Skin cancer and hyperthermia and radiotherapy – SAHARA: study protocol for a multicenter, two-arm, open-label, randomized controlled phase II non-inferiority trial

Abstract

Background

Non-melanoma skin cancer (NMSC) is common among Caucasians, particularly in elderly patients, with rising incidence due to aging populations. Primary risk factors include cumulative sun exposure, advanced age and immunosuppression. While surgery and radiation therapy (RT) are standard treatments, RT is often preferred for elderly patients with large tumors or comorbidities. Hypofractionated RT schedules are effective but can cause significant side effects. Enhancing radiosensitivity through water-filtered infrared-A (wIRA) hyperthermia may reduce required radiation doses and mitigate side effects.

Methods

This two-arm, prospective, open-label, randomized controlled phase 2 non-inferiority trial will compare local control outcomes between high-dose RT alone versus de-escalated RT, immediately following mild wIRA-hyperthermia in treating NMSC. The study aims to demonstrate noninferiority with a -10% margin and 80% power (alpha = 0.1, one-sided), enrolling 100 patients. The intervention group will receive wIRA-hyperthermia combined with RT (6 fractions of 5 Gy each over 3 weeks), while the control group will receive standard RT (12 fractions of 4 Gy each over 4 weeks). The primary endpoint is local control after two years, defined as ‘no need for further intervention’. Secondary endpoints include acute and late toxicities and quality of life (QoL), assessed using the QLQ-ELD14 questionnaire. Inclusion criteria are histologically confirmed invasive NMSC, tumor stage ≥ T2, local recurrence allowed after non-RT treatment > 6 months ago, age ≥ 65 years, and ECOG performance status 0–2. Exclusion criteria are non-basal/squamous cell carcinoma histology, T1 tumors, node-positive status, post-resection cancers < 6 months, tumor thickness > 2 cm, critical area invasion, multiple lesions exceeding treatment capacity, recent or concurrent chemo- or immunotherapy, connective tissue disorders, proximity to previously irradiated areas, medical immunosuppression, and wIRA-incompatible conditions (e.g., tattoos, increased photosensitivity).

Discussion

This study aims to determine whether de-escalated RT following wIRA-hyperthermia can achieve comparable local control rates to standard RT in treating NMSC, potentially offering a treatment with fewer side effects and shorter durations. Success in this trial could lead to improved treatment protocols for elderly patients with NMSC, reducing side effects and enhancing QoL.

Trial registration

The trial has been registered prospectively on ClinicalTrials.gov under the identifier NCT06384053, as of April 25th, 2022.

Administrative information

Title {1}	Skin cancer and hyperthermia and radiotherapy – SAHARA
Trial Registration {2a and 2b}	Registry: ClinicalTrials.gov Trial ID: NCT06384053 Date of Registration: April 25th, 2024 kofam.ch Identifier: SNCTP000005971 Date of Registration: October 6th, 2024
Protocol Version {3}	Version 1.2 dated July 22nd, 2024
Funding {4}	This study was supported by Dr. med. h. c. Erwin Braun Foundation, Basel, Switzerland
Author Details {5a}	Arnold, Winfried, MD, MA, Department of Radiation Oncology, Cantonal Hospital Lucerne; Switzerland. Email: Arnold.winfried@luks.ch Sturz, Maximilian, MD, Department of Radiation Oncology, Cantonal Hospital Lucerne, Switzerland; Batifi, Nidar, RN, MSc, Department of Radiation Oncology, Cantonal Hospital Winterthur, Switzerland; Vaupel, Peter, MD, MA, Department of Radiation Oncology, University Medical Center, University of Freiburg, Germany; Notter, Markus, MD, Department of Radiation Oncology, Lindenhof Hospital, Bern, Switzerland; Müller-Hübenthal, Boris, MD, ZIO Zurich, Switzerland; Puric, Emsad, MD, Centre for Radiation Oncology KSA, Cantonal Hospital Aarau, Switzerland; Brodmann, Stefan, MD, Department of Radiation Oncology, Cantonal Hospital Winterthur, Switzerland; Zwahlen, Daniel, MD, MBA, Department of Radiation Oncology, Cantonal Hospital Winterthur, Switzerland;
Name and contact information for the trial sponsor {5b}	Sponsor: Daniel R. Zwahlen, MD, MBA, Department of Radiation Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland
Role of Sponsor {5c}	The sponsor is involved in study design, data collection, management, analysis, and interpretation. The sponsor also contributes to the report writing and the decision to submit the report for publication. However, he does not have ultimate authority over any of these activities

Introduction

Background and rationale {6a}

NMSC is one of the most common types of cancer in Caucasians and predominantly impacts the elderly population [11]. Risk factors for NMSC development include cumulative sun exposure, particularly in sun-exposed areas of the body, advanced age and immunosuppression. Given the aging population, the incidence of NMSC is anticipated to increase in the future [2, 11].

