Integrated Early-CARE for Head & Neck Cancer.

Each year, more than 890,000 people worldwide receive a diagnosis of head and neck cancer. These patients face a devastating symptom burden: pain, difficulty swallowing, airway obstruction, speech loss, and disfigurement profoundly disrupt eating, communication, and social participation. At the time of diagnosis, patients with advanced head and neck cancer have a markedly reduced health-related quality of life, with global quality of life and emotional functioning approximately 50% lower than expected, compared with patients with other solid tumours. Treatment with surgery, radiotherapy, and chemotherapy often intensifies these symptoms during active therapy. Many patients experience persistent dry mouth, swallowing dysfunction, and taste changes that extend well beyond the first year. The physical morbidity of advanced head and neck cancer is associated with significant psychological distress, social isolation, and an increased risk of suicide compared with other cancer types. Despite this substantial burden, access to specialised palliative care services remains lower than the estimated need.

Given the aggressive biology of head and neck cancer and a palliative phase that may be shorter than six months, timely integration of oncology and specialised palliative care remains a clinical priority. In advanced cancers broadly, a systematic review and meta-analysis of 43 randomised trials found that early palliative care improved quality of life by approximately 11 points on a 0-184 scale and reduced overall symptom burden by approximately 10 points on a 0-90 scale at one to three months, with no effect on survival. The landmark trial by Temel et al. in patients with metastatic non-small-cell lung cancer demonstrated that early palliative care alongside standard oncological treatment improved quality of life, reduced depressive symptoms, and was associated with longer median survival. A subsequent large randomised trial further supported the benefit of early integrated palliative care on symptom burden and patient-reported outcomes in advanced cancer. Critically, however, none of these trials was designed for or reported outcomes specific to head and neck cancer. The only head and neck cancer-specific phase III randomised trial, by Patil et al. (n=180), found no significant improvement in quality of life or survival at 12 weeks, possibly reflecting the brevity of the intervention and high baseline supportive care intensity. Pilot and non-randomised studies suggest feasibility and potential benefit but remain underpowered. Ratnasekera et al. (2023) published the only scoping review protocol mapping palliative care interventions in head and neck cancer.

The lack of HNC-specific evidence limits the ability of multidisciplinary HNC teams to make evidence-based decisions regarding the integration of palliative care services. Clinical practice guidelines from organisations such as the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the Portuguese Ministry of Health recommend early palliative care for patients with advanced cancer, based largely on evidence from lung cancer and other solid tumours, with limited head and neck cancer (HNC)-specific guidance.

Establishing the effectiveness of integrated palliative care specifically in advanced HNC is essential to inform clinical practice, resource allocation, and future research priorities in this vulnerable population. Thus, the investigators hypothesise that the early integration of palliative care with standard oncological treatment will improve symptom burden and quality of life in patients with advanced head and neck cancer.

To evaluate the impact of early palliative care integration alongside chemoradiotherapy in patients with unresectable locally advanced head and neck cancer, on patient-reported outcomes and health resource utilisation. The study aims to determine whether palliative care, introduced at the outset of CRT, improves symptom burden, quality of life, treatment adherence, serum stress levels, inflammatory markers, and health resource utilisation.

Patient randomisation in the i-CARE-HN study may be performed up to seven days before cycle 1 of cisplatin/radiotherapy or on the day of chemoradiotherapy initiation (Day 1), provided that all inclusion and exclusion criteria have been confirmed and informed consent has been obtained from the participant. Randomisation will not incorporate stratification by any clinical or demographic factor. Treatment arm assignment will be performed using a permuted block randomisation method with variable block sizes, in a 1:1 allocation ratio, generated through the REDCap platform. Participants will be randomised to one of two arms:

• Control arm: Patients receiving standard chemoradiotherapy, with a total radiation dose of 70 Gy in 35 fractions over seven weeks, concurrently with cisplatin at a dose of 100 mg/m², administered every three weeks;
• Intervention arm: Patients receiving outpatient palliative care concurrently with standard chemoradiotherapy.

In the intervention arm, the first palliative care consultation must be scheduled within 28 days of signing the informed consent form and must coincide with the day of the first cycle of cisplatin chemotherapy and radiotherapy. The second consultation will take place between the 3rd and 7th week of treatment (D+21 to D+49). The third consultation will be conducted after completion of CRT (7th week) through to the 9th week. The fourth consultation will take place 12 weeks after study enrolment (primary outcome). Two long-term follow-up assessments (every 6 months) may be conducted either in person or remotely. Additional consultations will be at the discretion of the patient, the primary caregiver, the oncologist, and the palliative care physician.

