Quad Shot Versus Split Course Radiotherapy in Incurable Head and Neck Cancer

The optimal palliative radiotherapy regimen for incurable head and neck squamous cell carcinoma remains undefined. The standard approach at the Instituto Nacional de Cancerologia is the split-course regimen. Although effective for local symptom control, it requires a prolonged treatment course and is associated with significant acute toxicities that can compromise the comfort and quality of life of frail patients with a limited life expectancy.

The Quad Shot regimen, a hypofractionated approach initially evaluated in the RTOG 8502 trial for pelvic malignancies, offers a substantially shorter treatment duration. It has shown promising symptom control and lower toxicity profiles in retrospective and early phase studies for head and neck cancers. However, there is a lack of prospective, randomized data directly comparing the Quad Shot regimen to the split course approach.

This is a single-center, open-label, exploratory phase II randomized controlled trial designed to compare the efficacy, safety, and tolerability of the Quad Shot regimen versus the split course regimen. A total of 40 adult patients will be centrally randomized in a 1:1 ratio using permuted blocks of 4, stratified by tumor volume, to receive either the experimental hypofractionated regimen or the active comparator.

To ensure data quality, the study will utilize an institutional REDCap database for electronic case report forms (eCRF) with double data entry and monthly quality control checks. Quality assurance of the radiotherapy plans will be enforced through peer review and patient-specific pre-treatment dosimetry.

A formal interim analysis for safety and futility is planned once 50% of the recruitment target is reached. Final statistical analyses will follow the Intention-To-Treat (ITT) principle. Given the palliative nature of the cohort, competitive mortality will be factored into longitudinal statistical models (such as mixed-effects models) to adequately manage missing data without distorting efficacy and quality of life estimations.

• Quad Shot Radiotherapy (Radiation): A hypofractionated palliative radiotherapy regimen delivering a dose of 14.8 Gy divided into 4 fractions. Each fraction is 3.7 Gy, administered twice a day (with an interval of at least 6 hours between fractions) for 2 consecutive days. This cycle can be repeated up to three times with a resting interval of 3 to 4 weeks between each cycle, provided there is no limiting toxicity or disease progression.
• Split Course Radiotherapy (Radiation): A fractionated palliative radiotherapy regimen administered in two phases. The total dose is 60 Gy divided into 20 daily fractions of 3 Gy each. A planned resting interval of 3 to 4 weeks is introduced between the two treatment phases to maximize symptom control while maintaining acceptable toxicity.

Primary outcomes

• Objective Local Tumor Response Rate Assessed by RECIST 1.1 [Exactly 3 months (12 weeks) from the date of randomization]: The proportion of patients achieving an objective local tumor response, defined as either a Complete Response (CR) or a Partial Response (PR), evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Change in Quality of Life Assessed by FACT-H&N [Baseline, at the end of radiotherapy treatment, 3 months, and 6 months from the date of randomization]: Mean change from baseline in patient-reported quality of life, measured by the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H\&N) questionnaire. The FACT-H\&N assesses physical, social/family, emotional, and functional well-being, along with head and neck specific concerns. The total score ranges from 0 to 156, where higher scores indicate a better quality of life Assessment of Cancer Therapy-Head and Neck (FACT-H\&N) questionnaire. The FACT-H\&N assesses physical, social/family, emotional, and functional well-being, along with head and neck specific concerns. Higher scores indicate a better quality of life.

Secondary outcomes

• Incidence of Acute Treatment-Related Toxicity [From the start of treatment up to 3 months from the date of randomization]: The proportion of patients experiencing acute adverse events (Grade 2 or higher) associated with the radiotherapy regimens. Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Other outcomes

• Incidence of Late Treatment-Related Toxicity [At 3 months and 6 months from the date of randomization]: The proportion of patients experiencing new or persistent late adverse events (Grade 2 or higher) associated with the radiotherapy regimens. Toxicities will be graded according to the CTCAE version 5.0.
• Treatment Feasibility and Tolerance [Through the completion of the prescribed radiotherapy regimen, an average of 4 to 8 weeks]: The proportion of patients who successfully complete the prescribed radiotherapy regimen, defined as receiving 90% or more of the planned radiation dose/fractions without treatment abandonment, major modifications, or unscheduled interruptions longer than 7 consecutive days due to toxicity or clinical deterioration.
• Overall Survival (OS) [Up to 6 months from the date of randomization]: Overall survival is defined as the time from the date of randomization to the date of death from any cause. Patients alive at the end of their follow-up period will be censored.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Adult patients (18 years and older) with a histopathological diagnosis of incurable squamous cell carcinoma of the head and neck, not candidates for curative-intent treatment.
* Metastatic or locally advanced unresectable disease, in a strictly palliative setting.
* Medical indication for palliative radiotherapy.
* Performance status: Karnofsky 50 or higher or ECOG 3 or lower.
* Clinical capacity to receive radiotherapy in an outpatient setting.
* Estimated life expectancy greater than 3 months.
* Presence of at least one measurable lesion according to RECIST 1.1 criteria.
* Logistical capacity and willingness to adhere to follow-up clinical and radiological controls up to 6 months post-treatment.
* Signed informed consent.

Exclusion Criteria:

* History of previous radiotherapy to the same anatomical region to be treated.
* Diagnosis of a second active malignancy that could interfere with the evaluation of oncological outcomes.
* Presence of clinical instability or severe comorbidities that contraindicate radiotherapy treatment.
* Severe cognitive or psychiatric alterations that prevent the understanding of the nature of the study, signing the consent form, or adherence to the protocol.
* Women who are pregnant or breastfeeding

• Results publication: Corry J, Peters LJ, Costa ID, Milner AD, Fawns H, Rischin D, Porceddu S. The 'QUAD SHOT'--a phase II study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol. 2005 Nov;77(2):137-42. doi: 10.1016/j.radonc.2005.10.008. Epub 2005 Nov 2. PMID 16260054

• Oscar Gamboa, Md, Principal investigator, Instituto Nacional de Cancerologia, Columbia