Surgery and radiation-therapy (RT) are the primary treatment modalities for NMSC. However, for elderly patients with larger tumors in critical areas and/or comorbidities, surgery may not be suitable, leaving RT as the only curative option. Hypofractionated treatment schedules with fewer fractions of external beam RT provide a logistically feasible and well-tolerated treatment alternative [6, 17].

High-dose RT using superficial orthovoltage X-rays alone has demonstrated local control rates of 86–96% for basal cell carcinoma (BCC), and 58–94% for squamous cell carcinoma (SCC) over a 4—5 years period [1]. Despite these good results, external beam RT can lead to acute and chronic side effects, particularly impacting the cosmetic appearance of the treated skin areas. A strategy to mitigate these effects involves enhancing the radiosensitivity of tumor cells to reduce the necessary radiation dose for effective tumor control. One such method is the use of mild hyperthermia (39–43°C for 30–60 min) of tumors, using contact-free, thermography-controlled, localized water-filtered infrared-A- irradiation [7–9].

Water-filtered infrared-A hyperthermia utilizes a specific range of wavelengths within the infrared spectrum, typically between 590 to 1400 nm. This range is known to penetrate into the skin and underlying tissues effectively while the water filter is minimizing the absorption by water molecules in the outer layers of the skin. This special absorption profile allows for efficient heating of targeted tissues, including deeper tissue layers of the body, up to 3 cm depth, while minimizing overheating of the skin surface. The heating of the skin and underlying tissues induced by wIRA- irradiation leads to various physiological effects, including increased blood flow, higher vascular permeability and improved tissue oxygenation. These thermal effects induced by wIRA therapy can synergize with radiotherapy to enhance tumor cell killing and improve treatment outcomes [3, 16].

As already mentioned, the contact-free delivery of energy with wIRA allows for continuous thermography and visual monitoring of the entire treatment area. Moreover, this method covers extensive treatment areas, often exceeding the size of X-irradiation fields to ensure complete coverage of the defined treatment volume. The computerized closed-loop system is programmed to maintain a maximum skin surface temperature of 43°C. This temperature setting results in tissue temperatures of 40 °C at depths of approximately 15 mm, and above 39 °C up to depths of 25–30 mm [14, 15].

The approach of combining RT immediately following superficial hyperthermia enables effective treatment outcomes with lower total radiation doses, resulting in reduced side effects, shorter treatment durations, and potentially facilitating retreatment for local recurrences. Malignant melanoma and recurrent breast cancer are superficial tumors, where superficial hyperthermia is well established [9, 10]. For the combination of RT and superficial hyperthermia in the treatment of NMSC there is only limited retrospective evidence [13].

In this trial, local control outcomes of NMSC with high-dose RT alone (standard of care) will be compared to de-escalated RT applied immediately after mild/moderate wIRA-hyperthermia.

Objectives {7}

The primary objective of this study is to establish non-inferiority in terms of control rates between de-escalated RT immediately following wIRA-hyperthermia and RT alone, which represents a standard of care for NMSC treatment of elderly patients. The study aims to demonstrate that the combined treatment approach is not inferior to the standard treatment in achieving local control outcomes for NMSC.

Trial design {8}

The SAHARA Trial is structured as a two-arm, multicenter, randomized, open-label, controlled phase II clinical trial with a non-inferiority design with a 1:1 allocation ratio. The research will engage patients across multiple institutions in Switzerland, randomizing them to either the investigational or control arm, with the intent of determining the effectiveness and safety of wIRA-hyperthermia treatment just before (≤ 5 min) RT.

Methods: participants, interventions, and outcomes

Study setting {9}

This Trial is conducted in oncological centers in Switzerland. The study sites are chosen based on their capacity to administer advanced radiotherapy treatments and wIRA-hyperthermia, and manage the comprehensive data collection required for this trial.

Eligibility criteria {10}

Eligibility criteria for the participating centres:

• Swiss hospitals with facilities offering both wIRA-hyperthermia and RT treatments.

• Ability to comply with the study protocol and provide the necessary resources for patient recruitment, treatment administration, and data collection.

