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

Introduction

Cisplatin is an essential component in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN), both in locally advanced and metastatic/recurrent disease. Phase III studies that enrolled a large patient population have demonstrated its efficacy, either in locally advanced disease when combined with radiotherapy at high doses (100 mg/m² every three weeks), or in metastatic disease when combined with other chemotherapy agents and biological or immuno-oncology therapies.^1–5 However, cisplatin presents acute and late toxicity with important implications for patients’ quality of life and may not be suitable in some patients. There are some patients in whom cisplatin is completely contraindicated, while others may only meet some of the criteria for not receiving it. In fact, only about half of the patients treated in clinical trials were able to complete the planned three cycles of high-dose cisplatin.⁶ To reduce the toxicity of radiotherapy with cisplatin, previous guidelines and consensus statements have recommended the use of highly conformal radiation techniques, such as intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT), or to use alternative treatments to high doses of cisplatin.^7–9

In order to establish recommendations on the management of patients with SCCHN, a group of experts in medical and radiation oncology from Spain and Latin-American held several meetings to discuss the most relevant and recent scientific evidence. The objective of these discussions was to identify patients who are not candidates or who only meet some of the criteria for not receiving cisplatin in order to offer these patients the most suitable therapeutic alternative based on their clinical experience. This expert consensus is intended to guide and help health professionals when deciding on whether or not a patient is eligible to receive a drug, such as cisplatin, which has significant associated toxicities.

Suitability for Cisplatin Chemotherapy

The identification of predictive patient factors for acute and late toxicities may help to determine whether cisplatin should be administered or not, or whether it should be administered with careful monitoring. However, many of these factors alone do not always allow us to define an absolute contraindication to cisplatin. This section describes how to identify patients with SCCHN who may (are “fit” to) or may not (are “unfit” to) receive cisplatin, with special attention to those who meet only some of the criteria for not receiving cisplatin and where there are concerns about whether or not to administer it (“medium fit”). Table 1 shows a summary of the experts’ recommendations for identifying these patients.

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

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

Age

The impact of age on the choice of treatment is highly influenced by other patient factors, such as life expectancy, comorbidities, performance status, social support, and patient preferences; therefore, therapeutic decisions should be based on biological rather than chronological age.^10,11 For this reason, frailty has been established as a marker that is linked to biological age, and represents a crucial factor in making therapeutic decisions in elderly cancer patients.¹² To assess the frailty of patients, several geriatric screening tools have been developed, such as the G8 and VES13 tools.¹³ These assessments allow for discrimination between “fit”, vulnerable, and frail patients. Irrespective of chronological age, “fit” patients are able to tolerate high doses of cisplatin, while vulnerable patients require adaptive treatment, and frail patients are prevented from receiving curative therapy.¹² Although both tools show reliable screening performance, the G8 is considered better for predicting “fit” patients, whereas the VES13 has a greater capacity to identify frail patients who are in need of comprehensive geriatric assessment.¹⁴ Nevertheless, as the G8 has identified twice as many vulnerable patients as the Karnofsky index, it is the method of choice in patients aged ≥70 years.¹¹ Although these screening tools cannot replace comprehensive geriatric assessment, they may be useful to identify patients who are eligible for comprehensive geriatric assessment.

Several consensus statements have established a cut-off point of 70 years as the age at which cisplatin administration is not recommended, under the rationale that no benefit is obtained by adding chemotherapy to radiotherapy after that age.^7,15 However, this limitation has been changed, as several reports have shown that patients aged ≥70 years can achieve the same clinical benefit from cisplatin as younger patients.^12,16–19 Therefore, none of these consensus papers have stated that age by itself is a criterion for which cisplatin therapy is absolutely contraindicated.^7,12

What is known is that addition of cisplatin to radiotherapy increases the toxicity of treatment and the consumption of healthcare resources, including emergency department visits and inpatient admissions.^2,20,21 The incidence of this toxicity is significantly higher in people >70 years of age, with higher rates of thrombocytopenia, diarrhea, and grade ≥3 stomatitis.¹⁷ In contrast, a retrospective study showed that the rate of acute toxicities was not higher in older versus younger patients (<65 years).²²

