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The vicious circle of treatment-induced toxicities in locally advanced head and neck cancer and the impact on treatment intensity
Critical Reviews in Oncology/Hematology, Volume 116, August 2017, Pages 82–88
The intensity of the available treatment approaches for locally-advanced head and neck cancer (HNC) is at the upper limit of tolerance of acute toxicities. Several factors including breakthrough cancer pain, mucositis, dysphagia, local and systemic infections, and nutritional problems are related to treatment intensity. Particularly, pain, as symptom directly associated with the disease or combined with other treatment-related factors, has a major impact on quality of life of HNC patients and ultimately can influence the efficacy of treatments in HNC. Here, a Multidisciplinary Board of Italian Experts has addressed these issues, with the aim to identify the unmet need and appropriate strategies for the maintenance of optimal treatment intensity in HNC.
Keywords: Head and neck cancer, Breakthrough cancer pain, Mucositis, Dysphagia, Concurrent chemoradiotherapy, Treatment intensity, Quality of life.
Tumors arising from the head and neck are among the ten most common neoplasms worldwide (Siegel et al., 2017), and their incidence is increasing, with over 550,000 newly diagnosed cases each year (Ferlay et al., 2013). Nowadays the intensity of the current treatment approaches for locally advanced head and neck cancer (HNC) is at the upper limit of tolerance of acute toxicities. Conventional management strategies including definitive radiation with concurrent chemotherapy (CCRT) or biological therapy (cetuximab), surgery and adjuvant (chemo)radiation, or radiation given with altered fractionation schemes, are indeed associated with acute and long-term morbidity and impairment of patients’ quality of life (QoL) (Kelly et al., 2016). Considering the raising intensity of therapy, the costs of treatments for localized HNC far exceed those for other aspects of care (Wissinger et al., 2014). Moreover, these highly toxic contemporary treatments have significantly improved the locoregional control in advanced head and neck cancer, but the effects on patients mortality have been modest, without a substantial extension of the overall survival (Corry et al., 2010). Evidence from recent trials have suggested that de-escalation of treatment regimens as well as tailored treatment strategies for selected, specific subgroup of HNC patients may achieve similar or even superior efficacy with less toxicity (Kelly et al, 2016 and Corry et al, 2010).
However, the importance of maintaining treatment intensity remains a key factor for the success of the therapies in most combined approaches. Numerous negative factors contribute to the reduction of treatment intensity in HNC patients, including background and breakthrough cancer pain (BTcP), mucositis, dysphagia, local and systemic infections, and nutritional problems. All these factors, either alone or in different combination patterns, have also a major impact on QoL of HNC patients. At present, only modest attention has been paid, in clinical practice, to the correlation between those events and treatment intensity. To address this unmet need, a Multidisciplinary Board of Italian Experts (medical oncologists, surgeons, pain therapists, radiotherapy specialists) in the management of HNC has assembled with the aim to review relevant literature and identify strategies for the maintenance of optimal treatment intensity in HNC patients. Here we present the outcome of this Expert discussion.
The Expert Panel discussed the topics during two meetings, during which clinical experiences and literature were shared and reviewed. No formal techniques for the achievement of consensus were applied, but the discussion among Participants was handled by a professional facilitator.
During the first meeting, a series of keywords was identified: HNC; treatment intensity; treatment dose; pain; mucositis; infection; dysphagia; nutrition; education. Using these keywords, a systematic query-based MEDLINE search was carried out by a professional methodologist and editor in order to provide solid evidence on the topics of the review. No research limits were applied, but a focus was given on reviews and well-conducted studies published in the last 5 years. This search resulted in 126 papers; the Participants were offered the opportunity to revise the entire lists of papers and add others from their personal collection of literature. Papers were then selected for inclusion according to their relevance for the topic, on the base of Participants’ and editor’s judgment. A first draft of the paper was then prepared by the Participants, according to their clinical and research interests, and the editor; all Participants critically revised the manuscript over consecutive turnaround of revisions until a consensus on the final version was reached.