Inclusion criteria for participants:

• Personally signed and dated written informed consent

• Histologically confirmed invasive NMSC, including BCC and SCC of any differentiation

•  ≥ T2 (TNM Classification, 8th Edition)

• Tumor thickness up to 2 cm (maximum depth invasion and/or exophytic growth, measured on pathology report or imaging)

• Local recurrence allowed, if primary treatment longer ago than 6 months (after primary treatment other than RT)

• Patient age ≥ 65 years

• ECOG performance status 0–2 with a life expectancy of more than 6 months

• Presentation at the Swiss Hyperthermia Network (SHN) tumor conference mandatory

Exclusion criteria:

• Other histology than BCC or SCC

• T1 tumor and/or N + (according to TNM classification 8.^th edition)

• Tumors after resection (R1 or R2 as well as adjuvant indication)

• Tumor invasion into critical areas

• Several lesions exceeding the capacity of one treatment/radiation field (multiple lesions within one treatment field are acceptable)

• Previous (1 month) or concurrent Chemo- or Immunotherapy

• Patients with connective tissue disorders (e.g., Sclerodermia, Lupus erythematodes)

• Lesions inside or in proximity (within 3 cm) previously irradiated area

• Medical immunosuppression

• wIRA- incompatibility exclusion criteria

  • ◦ Tattoos in irradiated area
  • ◦ Increased photosensitivity (either due to simultaneous treatment with photosensitivity-enhancing medications or conditions such as porphyria)

Who will take informed consent? {26a}

Informed consent from potential trial participants or their authorized surrogates will be obtained by the radio-oncologists in the participating departments. The process will involve explaining the nature of the study, its purpose, procedures involved, potential risks and benefits, and the voluntary nature of participation. Participants will be given a participant information sheet and consent form, providing them with sufficient information to make an informed decision. They will have at least 24 h to decide whether to participate. The consent form will be signed and dated by both the participant and the investigator (or a designated representative) at the time of consent.

Additional consent provisions for collection and use of participant data, a general consent form {26b}

Participants will be asked for additional consent for the use of their data for future research related to bone metastases treatment. This will ensure that all data can be used to their fullest potential in improving treatment strategies and outcomes.

Interventions

Explanation for the choice of comparators {6b}

The control arm involves standard RT alone, which is an effective treatment option for NMSC. The experimental arm combines RT with preceding wIRA-hyperthermia, based on evidence that mild hyperthermia can enhance tumor radiosensitivity, allowing for lower radiation doses. This combination could reduce side effects and improve treatment tolerability by applying lower radiation doses. Additionally, in elderly patients with larger tumors and comorbidities, this approach may offer advantages. It also potentially facilitates re-irradiations, as less dose would have been applied before (Fig. 1).

Fig. 1.

Trial design

Intervention description {11a}

Arm A (intervention)

Participants in this arm will undergo radiotherapy at a dose of 5 Gy over 6 fractions, equating to a biological effective dose (BED₁₀) of 45 Gy, targeted at the designated treatment area. These fractions are administered 2 times per week, with at least 48 h, preferably 72 h between each fraction, culminating in a total treatment duration of 3 weeks. Optimal schedules may include sessions on Mondays and Fridays, Mondays and Thursdays, or Tuesdays and Fridays.

Prior to each radiotherapy fraction, the treatment site will receive 45–60 min of wIRA-Hyperthermia treatment (maximum surface temperature: 43 °C). The interval between the conclusion of hyperthermia and the onset of radiotherapy should not surpass 5 min.

Arm B (control)

Participants in this arm will be subjected to radiotherapy at a dose of 4 Gy over 12 fractions, which corresponds to a biological effective dose (BED₁₀) of 67.2 Gy, aimed at the treatment site. The regimen involves 3 fractions per week every other day, with the total duration of therapy spanning 4 weeks. Exceptions may be made in weeks with public holidays to ensure continuity of treatment. No hyperthermia treatment will be administered to participants in this arm.

Criteria for discontinuing or modifying allocated interventions {11b}

Patients may be withdrawn from the study for various reasons, including significant non-compliance, the occurrence of any clinical adverse event, laboratory abnormality, death or other medical condition that makes continued participation not in the best interest of the participant. Additionally, if a participant meets an exclusion criterion, whether newly developed or previously unrecognized, that precludes further study participation, they may be withdrawn. Patients who are unable to receive radiotherapy or hyperthermia will also be discontinued from the study.

The reason for a participant’s withdrawal will be documented in the Case Report Form (CRF). If a participant signs the informed consent but does not receive the study intervention, they may be replaced. However, if a participant receives the study intervention and is subsequently withdrawn or discontinues, they will not be replaced. Participants who agree will continue under follow-up, but if they do not agree, any further data collection will stop.

Other reasons for withdrawal include the decision of the patient or physician, the occurrence of death, or at the specific request of the study sponsor.

