subset analysis, patients who had at least one high-risk feature (e.g., size ≥4 cm, the presence of bone invasion, perineural invasion, immunocompromised status or recurrent disease) had a significantly lower five-year freedom from locoregional failure rate than those without any of these risk factors (68.5% vs 92.4%; p=0.004)

Advances in radiation therapy

Clinicians used to be hesitant to recommend radiation for these patients due to side effects such as skin tissue damage and damage to underlying organs. “With the emergence of advanced techniques such as intensity modulated radiation therapy and volumetric arc therapy, we can shape the radiation beams in a much more precise way, as opposed to earlier types of radiation where there was very heterogenous dose distribution,” says Dr. Koyfman. “We can now treat complex target areas like the scalp or large flank lesions while minimizing the dose to critical organs very close by. This has dramatically reduced side effects. Also, for larger lesions, slow and steady radiation over six weeks rather than higher dose regimens over a shorter period of time can allow improved normal tissue healing.”

Dr. Koyfman is quick to point out that radiation is not for everyone. This is not an option for younger patients with Gorlin syndrome or related genetic conditions. In those patients, the clinic may consider surgery, topical medications for lower risk sites as well as oral hedgehog inhibitors, which inhibit the gene involved with basal cell carcinoma.

Discussion

“We have very effective therapies for this disease, from medications to radiation to surgery,” says Dr. Koyfman. “Figuring out treatment sequencing is the trick.”

Surgeries can often be effective, even in larger tumors. Hedgehog inhibitors like vismodegib can have a dramatic response, and in roughly a third of cases, the tumor completely goes away. Radiation can also cure an overwhelming majority of these cancers. Often in larger tumors, a combination of surgery, radiation and systemic therapies are used. For example, a study of four patients with large, locally advanced basal cell carcinoma found that debulking followed by vismodegib improves outcomes over vismodegib alone.

Fostering multidisciplinary care

“If you have patients with larger basal cell tumors, engage them in a multidisciplinary discussion up front,” says Dr. Koyfman. “Don’t just refer them to a surgeon or radiation oncologist. You need to bring together multiple specialists to work as a team at diagnosis to figure out which therapy or combination of therapies to use first. And then throughout the course of treatment, these specialists should follow patients along to optimize the type and timing of treatment for these complex tumors.”

As a tertiary medical center, Cleveland Clinic follows this multidisciplinary approach to treatment decisions, involving a dermatologist, plastic surgeon, radiation oncology, medical oncologist and other experts from initial diagnosis through survivorship. Some patients, for example, may start with being treated with medication that works well initially but then side effects become untenable. It’s crucial for the other members of the medical team to know if and when they need to integrate additional treatments like radiation and/or surgery.

Cleveland Clinic also brings complex cases before its non-melanoma skin cancer tumor board, which includes dermatologists, surgeons, radiologists, pathologists, radiation oncologists and medical oncologists. “We present the tumor board’s recommendations to the patient and have a detailed discussion with them so they can make the best decision for themselves,” explains Dr. Vidimos. “We follow patients through treatment and also report back to the board about treatment effectiveness.”

The tumor board also serves as a resource for physicians around the country, giving them the ability to present their cases to the tumor board virtually.

Breaking down barriers to care

Knowing that travel costs and lack of insurance are common barriers to care, Cleveland Clinic works with patients to address these issues. The financial navigation team helps patients who have limited insurance or no insurance to receive care. In addition, for patients who can’t travel to the clinic, the team has a broad network of cutaneous oncologists and dermatologists around the country well versed in high-risk skin cancer.

“When you put your heads together as a team, you’re usually going to come to the right answer faster and better. My hope is that we change clinical care by enhancing early multidisciplinary evaluation of these patients,” says Dr. Koyfman.