3. Treatment intensity: basic concepts
Treatment intensity in oncology field is considered as a defined dose of radiation and/or systemic therapy over a pre-specified time, aimed at controlling tumor growth with curative intent. This goal should be pursued by keeping in mind the QoL of patients, with a focus on pain, treatment-related toxicities, comorbidities, self-sufficiency, ability to complete daily activities and nutritional issues as well as patient’s feeling and emotions concerning the disease and therapy. Importantly, most studies available to date do not distinguish between causes of dose reduction and those of treatment interruption and often specifications of adverse events leading to reduction in dose intensity are not fully reported; these issues largely limit available evidence on the topic. Moreover, in field-practice experience dose reduction is applied differently than in clinical trials, a setting in which defined rules for dose reductions are applied.
In patients with locally advanced HCN, the non-surgical standard of care is radiotherapy to a dose of 70 Gy with concurrent chemotherapy, as determined by a meta-analysis on 93 randomized trials over 17,000 patients (Pignon et al., 2009). Large portions of the pharynx and neck soft tissues receive high doses of radiation in patients undergoing standard management for HNC and the toxic effects are enhanced by radiosensitising chemotherapy. Therefore, numerous studies have explored the feasibility of reducing radiotherapy intensity or new technical delivery of radiotherapy; for instance, Chera et al. (Chera et al., 2015) investigated 60 Gy radiotherapy with concurrent low dose of chemotherapy in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma obtaining a high complete response and low toxicity. On the other hand, variations in radiotherapy protocols applied in several clinical trials suggest that total radiation dose and duration of treatment are both correlated with tumor control and survival. In particular, clinical evidence that interruptions adversely influence tumor control primarily comes from studies with planned treatment interruptions, also known as split-course therapy. Fesinmeyer and collegues (Fesinmeyer et al., 2010) described a statistically significant 68% increased risk of death associated with radiotherapy interruptions. This likely reflects a loss of tumor control caused by extended periods with no radiation delivered to the tumor. In addition, the tumor control rate has been estimated to decrease of at least 1% for each day of radiation treatment discontinuation (Russo et al., 2008).
Most of the randomized trials in HNC used cisplatin as chemotherapeutic agent at the dosage of 100 mg/m2, three times throughout the course of radiotherapy (cumulative dose of 300 mg/m2). Interestingly, lower doses of cisplatin (6 mg/m2 daily and 20 mg/m2 on day 1 and 5 of a 21-day cycle) administrated in combination with radiotherapy showed promising results in advanced HNC patients (Jeremic et al, 2000 and Huguenin et al, 2004); similarly, some groups advocate the use weekly cisplatin as a strategy to increase dose intensity and/or reducing the frequency and severity of adverse events (Ho et al., 2008). However, so far no trial showed the superiority of one regimen over the other and accumulating evidence seem to point to the importance of reaching doses of concomitant cisplatin higher than 200 mg/sm, at least for HPV negative diseases (Spreafico et al., 2016).
One alternative strategy for reducing chemotherapy-related toxicity is the replacement of cisplatin with cetuximab, a monoclonal antibody targeting the EGFR extracellular ligand binding domain, which was shown to improve survival over radiotherapy alone (Bonner et al., 2006). Several trials comparing these 2 strategies are ongoing (NCT01302834–NCT 01874171–NCT 01855451 clinicaltrials.gov). Often, treatment-induced toxicities lead to interruptions and discontinuations of the therapies, which can have a negative impact on subsequent management of HNC patients.
Overall, whenever possible, strategies aimed at preventing, rather than managing, toxicities, should be instituted. On the other hand, a prompt management of all symptoms which may impair treatment intensity is paramount. The management of HNC patients should base on: i) identification of the patients at risk; ii) the prevention of symptoms, whenever possible; iii) individualized treatment; in addition, it requires expertise from different areas of competence that need to be integrated in the treatment process. In this light, an approach based on a multidisciplinary team (MDT) in a tertiary referral Center could add value in the management of HNC patients (Bergamini et al, 2016 and Bossi and Alfieri, 2016). A MDT approach indeed allows reaching a prompt treatment after diagnosis, high adherence to clinical guidelines and an appropriate management of treatment-related toxicities, all potentially translating into better survival outcomes (Bossi and Alfieri, 2016).