Strategies to improve adherence to interventions {11c}

Adherence strategies include close monitoring of treatment attendance and side effects, regular follow-up appointments. Adherence will be further supported by regular communication with the treatment team. Comprehensive patient education will be provided to emphasize the importance of adherence and the potential benefits and risks of the treatment. Regular follow-up appointments will be scheduled to monitor progress and address any concerns. In this clinical trial, both arms utilize hypofractionated radiation therapy, which offers logistical advantages, particularly for the elderly patient population.

Adherence will be monitored using several methods. Electronic health records will track attendance and adherence to scheduled radiation sessions. CRFs will document adherence systematically and note any deviations. Review meetings with the study team will be held to discuss adherence rates and address any issues every 3 months.

Relevant concomitant care permitted or prohibited during the trial {11d}

During the trial, concomitant medications that do not interfere with the study interventions, including those for pre-existing conditions or unrelated medical issues, are permitted. Supportive care measures, such as pain management and treatment for skin reactions, are also allowed, provided they do not impact the study outcomes.

However, patients who are on medical immunosuppressive therapies will be excluded from the study, as these treatments may interfere with the efficacy of radiotherapy or hyperthermia. Additionally, the concurrent use of other investigational drugs or therapies for the treatment of non-melanoma skin cancer, any additional radiation therapy or hyperthermia outside the study protocol, or interventions that could compromise the assessment of study endpoints or participant safety are strictly prohibited.

Provisions for post-trial care {30}

Participants in the trial will have access to necessary ancillary and post-trial care, including follow-up appointments, monitoring of treatment outcomes, and management of any ongoing medical needs related to the trial interventions.

Liability insurance coverage is in place to provide financial protection in case of any legal claims arising from participation in the trial, ensuring that participants are supported in the unlikely event of harm resulting from the study.

After the trial, all patients will be monitored for potential long-term side effects. Provisions for post-trial care include follow-up visits and continued access to care teams to address any ongoing or emerging health concerns related to the treatments received during the trial.

Outcomes {12}

The primary endpoint of the study is local control, defined as the absence of the need for subsequent intervention. This will be measured by assessing the proportion of patients who achieve continuous local control throughout the follow-up period. In the experimental group, where hyperthermia enables the use of a lower radiation dose, local control will demonstrate the efficacy of the combined treatment.

Secondary endpoints include the analysis of acute toxicities, which will be measured by the severity of adverse events graded according to the Common Terminology Criteria for Adverse Events (CTCAE 5.0). The incidence and severity of these toxicities will be recorded as the proportion of patients experiencing each grade of toxicity at specific time points: immediately post-treatment, at 6 weeks, and 3 months post-treatment.

Monitoring of late toxicities will also be a secondary endpoint. These will be evaluated using the same CTCAE 5.0 criteria, with data collected at 6 months, 1 year, and 2 years after the completion of treatment. The incidence and severity of these late toxicities will be documented as the proportion of patients experiencing each grade.

Quality of Life (QoL) will be assessed using the QLQ-ELD14 questionnaire. This endpoint will measure changes in QoL scores from baseline, with mean scores evaluated at inclusion, immediately post-treatment, and at 3 months, 6 months, 1 year, and 2 years.

Participant timeline {13}

The participant timeline involves initial screening, randomization, treatment administration, and follow-up assessments at 3-, 6- and 12-months post-treatment. A schematic diagram of the timeline is recommended to visually depict these stages (Fig. 2).

Fig. 2.

Schedule of assessments

Sample size {14}

One hundred patients will be enrolled using a two-sample non-inferiority parallel design to assess the 24 months local control proportion, specifically the time until recurrence, defined as the absence of the need for subsequent intervention. The goal is to demonstrate that the intervention group (radiation therapy with preceding wIRA-hyperthermia) is non-inferior to the control group (standard radiation therapy).

The hypothesis being tested is H0: δ ≤ δ0 versus HA: δ > δ0, with a non-inferiority margin (δ0) set at −0.1, meaning a difference less than −10% is considered clinically unimportant. Statistical assumptions for the study include a one-sided test with a non-conservative Type I error rate (α) of 0.1 and a power (1-β) of 80%, corresponding to a Type II error rate of 0.2. The effect size (δ—δ0) is determined by the assumed difference in proportions under the alternative hypothesis. The Type I error rate of 0.1 has been selected due to the exploratory nature of the study design and the lack of robust statistical data.

Recruitment {15}

Strategies for achieving adequate participant enrollment to reach the target sample size include collaborating with multiple radio-oncology departments within the Swiss Hyperthermia Network. This collaboration expands the trial's reach and access to potential participants. Additionally, the use of flexible eligibility criteria for the elderly population broadens the pool of eligible participants, facilitating enrollment without compromising the trial's scientific integrity.