Performance Status

According to a consensus statement that established recommendations for the use of platinum-based therapy in patients with SCCHN across several categories, having an Eastern Cooperative Oncology Group (ECOG) performance status of 2 was considered a high risk factor for developing platinum intolerance, while an ECOG ≥3 was an absolute contraindication for platinum-based therapy, meaning these patients are only candidates for palliative treatment (Table 2). The rationale for this recommendation was that patients with reduced performance status (ECOG ≥2) have low therapeutic adherence due to fear of an increased risk of chemotherapy-related toxicity.⁷

Based on a meta-analysis that analyzed clinical trials comparing locoregional treatment with locoregional treatment plus chemotherapy, evidence for the effect of induction chemotherapy according to performance status on patient survival remains unclear.¹⁵ Regarding the appearance of late severe toxicity after concomitant chemotherapy plus radiotherapy in patients with locally advanced SCCHN, another study found that there was no difference according to Karnofsky index performance status.²³ For this reason, when using the Karnofsky performance status score, clinicians should ensure that patients with disabilities have equal access to treatment, as they may have difficulties with activities of daily living that are unrelated to their SCCHN prognosis. In such cases, an appropriate assessment of performance status should be made, taking into account the individual’s usual functional ability and their need for assistance with activities of daily living.⁷

Weight Loss

An involuntary weight loss of ≥20% has been established as a relative contraindication for receiving platinum-based treatment (Table 2).⁷ Nutritional deficiency and weight loss are important risk factors for receiving cisplatin. Weight loss has been shown to influence clinical outcomes in patients with SCCHN who receive chemoradiotherapy, with a weight loss of ≥20% before diagnosis being significantly correlated with treatment interruption, infections, early mortality, increased hospital readmission, and reduced survival.²⁴ Therefore, an early nutritional approach to patients with SCCHN can reduce weight loss and improve outcomes.²⁵

Weight loss in the 6 months prior to treatment does not appear to affect the development of late chemoradiotherapy-related toxicity.²³ However, pretreatment weight loss is associated with treatment failure, locoregional recurrence, distant metastases, and reduced overall survival (OS). The greater the weight loss, the worse the outcome. However, none of these outcomes seem to be affected if weight loss occurs during treatment.²⁶

Despite intense nutritional support following diagnosis and throughout treatment, patient nutritional status deteriorates during radiotherapy. However, induction chemotherapy may help improve nutritional status by reducing symptoms that limit oral intake.²⁷ Thus, a nutritional assessment before, during, and after treatment is essential to minimize symptoms or adverse effects that may arise. Some of the nutritional screening and assessment tools available and validated in cancer patients are the Subjective Global Assessment Tool, the patient-generated Subjective Global Assessment, and the Malnutrition Screening Tool.²⁸

Comorbidities

Given the usual cisplatin-related toxicities, such as neurotoxicity, nephrotoxicity, ototoxicity, and hematologic toxicities, especially when high doses have been administered,^9,29,30 the suitability of cisplatin administration will depend on the presence of comorbidities that may be exacerbated. Because performance status is not a reliable substitute for assessing comorbidities as a prognostic measure, different tools have been developed to measure and quantify patient comorbidities. Some of the more commonly used assessment tools are the Adult Comorbidity Evaluation and the Charlson Comorbidity Index.^31,32

According to previous consensus statements, some of the main comorbidities that are absolute contraindications to cisplatin administration are renal failure (creatinine clearance < 50 mL/min), hearing disorders (previous hearing loss or tinnitus grade ≥ 2), neurologic disorders (grade ≥ 2 diabetic neuropathy, peripheral sensory neuropathy, orthostatic hypotension, Lhermitte’s sign, seizures, or focal encephalopathy), hypersensitivity to platinum-based therapy, and pregnancy or lactation (Table 2).^7,8 Other absolute contraindication criteria are Child-Pugh B or C, platelets < 1 × 10⁵/mm³, neutrophils < 1500/mm³, hemoglobin < 9 g/dl, hepatitis B or C without antiviral treatment, congestive heart failure New York Heart Association (NYHA) class III or IV despite cardiovascular optimization therapy, and congestive heart failure NYHA class I or II with left ventricular ejection fraction (LVEF) ≤ 50%.^8,33 In addition, although high blood pressure is not a contraindication to cisplatin administration by itself, it may carry an increased risk of developing acute or chronic renal failure. Patients with more advanced cardiomyopathies, including heart failure, are more susceptible to developing cardiorenal syndrome.³⁴