In the next sections, the specific symptoms and their management will be reviewed and discussed.
The aggressive, erosive nature of HNC and the rich sensory innervation of this area make this malignant disease one of the most painful tumor worldwide (Caraceni and Portenoy, 1999). A population-based study conducted to obtain reliable information about the pain suffered by cancer patients revealed that in HNC the prevalence of pain was around 70% (van den Beuken-van Everdingen et al., 2007). In terminal HNC patients, the prevalence of severe pain increased to 78% (Talmi et al., 1997). A number of clinical conditions such as mucositis and infections are associated with pain development in HNC patients. In particular, CCRT-induced mucositis pain is experienced by more than 80% of HCN patients, interfering with their daily activities, social activities and mood; consequently CCRT-induced mucositis pain severely affect the patient’s overall QoL (Mirabile et al., 2016). The central role of pain in the symptoms perceived by the patients during CCRT is showed in Fig. 1.
The central role of pain in the symptoms perceived by patients with locally advanced head and neck cancer during chemo-radiotherapy.
Pain in CCRT-induced mucositis generally starts at week 3, with a peak at week 5 and persists for 2–4 weeks after the end of radiotherapy, with a gradual remission of signs and symptoms (Wong et al., 2006). Patients may experience long term spontaneous or evoked mucosal pain due to epithelial atrophy, neurologic sensitization and/or neuropathy. Mucosal sensitivity is associated with several risk factors, including aggressive chemoradiation regimens, xerostomia, and active cigarette smoking. Pain may also be evoked by hot or spicy food/liquids, acidic food/liquids and dry air (Konopka-Filippow et al., 2015).
Of note, recent estimates suggest a prevalence of 25–50% of BTcP, defined as a transitory exacerbation of pain that occurs against a background of stable pain otherwise adequately controlled by around-the-clock opioid therapy, in HNC patients treated with CCRT (Mirabile et al, 2016 and Konopka-Filippow et al, 2015). Beside tumor-related pain, is not unusual for patients with HNC to suffer also from treatment-related pain; both pain conditions are difficult to alleviate despite individualized pain management (Schaller et al., 2015).
Overall, as the prognosis of these tumors remains poor, a large number of these patients should be considered at risk of disease progression, and, consequently, at risk of pain progression. In addition, the increasing incidence of pain associated with radiotherapy or CCRT highlights the importance of pain monitoring and management during cancer therapy. In patients with progression of disease, it would be appropriate to use strong opioids also in mild to moderate pain (Marinangeli et al., 2004) and skip the first and second step of the WHO ladder, to obtain the best QoL and to prevent the peripheral and central sensitization. Disappointingly, about 10% of HNC patients with pain did not receive any analgesic therapy (Mirabile et al., 2016). From a recent interview to eight HNC patients undergoing radiotherapy emerged the need for pain relieving interventions delivered by pain specialists, in tandem with the development of robust self-management strategies (Pattison et al., 2016).
Detailed recommendations on the management of pain in HNC are provided in the recently published consensus paper by Mirabile et al. (Mirabile et al., 2016).
Several studies have shown that appropriate treatment of HCN pain allows the completion of planned radiotherapy regimens and the maintenance of a proper treatment intensity (Mazzola et al, 2016 and Bossi et al, 2014). Although, treatment of HCN pain may benefit from topical anesthetics, the use of an opioid-based, systemic, pain-control program is almost always necessary for pain relief. However, systemic administration of opioids may be complicated by well-known side effects, namely nausea, vomiting, mental clouding, constipation, sedation and tolerance; therefore, effective measures to prevent and treat opioid-induced side effects are critical in order to optimize patient compliance with pain regimens. In particular, the management of acute, uncontrolled BTcP often requires the administration of short-acting opioids, such as morphine, hydromorphone, or fentanyl.