By leveraging these partnerships and inclusive criteria, the study aims to ensure that a sufficient number of participants can be enrolled to meet the target sample size efficiently.

Assignment of interventions: allocation

Sequence generation {16a}

The allocation sequence will be automatically generated by the SecuTrial® data management software using computer-generated random numbers. Stratification factors such as sex, tumor class, and cancer type will ensure balanced distribution across treatment arms. A stratified block randomization method with pre-defined blocks of varying sizes will be used to prevent predictability. The blocking details will be recorded separately, ensuring that those responsible for enrollment or intervention assignment do not have access to the allocation sequence or block information.

Concealment mechanism {16b}

SecuTrial® will centrally implement the allocation sequence, ensuring that participants are automatically assigned to treatment arms after stratification without any influence from study staff. Those involved in enrollment or intervention assignment will not have access to the randomization list, maintaining full concealment of the sequence until the point of assignment.

Implementation {16c}

Once a patient is enrolled by a participating center, the study office in Winterthur will trigger the randomization via SecuTrial®. This centralized approach ensures consistent, unbiased assignment of participants to the appropriate intervention arms across all centers.

Assignment of interventions: blinding

Who will be blinded {17a}

There will be no blinding of trial participants or care providers, as the interventions (standard radiotherapy versus radiotherapy combined with wIRA hyperthermia) are distinct and easily identifiable. Outcome assessors will also not be blinded due to the obvious nature of the treatments.

However, to preserve objectivity in the analysis, statisticians and data analysts will remain blinded to the allocation. Additionally, participating centers will not have access to each other’s aggregate data to minimize potential bias in patient management and outcome assessments. This open-label design allows for transparency in treatment assignments while ensuring impartiality in data analysis.

Procedure for unblinding if needed {17b}

In this open-label study, formal blinding of participants and healthcare providers is not applicable. However, maintaining the blinding of statisticians and data analysts is essential and will be upheld strictly. If unblinding becomes necessary due to safety concerns or other critical reasons, it will be conducted in a controlled and documented manner through the SecuTrial® system, ensuring transparency and accountability throughout the process.

Data collection and management

Plans for assessment and collection of outcomes {18a}

To ensure high data quality throughout the study, validated measures will be implemented. The ELD14 questionnaire, which has established reliability and validity, will be used to assess Quality of Life (QoL). Acute and late toxicities will be evaluated using the CTCAE criteria, which provide standardized criteria for assessing adverse effects. Standardized guidelines for photographic documentation will ensure consistent and accurate visual records of skin lesions. These photographs will be promptly reviewed after uploading by the sponsor-investigator or the lead study coordinator to ensure they meet guidelines, such as image sharpness and correct (encrypted) labeling. If discrepancies are identified, the images will be sent back to the center for correction or repetition.

Additionally, independent monitoring will oversee data collection, ensuring adherence to study protocols and promoting data quality. Data collection forms and related materials are referenced in the study’s data management plan.

Plans to promote participant retention and complete follow-up {18b}

To promote participant retention and ensure complete follow-up, flexible appointment scheduling will be provided (with a window of plus/minus 2 weeks, and up to 1–2 months after the one-year follow-up) to accommodate participants' needs. Additionally, participants can opt to have follow-up visits conducted by their family doctor or dermatologist to reduce travel time and make the process more convenient.

Data management {19}

Data will be prospectively collected from the medical files and QoL questionnaires (source data) of participating patients by co-investigators and their delegated personnel, such as Study Nurses and investigative staff. The data will be entered into electronic case report forms (eCRFs) via the secuTrial® system by a dedicated data manager. Access to the secuTrial® system will be provided to all participating centers, ensuring standardized and secure data entry.

To ensure data quality, range checks and consistency checks will be applied during data entry. For key variables, double data entry may be employed to minimize errors. The data will be recorded using only a unique subject identification number to maintain participant confidentiality. Investigators will keep a personal patient identification list to link patient numbers with patient names for accurate record-keeping. Collected data will include demographics, tumor characteristics, diagnostic and treatment information, and treatment outcome variables. CRFs will be completed in English, with local language allowed for trade names of medications.

Independent monitoring will be carried out according to a separate monitoring plan, ensuring regular reviews of data quality, protocol adherence, and timely correction of discrepancies. The monitoring team will verify data integrity, review source documents, and ensure compliance with regulatory and ethical standards.

Confidentiality {27}

All records identifying patients will be kept confidential and will not be made publicly available to the extent permitted by applicable laws or regulations. In compliance with Federal regulations, the ICH Guidelines for Good Clinical Practice (E6 R2), and the World Medical Association Declaration of Helsinki, the investigator and institution will permit authorized representatives of regulatory agencies and the Ethics Committee (EC) direct access to review the subject's original medical records for verification of study-related procedures and data.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}

N/a. This trial does not involve the collection, laboratory evaluation, or storage of biological specimens for genetic or molecular analysis. Any changes regarding this will be documented and communicated as per protocol amendments.

