Ibero-American Expert Consensus on Squamous Cell Carcinoma of the Head and Neck Treatment in Patients Unable to Receive Cisplatin: Recommendations for Clinical Practice

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Table 1 Summary of Expert Recommendations for Identifying SCCHN Patients with Absolute or Relative Contraindications to Cisplatin Administration or Who Do Not Meet All of the Criteria

Age

● Biological age must prevail over chronological age in order to establish therapeutic decisions. ● Chronological age alone should not be an absolute contraindication for receiving platinum; and it should not limit the administration of cisplatin to full doses. ● Patients over 70 years of age are at greater risk of toxicity and non-cancer-related mortality, and there may be no benefit from cisplatin treatment. However, frailty seems to be a stronger risk than age alone, and should always be considered when making treatment decisions. ● Geriatric screening tools (G8 or VES13) allow for discrimination between “fit”, vulnerable, and frail patients.  ∘ G8 geriatric screening tool is better for predicting “fit” patients, whereas VES13 has a higher capacity for identifying frail patients in need of comprehensive geriatric assessment.  ∘ G8 geriatric screening tool should be the method of choice for patients under 70 years of age, as it has been able to identify twice as many vulnerable patients as the Karnofsky index. ● Regardless of chronological age, “fit” patients may be able to tolerate high doses of cisplatin and get similar benefit as the general population, and they should be treated with curative intent.

Performance status

● Despite scarce evidence, ECOG > 2 is an absolute contraindication to platinum administration, while ECOG = 2 is a relative contraindication. ● Assessment of each individual patient will determine whether performance status is influenced by the disease itself, by the treatment, or by the comorbidities. If performance status is influenced by:  ∘ The disease, then treatment should be administered;  ∘ The on-going treatment, then treatment should be adjusted;  ∘ Comorbidities, then treatment should not be administered.

Weight loss

● Weight loss of > 30% is an absolute contraindication to cisplatin treatment. ● Weight loss of 20–30% is a relative contraindication, and other factors should be considered. ● Nutritional assessment should be made before making a therapeutic decision using validated screening and assessment tools, such as the Subjective Global Assessment tool, the patient-generated Subjective Global Assessment tool, and the Malnutrition Screening tool.

Comorbidities

● It is important to define previous comorbidities (and their clinical impact) when making treatment decisions in the curative or palliative setting. ● Functional tests with well-established cut-off points should be performed in all patients, including audiometry, renal function, echocardiogram, lung function, and nutritional status. ● These tests would be advisable for both asymptomatic patients and those with previous history of these comorbidities. ● Depending upon the severity of the comorbidity, an absolute contraindication may be established (see Table 2). ● For relative contraindications due to comorbidities, it is necessary to take into account the additive effect of several lower severity comorbidities, which can mean an absolute contraindication of treatment. ● Patients with > 1 relative contraindication should be analyzed individually by the multidisciplinary team in order to establish the best treatment. ● In situations where toxicity may be a problem for the patient, despite initially meeting the requirements for cisplatin, closer monitoring should be established.

Chronic viral infections

● HIV and hepatitis B and C virus screening is recommended for all patients who are scheduled to receive cisplatin. Additionally, depending on the endemic areas, it is also advisable to screen for HTLV-1. ● In patients with an active hepatitis B or C infection, liver function status should be checked to see if antiviral administration is appropriate. If so, chemotherapy should be started. ● It is necessary to perform cost-effectiveness studies to evaluate the need for screening of these viruses in the oncological population.

COVID-19

● Screening for SARS-CoV-2 virus is advisable in all patients who will undergo surgery, systemic therapy, or radiotherapy. ● In patients with locally advanced SCCHN, radiotherapy with curative intent should only be interrupted in patients with severe COVID-19, but chemotherapy should be interrupted in all patients, regardless of whether they are asymptomatic or have mild or severe symptoms. ● In patients with recurrent and metastatic SCCHN, treatment should be interrupted in all patients with COVID-19, regardless of whether they are asymptomatic or have mild or severe symptoms. ● In the palliative treatment scenario, it is necessary to consider age, comorbidities, and the risk-benefit ratio when deciding whether to continue treatment. In addition, this decision must be discussed with the patient.

Pre-chemotherapy toxicity

● Contraindication to platinum depends on the type of hypersensitivity developed as a result of previous drug exposure: relative contraindication for mild hypersensitivity, and absolute contraindication for severe hypersensitivity (anaphylaxis). ● Hypersensitivity to carboplatin can be controlled by a desensitization program. ● A cisplatin dose of > 200 mg/m^2 confers a survival benefit when combined with radiotherapy with curative intent. ● Regarding hematologic toxicity, the use of granulocyte colony-stimulating factors is recommended if an episode of febrile neutropenia occurs in the previous cycle, especially when high-dose cisplatin is administered in combination with radiotherapy. ● Patients should be informed about the possibility that an initial mild reaction may evolve into a serious reaction over time.

Alternative treatment to high-dose cisplatin

● The following treatments should be considered in patients who cannot received high-dose cisplatin: ∘ Locally advanced disease: carboplatin + 5-fluorouracil, cetuximab, weekly cisplatin (only in the adjuvant setting), or hyperfractionated radiotherapy alone. ∘ Recurrent, unresectable, or metastatic disease: pembrolizumab in tumors that express PD-L1 (CPS ≥ 20). ● Carboplatin + 5-fluorouracil with radiotherapy is an alternative to high-dose cisplatin in patients with oropharyngeal tumors; however, due to significant toxicity, it is generally reserved for centers with extensive experience in the use of this scheme in combination with radiotherapy.