Noteworthy, the European Association for Palliative Care has issued recommendations for the use of opioids for BTcP: “episodes of breakthrough pain should be treated with immediate release oral opioids or with buccal or intranasal fentanyl preparations; these fentanyl preparations in some cases are preferable because of more rapid onset of action and shorter duration of effect” (Table 1) (Caraceni et al., 2012). Therefore, transmucosal immediate-release fentanyl formulations represent alternative options to traditional palliative care for the management of BTcP in HNC and/or radiation-induced mucositis. (Chang et al., 2015).
Characteristics of common drugs used for the management of breakthrough pain.
|Onset of analgesic effect (minutes)||Time of availability (minutes)||Dwell time (minutes)|
|Oral transmucosal fentanyl citrate||15–30||50||15|
|Fentanyl buccal tablet||15||65||15|
|Fentanyl buccal soluble film||15||65||2–5|
|Intranasal fentanyl spray||5–10||80–90||NA|
|Fentanyl pectin nasal spray||5–10||70||NA|
|Fentanyl citrate sublingual||6||∼70||NA|
NA: not available.
Unfortunately, the use of transmucosal fentanyl in patients with a morphine dose less than 60 mg per day for the BTcP is considered off label in many countries. These regulatory barriers should be torn down because they do not respond to the real needs of patients. Fentanyl cytrate, considering its pharmacokinetic and pharmacodynamic characteristics, should also be considered useful in procedural pain. Going to the hospital for radiotherapy as well as maintaining the position during treatment result painful for many HNC patients. Prophylactic administration of fentanyl citrate could allow patients to overcome these problems. In this light, the procedural pain management has to be considered strategic to encourage adherence to radiotherapy, and effective pain management is a key component of the post-radiotherapy recovery process.
5. Infections, systemic inflammatory response syndrome and sepsis
Overall, patients with HNC are often frail, with several access sites, and therefore particularly prone to infections. Moreover, HNC patients are at high risk of Systemic Inflammatory Response Syndrome (SIRS), a systemic activation of the host immune response system which normally acts as an immunosuppressive milieu (Cavaillon, 2002), against the initiation of a deleterious process.
In clinical practice, local infections (e.g., mucosal candidiasis, abscesses) generally are related to increase of pain and consequently causes a reduction of the patient compliance to radio-chemotherapy.
Although infections have been identified as one of the main causes of acute mortality in HNC (Argiris et al., 2004), these events are rarely reported, even in randomized trials; consequently, the incidence of infections in HNC is likely underestimated. In CCRT trials the reported rate of infection was around 19%, the acute mortality was between 2% and 9.3%, with the majority of deaths occurring within 30 days from the end of infection-related treatments (Mirabile et al., 2015).
The onset of SIRS and the overlapping systemic infections represent a major impediment to the maintenance of proper treatment intensity. Therefore, at the initiation of CCRT treatment, a prompt and early identification of any predisposing factors is essential; these predisposing factors include active smoking, alcohol consumption, worse condition of the oral cavity with low hygiene, gingival pocket and caries as well as age, social status, comorbidities and the presence of medical devices which can favor subsequently infections. Weekly clinical evaluation of patients, recording of vital parameters and biochemical exams such as protein C reaction (PCR) might be helpful to intercept early signs of SIRS and to look for possible site of early infections. In addition, a comprehensive evaluation with an early and clear explanation of the possible trigger role of these conditions to patients and their families or care givers might be useful. The early identification of sepsis as well as implementation of prompt therapies have been documented to improve outcomes and decrease sepsis-related mortality (Levy et al, 2010 and Jones et al, 2010). A recent consensus paper draft by a multidisciplinary group of HNC specialists stated that during CCRT, HCN febrile patients should be treated with empirical antibiotic therapy including both anti-Gram + and anti-Gram − antibiotics, starting within 3 h from clinical presentation (Mirabile et al., 2015). In addition, the empirical antibiotic therapy has to be based on local surveillance, antibiotic sensitivity and infection rate/prevalence; otherwise a rational use of antibiotics in accordance with international guidelines is advisable (Mirabile et al., 2015). In particular, given the very high rate of infection sustained by multi- and pan- resistant microorganisms, when local guidelines are not available, treatment with broad spectrum, potent antibiotics active against enterobacteriaceae and methicillin-resistant Staphylococcus aureus should represent the preferred option (Mirabile et al., 2015). An adequate sepsis management including careful and prompt diagnosis of infections and appropriate treatments, requires the involvement of a MDT. Moreover, HNC patients undergoing CCRT should be hospitalized when diagnostic criteria for sepsis are associated with a suspected infection (Mirabile et al., 2015). With this approach, specific antineoplastic treatments can be continued safely by limiting interruption as much as possible.