Statistical methods

Statistical methods for primary and secondary outcomes {20a}

The primary outcome is the 24 months local control rate, defined as the absence of subsequent intervention due to tumor persistence or recurrence. This will be analyzed using a 24 months local control proportion. The primary analysis will compare the difference in proportions in intervention and control group in 24 months. Non inferiority will be concluded if the lower bound of the one sided 90% confidence interval for the difference in proportions (πI – πC) exceeds −10%.

To account for potential variability in follow up times, time to event methods (Kaplan–Meier survival curves, log-rank test and Cox proportional hazards regression) will be performed as supportive analysis to address varying follow up durations and to confirm robustness of results.

Secondary outcomes include acute and late toxicities, which will be assessed using CTCAE 5.0 criteria and analyzed through descriptive statistics and chi-square tests for categorical variables. QoL will be measured using the QLQ-ELD14 questionnaire and analyzed using repeated measures ANOVA or mixed-effects models to account for intra-patient variability over time.

Interim analyses {21b}

Not applicable. Interim analyses are not planned.

Methods for additional analyses (e.g. subgroup analyses) {20b}

Not applicable.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

The analysis will focus on participants who adhere to the study protocol, excluding those with significant deviations. Missing data will be handled using random imputation techniques, as the dropout rate of 10–15% has already been accounted for in the sample size calculation.

Plans to give access to the full protocol, participant level-data and statistical code {31c}

The full protocol will be provided to all participating centers. For external parties interested in accessing the protocol, inquiries can be directed to the Cantonal Hospital Winterthur or Cantonal Hospital Lucerne. Currently, there are no plans to publicly share the participant-level dataset or statistical code. Access will be granted in accordance with institutional policies and data-sharing agreements.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee {5d}

The trial is coordinated by the Department of Radiation Oncology at Cantonal Hospital Winterthur, which serves as the central coordinating center, overseeing all aspects of the study, including protocol adherence, daily operations, and organizational support.

The SAHARA Trial team, consisting of physicians and the lead clinical research coordinator (CRC) from the sponsor's site (the Department of Radiation Oncology at Cantonal Hospital Winterthur and the Department of Radiation Oncology at Cantonal Hospital Lucerne), will meet every three months to assess trial progress, operational details, and address any emerging issues. The Sponsor-Investigator will lead these meetings, providing updates and facilitating discussions on trial challenges or necessary protocol modifications. The Sponsor-Investigator will also be available to address any urgent issues between scheduled meetings.

Data management will be handled by the clinical research coordinator from the sponsor's site, working in collaboration with SecuTrial® (Notwil, Switzerland) to ensure secure and efficient data entry, storage, and analysis. SecuTrial® will support electronic case report forms (eCRFs) and data management, ensuring data quality and regulatory compliance.

Additionally, an independent Data Monitoring Committee (DMC), provided by the Clinical Trials Unit (CTU) Bern, will oversee the trial’s safety data and provide an impartial review of trial conduct and participant safety.

All participating centers, part of the Swiss Hyperthermia Network (SHN), will join the weekly SHN tumor conference to discuss ongoing cases, including trial-related matters, ensuring consistency in patient management across all centers.

This structure combines efficient day-to-day management through the SAHARA Trial team and data handling by the CRC and SecuTrial®, with independent oversight provided by the the CTU Bern's DMC, ensuring robust trial conduct, data quality, and participant safety. Independent monitoring will further enhance adherence to the protocol and data integrity throughout the study.

Composition of the data monitoring committee, its role and reporting structure {21a}

The DMC is composed of clinical and methodological experts from the Clinical Trials Unit (CTU) Bern, and it operates independently from the sponsor, ensuring no conflicts of interest. The DMC’s primary role is to provide ongoing oversight of trial safety and data integrity. It will regularly review interim safety data, assess participant risk, and make recommendations to the Sponsor-Investigator regarding any necessary changes or adjustments to the trial. The DMC will report its findings directly to the Sponsor-Investigator and will also provide guidance on whether the trial should continue as planned or if modifications are required. The DMC is independent from both the sponsor and any competing interests, ensuring objective decision-making throughout the study. Details about the DMC’s charter and responsibilities, along with monitoring procedures, are outlined in the trial's dedicated monitoring plan. This document defines the DMC's roles, oversight responsibilities, and processes for ensuring data integrity, safety, and protocol compliance. The monitoring plan is available upon request and ensures high standards of safety and data quality throughout the trial.