Many of these absolute contraindication criteria can become relative contraindications, or high risk, depending on how they develop. Thus, relative contraindication criteria are: receiving cisplatin with a creatinine clearance of 50–60 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; previous platinum treatment (> 200 mg/m² or more than three induction cycles with docetaxel, carboplatin, and 5-fluorouracil); or concomitant use of nephrotoxic drugs (Table 2).^7,8

Chronic Viral Infections

Chronic viral infections that can condition the administration of platinum-based therapy are those caused by human immunodeficiency virus (HIV) and hepatitis B or C virus. According to previous consensus statements, cisplatin is completely contraindicated in patients with HIV, with CD4 cells < 200/µL, with detectable viral load, and with acquired immunodeficiency syndrome. However, if the CD4 cell count is between 200 and 350/µL, the contraindication to cisplatin is only relative (Table 2).^7–9,35 The main rationale for these recommendations is the weakening of the immune system by HIV. Another factor to consider is that some antiretroviral drugs used by patients with HIV are inducers or inhibitors of certain cytochrome enzymes, which can influence the effectiveness or tolerability of cisplatin or other concomitant treatments, such as antiemetics and corticosteroids.³⁶

In chronic active hepatitis B or C virus infection, contraindication to cisplatin administration is absolute in patients who are not receiving antiviral treatment (Table 2).^8,35 This is due to the possibility of exacerbation of hepatitis during cancer treatment. Many chemotherapeutic agents, including cisplatin and carboplatin, are associated with reactivation of hepatitis B virus.³⁷ To avoid virus reactivation in patients scheduled to receive chemotherapy, screening for virus surface antigen (HBsAg), anti-surface antigen antibodies (antiHBs), and anti-core antibodies (anti-HBc) is recommended for all patients.³⁷ In patients with an active infection (HBsAg-positive) liver function status would be checked. If liver function allows for antiviral administration, chemotherapy would be started. In patients with resolved hepatitis B infection (HBsAg-negative and anti-HBc-positive), liver function and virus DNA should be measured before starting antiviral prophylaxis, after which chemotherapy can be initiated.³⁷

Because curative treatment for hepatitis C is now available, the number of patients with this infection is expected to decrease. Even so, several retrospective studies have detected a higher rate of hepatitis C infection in patients with SCCHN than in the general population, although with a similar prognosis.^38,39 Because of this, it is important to screen for this virus in patients with SCCHN before chemotherapy administration.

COVID-19

The SARS-CoV-2 virus pandemic, which causes COVID-19, has disrupted all health programs and protocols at all levels, including in patients with SCCHN, by interrupting, delaying, or discontinuing treatment. As the pandemic evolves, and as more information about the virus becomes available, it will be necessary to determine whether measures taken to address these disruptions are temporary or permanent.

Depending on the severity of COVID-19, chemotherapy administration may increase mortality risk in cancer patients. However, administration of chemotherapy or other anticancer treatments does not increase the risk of death from COVID-19, but rather that the mortality risk depends primarily on the patient’s age, sex, and comorbidities.⁴⁰ Although patients receiving chemotherapy have a higher risk of death from COVID-19 than from immunotherapy, radiotherapy, or targeted therapy, the difference in mortality risk was not statistically significant. The risk of death in patients receiving palliative chemotherapy is higher than in those receiving non-palliative chemotherapy (35% vs 16%).⁴⁰

Various recommendations have been established for patients with SCCHN and COVID-19.^41–43 These recommendations all agree on the importance of individualizing therapy and not delaying or interrupting treatment in patients without virus infection. They also agree that systemic therapy should be avoided in patients aged > 70 years or in younger patients with high-risk comorbidities (ie diabetes or cardiovascular disease); induction therapy with cisplatin should avoided, since this strategy has not been shown to provide added benefit over that provided by standard radiochemotherapy; and total treatment time should be reduced.^41–43 In patients who are not candidates for platinum-based therapy, these guidelines recommend that exclusive radiotherapy be prioritized and that suitability of concomitant cetuximab administration be assessed on an individual patient basis.⁴³