Abbreviations: CPS, combined positivity score; HIV, human deficiency virus; HTLV, human T-cell leukemia-lymphoma virus; PD-L1, programmed-death ligand1.

Table 2 Absolute and Relative Contraindications to Cisplatin Administration in Patients with SCCHN

Absolute Contraindications

Relative Contraindications

● ECOG of 3–4. ● Weight loss of > 30%. ● Renal failure (creatinine clearance < 40 mL/min). ● Hearing disorders: previous hearing loss or grade ≥ 2 tinnitus. ● Neurologic disorders: grade ≥ 2 diabetic neuropathy, peripheral sensory neuropathy, orthostatic hypotension, Lhermitte’s sign, seizures, focal encephalopathy. ● Pregnancy or lactation. ● Child-Pugh B or C liver disease. ● Platelet count < 1×10^5 /mm^3. ● Neutrophil count < 1500 /mm^3. ● Hemoglobin level < 9 g/dl. ● Congestive heart failure NYHA Class III or IV despite cardiovascular optimization therapy. ● Congestive heart failure NYHA Class I or II with LVEF ≤ 50%. ● Hepatitis B or C virus infection without antiviral treatment. ● HIV infection with CD4 cell count < 200 /µL, detectable viral load, and acquired immunodeficiency syndrome. ● Hypersensitivity to platinum-based therapy. ● Asymptomatic or symptomatic COVID-19 confirmed.

● ECOG of 2. ● Involuntary weight loss of 20–30%. ● Creatinine clearance of 40–60 mL/min. ● Grade 1 hearing or neurologic disorders. ● Grade ≥ 2 bone marrow, liver, and lung disorders. ● Hypertension, previous heart disease, diabetes, and recurrent pulmonary infections. ● Concomitant use of nephrotoxic drugs. ● HIV infection with CD4 cell count 200–350 /µL. ● Previous platinum treatment (> 200 mg/m^2 or > 3 induction cycles with docetaxel, carboplatin, and 5-fluorouracil). ● Cumulative cisplatin dose of > 200 mg/m^2 or having received > 3 induction cycles with docetaxel, cisplatin, and 5-fluorouracil. Two or more mild contraindications can mean an absolute contraindication for platinum treatment.

Abbreviations: ECOG, Eastern Cooperative Oncology Group; HIV, human deficiency virus; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Table 3 Cumulative Doses and Risk Factors Associated with Cisplatin Toxicity

Cumulative Dose of Cisplatin	Toxicity	Risk Factors	Test
≥ 300 mg/m^2	Neurotoxicity	● Drug ● Alcohol ● Diabetes ● Older age ● High serum creatinine	● Vibration perception test ● Deep tendon reflexes
60 mg/m^2	Ototoxicity	● Hearing impairment ● Older age ● Genetic polymorphism ● Systemic inflammation	● Audiometric tests
50 mg/m^2	Nephrotoxicity	● Low ECOG PS ● Regular NSAIDs ● Tobacco ● Hypoalbuminemia ● GFR < 60 mL/min/1.73 m^2	● Creatinine clearance ● Serum creatinine level
Any dose	Hematologic toxicity	● Older patients ● Pre-existing anemia	● Blood tests

Abbreviations: ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; NSAID, non-steroidal anti-inflammatory drugs; PS, performance status.

Table 4 Summary of Expert Recommendations for Supportive Measures to Improve the Treatment of Patients with SCCHN

Socioeconomic Factors

● In order to define treatment administration for organ preservation in SCCHN, the characteristics of the healthcare institutions, health system, clinical conditions of the patient and other socioeconomic factors must be taken into account to make the best treatment choice for each case. ● Socioeconomic factors are associated with advanced clinical status at initial diagnosis of SCCHN; in addition, presence of comorbidities are important predictors of quality of life in survivors. All of these should be considered when deciding the best therapeutic approach for each patient. ● Given the nature of the disease, patients will likely require a regular caregiver; therefore, it is advisable to develop education programs specifically for patients’ caregivers. ● After treatment, it is important to take an individualized rehabilitation approach to guide and help patients to return to work and resume their daily lives. ● Clinical and social variables of each patient should be used to better define candidates for intensive rehabilitation and comprehensive social support, with the goal of reducing work disability.

Multidisciplinary Approach

● A multidisciplinary approach is essential for the management of patients with SCCHN. Patients should be managed by a multidisciplinary team at all times until survivorship is reached. ● Specialized nurses ensure the coordination of multimodal treatment and its teams, the continuous assistance of patients and their caregivers, and the early detection of toxicity or potentially serious conditions. Advanced nurses should be recommended as part of the multidisciplinary team for SCCHN management. ● Nutritional status should be assessed by a specialist before, during, and at the end of treatment. Adequate nutritional function can favorably impact treatment outcomes, as well as recovery from toxicity. ● Nutritional assessment is advisable in patients who, at diagnosis, do not appear to be malnourished or have weight loss, as they may have muscle mass loss and/or potential risk factors for malnutrition. ● Comprehensive assessment by an oncogeriatrician to help with optimal treatment choice should be conducted in patients identified as fragile by the oncologist using geriatric screening tools (G8 or VES13). ● Patients (and caregivers) should be screened for psychological distress (anxiety, depression) and should be offered a referral for specialized support. ● Patients should be evaluated by a dentist, speech therapist, and physical therapist before, during, and after treatment. ● Survivors should be followed-up by the multidisciplinary team for identification of late toxicities, the potential need for further rehabilitation, and to get support for social relocation after treatment.