Additionally, the Sponsor-Investigator, along with the lead clinical research coordinator (CRC), will handle site initiation and close-out visits.

An annual safety report (ASR) is prepared and submitted by the sponsor site each year, summarizing current recruiting status, and addressing identified and potential risks throughout the trial. The ASR is distributed annually to all participating centers to keep them informed of safety issues and trial progress.

Adverse event reporting and harms {22}

Adverse events are systematically collected, assessed, and managed by the study office in Winterthur according to predefined criteria. All serious adverse events are immediately reported to this office, which subsequently notifies the relevant ethics committee and regulatory authorities as required. DMC support ensures that all participating centers comply with Good Clinical Practice (GCP) standards, with regular checks for GCP understanding and certification among study participants. Adverse Events (AEs) and Serious Adverse Events (SAEs) are reported in accordance with the current guidelines of Swissethics by the designated responsible personnel.

Frequency and plans for auditing trial conduct {23}

Regular auditing of trial conduct is planned to ensure adherence to protocols and regulatory standards. Audits will be conducted quarterly, coordinated by the Department of Radiation Oncology at Cantonal Hospital Winterthur, and will involve thorough reviews of study documentation, data management processes, and site activities. Additionally, the Data Monitoring Committee (DMC) will conduct three scheduled audits at all participating centers during the recruitment phase to ensure compliance with study protocols and to review site performance.

Plans for communicating important protocol amendments {25}

Any significant protocol modifications will be promptly communicated to all relevant stakeholders, including the DMC, principal investigators, trial participants, and ethics committees. Changes to eligibility criteria, outcomes, or analyses will be thoroughly documented and submitted for review and approval by the appropriate regulatory authorities. Communication will be carried out through direct notifications to investigators and participants, updates to trial registries, and publication in relevant scientific journals.

Dissemination plans {31a}

The investigators and sponsor are dedicated to openly communicating the trial results. The findings will be shared through peer-reviewed publications, conference presentations, and made available to healthcare professionals and the public via open-access databases and other data-sharing platforms.

Discussion

The combination of radiotherapy and wIRA hyperthermia has gained increasing attention in radiation oncology over the past years. It has become an established approach for both primary and recurrent cancer treatments. For specific indications, such as malignant melanoma or previously irradiated recurrent breast cancer, the safety and efficacy of radiotherapy and wIRA-hyperthermia has been supported by several publications and is reimbursed by health insurance providers in Switzerland [12].

Despite there is literature on wIRA + RT in the treatment of superficial cancers [9, 10], data supporting its use for the treatment of NMSC remain sparse. There is retrospective Data showing the effectiveness and feasibility for the combination of RT and wIRA in the treatment of NMSC [13]. Due to the demographic change with an ageing population, the incidence of NMSC is expected to rise continuously [2, 11].

The SAHARA trial addresses this gap by targeting elderly patients with larger tumors (≥ cT2), who often face complex surgical interventions that may involve multiple stages and plastic reconstructions. Radiotherapy, as an alternative, offers several advantages, including possible treatment of also larger tumors without anasthaesia and on an outpatient basis. RT has no need for discontinuation of anticoagulation therapy and simplified follow-up procedures, which can be managed by primary care physicians or dermatologists [4]. Especially hypofractionated concepts with fewer treatment days have the potential to enhance patient compliance and reduce the burden on specialized oncology centers [5]. The standard arm of 12 × 4 Gy in this protocol was found to be a well-known and widely used concept for many decades in all participating centers in patients with larger NMSC. 12 × 4 Gy corresponds to a BED₁₀ of 67.2 Gy, which corresponds to a guideline-compliant dose for hypofractionated regimens [6].

The experimental arm’s reduced treatment regimen (6 × 5 Gy), delivering a BED₁₀ of 45 Gy, leverages the radiobiological enhancement provided by wIRA hyperthermia and can therefore be seen as radiobiologically equivalent to 12 × 4 Gy. This approach enables a 50% reduction in treatment fractions compared to the standard regimen, offering significant benefits for older patients. The lower total dose in the experimental arm also facilitates potential re-irradiation in nearby regions, a critical consideration for managing recurrent or new lesions. If the experimental arm demonstrates non-inferiority compared to the standard approach, it will significantly expand the therapeutic options available for treating NMSC. Additionally, the study holds promise for socioeconomic benefits, reducing treatment time and associated costs while maintaining clinical efficacy.

To minimize the diagnostic burden on this older population, the trial adopts a pragmatic primary endpoint — local control defined as "no need for further intervention". This patient-centered design reflects the realities of an elderly demographic, balancing clinical relevance with feasibility.