Pre-Chemotherapy Toxicity

The risk of cisplatin toxicity increases due to the accumulation of cisplatin doses over time, which can remain in the plasma for up to 20 years. Therefore, previous cisplatin administration must be taken into account in order to avoid excessive drug accumulation and serious toxicities.⁴⁴

Neurotoxicity can occur with cumulative cisplatin doses of ≥ 300 mg/m², especially in patients with a history of drug and alcohol use, diabetes, older age, and elevated serum creatinine levels.⁹ The incidence of clinical neurotoxicity with cisplatin does not seem to be directly related to the response rate.³⁰ This detail is important because, although cisplatin use is associated with the risk of neurotoxicity, this does not have to necessarily be a problem as their symptoms could be prevented or mitigated.³⁰

Ototoxicity may occur with cumulative cisplatin doses of 60 mg/m², especially in patients with previous hearing impairment, older age, some genetic polymorphisms (megalin, ACYP2, TPMT, COMT, XPC) or systemic inflammation.⁹ It is known that from 300 mg/m² of cisplatin, the risk of ototoxicity increases by 5% for every 100 mg/m² accumulated.²⁹

Nephrotoxicity can arise from cumulative cisplatin doses of 50 mg/m²; risk factors for nephrotoxicity include low ECOG performance status, regular use of nonsteroidal anti-inflammatory drugs, older age, tobacco use, hypoalbuminemia, and a previous glomerular filtration rate < 60 mL/min/1.73 m².⁹

Finally, hematologic toxicity, which can arise from any dose, is common in older patients and those with pre-existing anemia.⁹ The development of any of these adverse events will determine the next treatment administered.

To mitigate or reduce the risk of these toxicities, in addition to taking into account previous cisplatin administrations, laboratory tests to detect for the presence or worsening of toxicities should be conducted. For example, to test for neurotoxicity, vibration perception tests or exploration of deep tendon reflexes can be done. Audiometric tests should be performed for ototoxicity. For nephrotoxicity, the rate of creatinine clearance or serum creatinine levels should be measured, and a complete blood count for hematologic toxicity (Table 3).⁹

Table 3 Cumulative Doses and Risk Factors Associated with Cisplatin Toxicity

According to previous consensus statements, an cumulative cisplatin dose of > 200 mg/m² or more than three induction cycles with docetaxel, cisplatin, and 5-fluorouracil has been established as a relative contraindication for further cisplatin administration (Table 2).^7–9,35,44 However, it should be noted that a cisplatin dose of > 200 mg/m² confers a survival benefit when combined with radiotherapy with curative intent.⁴⁵

An absolute contraindication to cisplatin is hypersensitivity to platinum-based therapy (Table 2).^7,8,35,46 The incidence and severity of hypersensitivity to platinum varies from one agent to another. While cisplatin or carboplatin can cause type I (early-onset, IgE-mediated) or type IV (late-onset, T-cell-mediated) hypersensitivity, oxaliplatin primarily leads to type I hypersensitivity, but also type II and III hypersensitivity.⁴⁶

Alternative Treatments to High-Dose Cisplatin

Locally Advanced Disease

In patients with locally advanced SCCHN who are not candidates for high-dose cisplatin, current National Comprehensive Cancer Network (NCCN) guidelines recommend primary systemic treatment plus concurrent radiotherapy with carboplatin + 5-fluorouracil (category 1, preferred regimen), cetuximab (category 2B, useful in certain circumstances) or cisplatin 40 mg/m² weekly (category 2B).⁴⁷ According to the Spanish Society of Medical Oncology (SEOM), radiotherapy alone should be considered in patients with locally advanced disease who are not candidate for platinum-based chemotherapy (Quality of evidence I, strength of recommendation A).⁴⁸