Patients randomised to the standard treatment arm will not have palliative care consultations systematically scheduled. Should a referral be requested (by the patient, family, or oncologist), patients will be referred accordingly, but will remain in the control arm for intention-to-treat (ITT) analysis.

The ESAS-R (Edmonton Symptom Assessment System - Revised), validated in Portuguese oncology patients in palliative care by the University of Coimbra, will be used to assess patient-reported symptoms and constitutes the primary outcome of the study: total ESAS-R score at 12 weeks after enrolment.

Additional validated instruments will be applied to assess quality of life (EORTC QLQ-C30), adverse events during oncological treatment (CTCAE - Common Terminology Criteria for Adverse Events), functional status (ECOG - Eastern Cooperative Oncology Group performance status), and palliative care complexity (IDC-Pal - Instrumento de Avaliação da Complexidade em Cuidados Paliativos, administered exclusively to participants in the intervention arm).

The IDC-Pal will be used as a professional instrument for the assessment of palliative care complexity, complementing the ESAS-R and EORTC QLQ-C30. The same applies to the CTCAE and ECOG, which will be used as clinical instruments for symptom assessment and performance status monitoring.

Assessment Timeline:

• ESAS-R: screening; at the start of each cisplatin cycle (C1, C2, C3); end of CRT; 12 weeks after enrolment (primary outcome); 6-month follow-up; 12-month follow-up.
• EORTC QLQ-C30: screening; start of CRT; end of CRT; 12 weeks after enrolment; 12-month follow-up.
• ECOG: screening; at the start of each cisplatin cycle (C1, C2, C3); end of CRT; 12 weeks after enrolment; 6-month follow-up; 12-month follow-up.
• CTCAE: at the start of each cisplatin cycle (C1, C2, C3); end of CRT; 12 weeks after enrolment; optional assessments: 6-month follow-up; 12-month follow-up.
• IDC-Pal (intervention arm only): start of CRT; 12 weeks after enrolment (primary outcome); optional assessments: at each cisplatin cycle (C1, C2, C3); end of CRT; 6-month follow-up; 12-month follow-up.

CLINICAL AND LABORATORY PROCEDURES AND ASSESSMENTS

• Screening visit and informed consent The screening visit will be conducted by the oncologist, who will confirm inclusion and exclusion criteria, characterise the disease (staging, comorbidities), and assess functional status using the ECOG performance scale. At this visit, the i-CARE-HN study will be presented and discussed with the patient, and written informed consent will be obtained.
• Laboratory Assessments Screening, throughout CRT, end of CRT, 12 weeks after enrolment, and Follow-up 1 and 2 (8 timepoints) Assessments will include: full blood count, electrolyte panel, renal function (creatinine and urea), and hepatic function (AST, ALT, and bilirubin), enabling systematic monitoring of treatment-related toxicity. Assessments will also include serum inflammatory markers - specifically procalcitonin and C-reactive protein - and biochemical stress parameters (cortisol), allowing systematic evaluation of haematological, electrolytic, and organ toxicity associated with treatment.
• Scheduling of oncology consultations (both arms) and palliative care consultations (intervention arm) Following the screening visit, medical oncology consultations will follow the same interval schedule defined for palliative care consultations, integrating clinical assessment, PRO collection, and symptom monitoring without unnecessarily increasing the number of visits for the patient. Additional outpatient oncology and/or palliative care consultations may be scheduled as clinically indicated, at the joint discretion of the patient, the medical oncologist, and the palliative care physician, without compromising the study assessment flowchart.
• Start of chemoradiotherapy (both arms) Chemoradiotherapy must commence within a maximum of 28 days following confirmation of eligibility and signature of the informed consent form, ensuring a reasonable interval between diagnosis, multidisciplinary assessment, and initiation of standard treatment.
• End of CRT (after 7 weeks) Clinical assessment and administration of the ESAS-R, EORTC QLQ-C30, ECOG, CTCAE, and IDC-Pal questionnaires will be conducted for both study arms.
• End-of-study visit Clinical assessment and administration of the ESAS-R, EORTC QLQ-C30, ECOG, CTCAE, and IDC-Pal questionnaires will be conducted for both study arms.
• Follow-up at 6 and 12 months Clinical assessment and administration of the ESAS-R, EORTC QLQ-C30, ECOG, CTCAE, and IDC-Pal questionnaires will be conducted for both study arms, including 12-month survival assessment.