The trial’s two-year follow-up period was deliberately chosen to accommodate the specific challenges of the elderly population, such as mobility issues, comorbidities, and cognitive impairments, which could impact their ability to consistently attend follow-up appointments. While a five-year follow-up period is usually applied in surgical studies with younger patients, a shorter duration helps ensure feasibility and limits the risk of high dropout rates, which could undermine the study’s statistical power and generalizability.

From a statistical perspective, the trial was powered at 80%, balancing logistical and financial constraints with the need to produce meaningful preliminary data. While a power of 90% would offer a more robust foundation, achieving this within the context of the SAHARA trial was deemed impractical. The hyperthermia intervention is only available at specialized centers, limiting the potential sample size within the study’s two-year timeframe. Given these constraints, the choice of 80% power represents a pragmatic compromise, enabling the study to generate relevant phase II data. These findings will serve as a foundation for a potential phase III trial, which could be designed with broader national recruitment and higher statistical power to validate the results more comprehensively.

In conclusion, the SAHARA trial exemplifies a patient-centered and pragmatic approach to clinical research, balancing scientific rigor with the unique challenges of an aging population. If the experimental arm demonstrates non-inferiority, it could significantly expand therapeutic options for NMSC while offering socioeconomic benefits. The study also provides a pathway for future research, laying the groundwork for larger, more definitive trials in this field.

Trial status

Protocol Version: 1.2 (dated 22nd July 2024)

Recruitment: January 2025

Start Date: October 2024

Estimated Completion Date: December 2026

Abbreviations

AE

Adverse Event

ASR

Annual Safety Report

BCC

Basal Cell Carcinoma

BED10

Biological Effective Dose using a 10 Gy/fraction model

CRC

Clinical Research Coordinator

CTCAE

Common Terminology Criteria for Adverse Events

CTU

Clinical Trials Unit

DMC

Data Monitoring Committee

ECOG

Eastern Cooperative Oncology Group

eCRF

Electronic Case Report Form

EC

Ethics Committee

GCP

Good Clinical Practice

IRB

Institutional Review Board

KSA-KSB

Centre for Radiation Oncology at Cantonal Hospital Aarau and Cantonal Hospital Baden

LPLV

Last Patient Last Visit

NMSC

Non-Melanoma Skin Cancer

PI

Principal Investigator

PP

Per-Protocol

QoL

Quality of Life

RN

Registered Nurse

RT

Radiation Therapy

SAE

Serious Adverse Event

SCC

Squamous Cell Carcinoma

SHN

Swiss Hyperthermia Network

wIRA

Water-Filtered Infrared-A Hyperthermia

Authors’ contributions {31b}

Initial draft of the protocol: WA, MS, NB, DZ. Final manuscript: Principal investigator, initial draft of the protocol: WA, MS, NB, DRZ; study design and protocol development: WA, MS, MN, NB, DRZ; funding acquisition: DRZ; regulatory affairs, trial coordination: NB; data collection, patient enrollment, site principal investigators, study implementation: WA, MS, NB, DRZ, SB, MN, BMH, EP; sponsor: DRZ; writing-review and editing: WA, MS, NB, DRZ, SB, MN, BMH, EP, PV.

Funding {4}

The study is funded by the Dr. med. h. c. Erwin Braun Foundation, Basel, Switzerland with additional support from the staff of the Department of Radiation Oncology at Cantonal Hospital Winterthur and Cantonal Hospital Lucerne.

Data availability {29}

Access to the final trial dataset will be restricted to the SAHARA trial group, in accordance with the Clinical Data Agreement signed by each participating center. Statistical and data analysts will have access only to the data necessary for performing their analyses.

Participating centers agree not to publish or present individual results from the multicenter study unless a multicenter publication has not been completed within one year of the study's conclusion. In such cases, centers may publish their individual results in accordance with the terms of the agreement. All rights and intellectual property generated from the study will belong exclusively to the Sponsor, and the participating sites agree to assign these rights to the Sponsor upon request.

Declarations

Ethics approval and consent to participate {24}

Ethics approval has been obtained from Ethics Committee Zurich (BASEC2024-00546), Ethics Committee Bern and the Ethics Committee Northwest and Central Switzerland. All methods are carried out in accordance with the current version of the World Medical Association Declaration of Helsinki, and ICH-GCP guidelines as well as the local legally applicable requirements. All individual study participants will provide written informed consent to participate in the study, which will be obtained during a dedicated visit by the Principal Investigator (PI) at site.

Consent for publication {32}

Written informed consent is obtained prior to study participation, including permission for publication of study findings.

Competing interests {28}

All other authors declare no conflicts of interest and that the research is conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.