The combination of carboplatin and 5-fluorouracil administration with radiotherapy was supported by a phase III study that demonstrated its superiority in both OS and locoregional control compared with radiotherapy alone in patients with advanced oropharyngeal carcinoma.⁴⁹ Although there are no direct comparisons, a subsequent retrospective analysis showed median OS was prolonged in patients treated with cisplatin compared with those receiving carboplatin + 5-fluorouracil. In addition, adherence was lower with carboplatin + 5-fluorouracil, possibly because of its higher rates of toxicity.⁵⁰ A meta-analysis also showed that OS was shorter with carboplatin than with cisplatin, with more hematologic toxicity and mucositis.⁵¹

Clinical evidence supporting the cetuximab use as an alternative to cisplatin in locally advanced disease was provided by a phase III study, in which the use of radiotherapy with or without cetuximab was evaluated. The combination of cetuximab and radiotherapy significantly prolonged locoregional control versus radiotherapy alone (24.4 vs 14.9 months, p = 0.005) and significantly increased median OS (49.0 vs 29.3 months, p = 0.03) without increasing toxicity associated with radiotherapy.^52,53 However, in a later study, the combination of radiotherapy and cetuximab led to lower rates of 5-year progression-free survival (PFS; 67% vs 78%) and OS (78% vs 85%) compared with radiotherapy and high-dose cisplatin.³ A previous study showed that only 27.5% of patients received three-weekly cisplatin and radiotherapy for locally advanced SCCHN treatment.⁵⁴ The combination of cetuximab and paclitaxel may be a treatment option in patients with recurrent/metastatic disease for whom platinum is contraindicated, showing an overall response rate of 54% (22% complete response), a disease control rate of 80%, a median PFS of 4.2 months, and a median OS of 8.1 months.⁵⁵ However, this combination is not yet approved by the European Medicines Agency (EMA) or the Food and Drug Administration (FDA) for this indication.

The use of weekly cisplatin has also been tested as an alternative to high-dose cisplatin. The combination of weekly cisplatin 50 mg and postoperative radiation therapy improved locoregional control and survival of patients with locally advanced SCCHN versus radiation therapy alone without significantly increasing the rate of late radiation complications in this group.⁵⁶ However, cisplatin 100 mg/m² administered once every 3 weeks resulted in superior locoregional control in the adjuvant setting, albeit with higher rates of toxicity, than did cisplatin 30 mg/m² administered once a week.⁵⁷ On the other hand, recent publications showed that weekly cisplatin 40 mg/m² plus radiotherapy is non-inferior to cisplatin 100 mg/m² once every 3 weeks plus radiotherapy in patients with post-operative high-risk locally advanced SCCHN and has a favorable toxicity profile.^58,59 Thus, weekly cisplatin plus radiotherapy could be considered as an option for these patients in the adjuvant setting.

Another alternative to high-dose cisplatin is hyperfractionated radiotherapy.⁶⁰ Hyperfractionation is considered as standard-of-care in patients with locally advanced SCCHN undergoing definitive radiotherapy, as it has demonstrated an improvement in OS compared with conventional fractionated radiotherapy.⁶⁰

Recurrent, Unresectable, or Metastatic Disease

In patients with recurrent, unresectable, or metastatic disease with no surgery or radiotherapy option, the preferred alternative regimen to cisplatin according to NCCN is pembrolizumab as first-line therapy (for tumors that express PD-L1 with a combined positivity score [CPS] ≥ 1; category 1 if CPS ≥ 20),⁴⁷ and according to SEOM the combination of paclitaxel plus cetuximab (ERBITAX) should be considered (IIB).⁴⁸

The efficacy of pembrolizumab was demonstrated in the KEYNOTE-048 trial, an open-label, phase III study in which patients were randomized to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil, or cetuximab plus a platinum and 5-fluorouracil.⁵ Pembrolizumab monotherapy improved OS versus cetuximab plus platinum and 5-fluorouracil in the combined positivity score (CPS) ≥ 20 (median 14.9 vs 10.7 months, p = 0.0007) and CPS ≥ 1 (12.3 vs 10.3 months, p = 0.0086) patient populations, and was non-inferior in the total population (11.6 vs 10.7 months).⁵

Supportive Measures to Improve the Treatment of Patients with SCCHN

In addition to the therapeutic alternatives described in the previous section, all patients with SCCHN also require a series of supportive measures (described below). Table 4 provides a summary of expert recommendations about supportive measures in these patients.