Test Description:

Edmonton Symptom Assessment System R (ESAS-R) is a validated assessment tool, based on patient reported outcome measures (PROM) used for symptom evaluation by HNC patients. It comprises evaluation of 9 relevant symptoms (pain, fatigue, somnolence, nausea, loss of appetite, dyspnoea, depression, anxiety and well-being) and an open section for reporting "other problems". It uses a scale from 0 (no symptom) to 10 (maximum intensity symptom) for every symptom. Final score is obtained by the sum of every symptoms evaluation (ranging from 0-100).

EORTC QLQ-C30 This 30-item questionnaire comprises five functional domains (physical, social, emotional, cognitive, and role functioning), eight symptom domains (fatigue, pain, nausea/vomiting, dyspnoea, insomnia, appetite loss, constipation, and diarrhoea), and a global quality of life scale. Items 1-28 are rated on a 4-point Likert scale (1 = Not at all, 2 = A little, 3 = Quite a bit, 4 = Very much), while items 29-30 assess global quality of life on a 7-point scale (1 = very poor, 7 = excellent). No overall score is generated; each functional and symptom domain is scored separately. Higher scores on functional scales indicate better quality of life, whereas higher scores on symptom scales indicate greater symptom burden and poorer quality of life.

Common Terminology Criteria for Adverse Events (CTC-AE) is used for the standardised characterisation of adverse event severity during oncological treatment, enabling toxicity grading on a scale from 1 to 5: 1- Mild symptoms; 2: Moderate, needing minimal intervention; 3- Severe, non-life-threatening, requiring intervention; 4- Life-threatening, requiring urgent intervention; 5: Death related to the adverse event.

The Eastern Cooperative Oncology Group (ECOG) Performance Status scale classifies patients' functional status on a scale from 0 to 5, providing an objective assessment of their level of independence and ability to perform activities of daily living. The categories are defined as follows: 0 = fully active; 1 = restricted in physically strenuous activity but ambulatory and able to carry out light work; 2 = ambulatory and capable of self-care but unable to work; 3 = capable of only limited self-care and confined to a bed or chair for more than 50% of waking hours; 4 = completely disabled and totally dependent; 5 = deceased.

In the i-CARE-HN study, ECOG performance status will be assessed by the treating oncologist at each study visit. Its use ensures a standardised evaluation of functional status throughout follow-up, facilitating comparisons between study groups and supporting secondary prognostic analyses.

The IDC-Pal evaluates four key domains: cancer diagnosis and disease progression, comorbidities, social resources, and special needs (spiritual, psychological, and ethical). Scores classify patients as having low (0-3), medium (4-7), or high complexity (≥8). IDC-Pal will be administered by a palliative care physician.

Inclusion criteria

Each patient must fulfil all of the following criteria:

• Diagnosis of locally advanced (unresectable) head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, larynx, and hypopharynx, staged according to the TNM AJCC 8th edition, proposed at a multidisciplinary team (MDT) meeting for definitive chemoradiotherapy (CRT) on an outpatient basis;
• Age ≥18 years;
• ECOG performance status 0-2;
• Adequate organ function: haemoglobin ≥9 g/dL; neutrophils ≥1.5×10⁹/L; platelets ≥100×10⁹/L; creatinine ≤1.5×ULN; bilirubin, AST, ALT, LDH ≤1.5×ULN;
• Signed informed consent by the participant.

Exclusion criteria

Each patient will be excluded if they meet any of the following criteria:

• ECOG performance status 3-4;
• Previous follow-up by specialised palliative care;
• Primary tumours of the nasopharynx, oesophagus, lip, or salivary glands;
• Metastatic head and neck cancer (oral cavity, oropharynx, larynx, and hypopharynx);
• Severe comorbidities: decompensated cardiovascular disease (NYHA class III/IV heart failure, recent myocardial infarction), severe COPD (FEV₁ <50% predicted), renal insufficiency (eGFR <30 mL/min), hepatic insufficiency (Child-Pugh B/C);
• Laboratory values: neutrophils <1.5×10⁹/L, platelets <100×10⁹/L, haemoglobin <9 g/dL, creatinine >1.5×ULN;
• Diagnosis of dementia;
• Participation in another clinical trial.