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

Socioeconomic Factors: Family Support, Cultural Factors, Educational Level

Socioeconomic factors and family support are critical factors in ensuring safety and adequate adherence to both high-dose cisplatin treatment and radiotherapy.⁶¹ Social considerations include the patient’s understanding and willingness to undergo the recommended treatment, family and social support during and after treatment, and health insurance coverage in the absence of public healthcare.⁸ Socially vulnerable and institutionalized patients present greater difficulties in treatment adherence.⁸ Even in developed countries, only about 50% of patients are able to return to work after 2 years and this is directly related to quality of life.⁶²

The healthcare systems of developing countries predominantly have marked heterogeneity and difficulties in patient access, and as such, a high proportion of patients are diagnosed in advanced stages of SCCHN. Protocols for organ preservation usually apply to patients with a T2–3 N1 staging, while patients from developing countries are usually diagnosed at T4 N1–2 stage.⁶¹ In most of the available studies, < 30% of patients have advanced stage SCCHN. In this population, other factors associated with treatment adherence must be taken into account, such as the distance they have to travel to receive medical care, the availability of radiotherapy centers and chemotherapy administration units, and the experience of the surgical group.⁶¹

According to a Canadian study, the incidence of SCCHN was found to be higher in lower-income patient populations. However, the gap in incidence between the highest and the lowest incomes was narrowed for oropharyngeal cancer.⁶³ Another study showed that the highest incidence of advanced stages occurred in low-income groups and in men living alone. The authors concluded that focus on the high risk of advanced stage SCCHN among vulnerable patients may be beneficial during referral and early diagnosis in order to improve outcomes in these patients.⁶⁴

Socioeconomic factors not only have an impact during treatment, but also after completion of therapy. It is important to evaluate the patient’s ability to return to work, identifying those patients who may require more intensive rehabilitation. Up to one-third of SCCHN patients in Brazil who are free of disease after 2 years of treatment cannot return to work. Advanced clinical stage, alcohol consumption, and low education level are independently associated with work disability.⁶⁵ Moreover, education status, perceived economic status, and social security status have a significant effect on the quality of life of SCCHN patients after radiotherapy.⁶⁶

Multidisciplinary Support: Advance Nursing, Nutrition, Geriatric Assessment

The care of patients with SCCHN is complex and requires the involvement of a wide range of services and experienced specialists for optimal treatment and follow-up, including specialized nursing care and clinical nutrition.⁴⁷ Although oncogeriatrics does not appear in many of the guidelines, we expect that these specialists will gradually be incorporated into the multidisciplinary team. Other specialists and services involved in the management of patients with SCCHN are psychiatry, dentistry, speech and swallowing therapy, physical medicine and rehabilitation, and clinical social work.⁴⁷

Advanced Nursing

Nursing staff are the backbone of managing patients with SCCHN, especially those receiving multimodal treatments, for which the participation of many specialists is necessary. In most cases, the success of treatment and coordination depends on nurses. Nurses are not only in charge of attending to patients, coordinating their treatment, and acting as a liaison between the patient and the multidisciplinary team, but also performs operational functions, referring patients, performing psychosocial evaluations, and providing health education once the multidisciplinary team has decided on a therapeutic strategy.⁶⁷ At the level of care, nursing staff also offer emotional support, collaborate with other health professionals, and attend to the post-surgical needs and treatment-related toxicities.⁶⁷

Nutrition

The nutritional approach is fundamental in any oncologic treatment, but especially in patients with SCCHN. Several studies have demonstrated that poor nutritional status and severe weight loss during chemoradiotherapy are associated with increased morbidity and mortality.^24,68–70 The difficulty in providing and maintaining adequate nutrition before and during treatment may result in the patient receiving suboptimal treatment or waiting too long before starting it, with the risk of becoming “unfit”.^24,61 However, despite intensive nutritional support from diagnosis to treatment for patients with advanced SCCHN, nutritional status deteriorates during multimodal treatment. Induction chemotherapy can improve nutritional status by reducing symptoms caused by the tumor itself that may limit oral intake. This improvement in nutritional status may help to minimize further deterioration during ongoing treatment.²⁷ Nutritional assessment should be done not only at the time of diagnosis before receiving any treatment, but also daily after surgery, and later after chemoradiotherapy.⁶⁷ In addition, nutritional assessment is advisable in patients who do not appear to be malnourished or have weight loss at diagnosis, as they may have loss of muscle mass and/or potential risk factors for malnutrition, either because of clinical dysphagia caused by the disease or because the volume and/or location of the radiotherapy may pose a special risk of weight loss and malnutrition during treatment, especially when combined with chemotherapy).^71,72

Oncogeriatry

A comprehensive geriatric assessment should be performed in all patients for whom treatment optimization is required due to their functional baseline status. This assessment includes the patient’s quality of life, psychosocial support, independence, physical, and nutritional status, and cognitive and performance status.¹³ Through the comprehensive geriatric evaluation, the cost-benefit of whether or not to propose a treatment strategy is evaluated, and therefore, treatment can be adapted to patient’s needs.

Psychiatry

Psychological distress is very common in SCCHN patients, with about 40% of patients experiencing depressive symptoms. Besides psychological distress, smoking and hazardous alcohol use are also common; even potential sexually transmitted diseases, like human papillomavirus-related SCCHN, are common.^73–75 The suicide risk among SCCHN survivors is the higher than among other cancer survivors, and thus suicide contributes as a competing cause of non-cancer-related death in survivors of SCCHN.^76,77 Although the prevalence of emotional distress is high in patients with SCCHN, the referral rate for specialized support is very low.⁷⁸ This led to the development of strategies for screening and referral of these patients, such as the anxiety and depressive symptoms questionnaires for adults with cancer developed by the American Society of Clinical Oncology (ASCO).⁷⁹ In a prospective controlled trial, patients with SCCHN were randomized to a stepped-care or a standard-of-care approach.^80,81 The stepped-care protocol consisted of watchful waiting, guided self-help, problem-solving therapy, and psychotherapy and/or psychotropic medication. This study showed that the stepped-care approach not only led to a better patient quality of life, but was also a cost-effective strategy.^80,81

Dentistry

Dentistry plays a very important role before (ie repair or removing compromised teeth), during (ie treatment of xerostomia and mucositis), and after treatment (ie looking for long-term toxicities during the follow-up phase).^67,82 In fact, the NCCN guidelines recommend that all patients with SCCHN be evaluated by a dentist before, during, and after treatment.⁴⁷ The establishment of a multidisciplinary team can improve patient access to dentistry services, and improved dental assessment leads to improvements in other endpoints.⁸³

Speech and Swallow Rehabilitation

Several guidelines recommend speech and swallow rehabilitation. All SCCHN patients should undergo pre-treatment assessment of speech and swallowing, a program of prophylactic exercises, and continuous follow-up by a speech/swallow therapist after treatment, especially after laryngectomy.⁶⁷ Developing a speech and swallow rehabilitation program improves patient satisfaction using a multidisciplinary approach.⁸⁴

All these specialties are deeply interconnected. For example, the alleviation of dry mouth by a dentist improves swallowing function and nutritional status.⁸⁵ Moreover, when patients are treated for depressive symptoms, their quality of life and swallowing function are improved.⁸⁶ Studies have shown that a multidisciplinary approach lead to an improvement in OS for these patients.^87,88 Another important part of the rehabilitation process is the patient’s return to society and/or work.

Conclusions

Patients with SCCHN are often affected by comorbidities that hamper appropriate management and must be evaluated on an individual basis. Although cisplatin is an essential component of treatment in these patients, due to its acute and late toxicity, the administration of this drug is not suitable for all of them.

There are predictive patient factors that may help to determine whether cisplatin should be administered or not, or whether it should be administered with careful monitoring. These factors include biological age (rather than chronological age), performance status, weight loss, comorbidities, chronic viral infections, pre-chemotherapy toxicity, and even COVID-19. The suitability of cisplatin must be discussed individually considering these predictive factors, even the combination of several of them.

The final decision must be based on a consensus by a multidisciplinary team in order to ensure that appropriate treatment and supportive measures are provided to these patients.