Several are the unmet need in this topic and only few are addressed in current literature: the standardization of clinical definitions, diagnosis, management and treatment of this multifactorial condition; the need to spread the awareness that the process from SIRS to sepsis is closely related to other side effects described in this paper, such as mucositis, dysphagia and weight loss; adequate training of clinician on an early education of patients and care givers in preventing SIRS and infections; the availability of shared guidelines in communication and prevention of these condition before, during and after CCRT treatment. Each of them, if not properly supervised and managed, lead to and overlap others complications increasing the complexity and reducing the overall survival benefit.
Due to the lack of randomized clinical trials, recommendations/suggestion based on consensus among MDT could be useful to improve knowledge on this topic and standardize behavior.
6. Mucositis and dysphagia
More than 90% of HNC patients undergoing CCRT develop any-grade mucositis and dysphagia, often impairing food intake and increasing the risk of other complications such as pain and infections (De Sanctis et al., 2016). Noteworthy, while other side effects of anticancer treatments, such as emesis, anemia, and neutropenia, are relatively well-controlled with validated supportive care, the therapeutic armamentarium towards mucositis is still scarce. Nowadays, the suggested preventive strategies rely on basic oral care and the use of benzydamine, while available treatments for mucositis in HNC are limited to adequate analgesic approaches (Lalla et al., 2014). Moreover, in recent years, other therapeutic strategies are developing, such as low level laser therapy, but more grounded evidence is necessary to investigate these potential treatments or preventive measures (Lalla et al., 2014). Interestingly, it has been shown that an adequate management of mucositis does result in improved maintenance of proper treatment intensity and reduction in HNC therapy breaks (Milazzo-Kiedaisch et al, 2016 and Rosenthal, 2007). In this regard, mucositis represents an important dose-limiting factor for HNC treatment. Therefore, in order to provide an uniform approach to mucositis prevention and treatment, Multinational Association of Supportive Care in Cancer released evidence-based guidelines, built with a formal and solid methodology (Lalla et al., 2014). A consensus paper on the management of mucositis specifically directed to HNC patients has been recently draft by De Sanctis et al. (De Sanctis et al., 2016).
In addition, the risk to develop severe mucositis is also associated to some clinical and therapeutic variables; therefore, pre-treatment identification of these factors may help physicians in anticipating the need for nutritional and analgesic support (De Sanctis et al., 2016). These patient-related risk factors include older age, immunosuppression, poor oral hygiene, alcohol abuse, tobacco smoking, comorbidities such as diabetes mellitus, and xerostomia (De Sanctis et al., 2016). In this light, in order to integrate oral, dental and medical care in HCN management, an experienced dentist should be included in the MDT.
The management of dysphagia also requires a MDT approach to adequately approach the symptoms and institute preventative exercises (Schindler et al., 2015).
Dysphagia defined as the difficulty in swallowing liquids, food, or medication, occurring during the oropharyngeal or the esophageal phase of swallowing, has been often reported in HCN patients undergoing intensive, non-surgical regimens (Cavaillon, 2002).
The maintenance of the swallowing ability during CCRT reduces the use of artificial enteral nutrition, a faster recovery of adequate oral intake and fewer episodes of aspiration (Roe and Ashforth, 2011). Pain due to swallowing (odynophagia) is one of the main causes of dysphagia. From the third week after radiotherapy starting to the one month follow-up, patients report significantly higher pain intensity scores with swallowing compared to those without swallowing (Wong et al., 2006).
So, the ability to control pain is essential to reduce the burden of dysphagia. The analgesic strategies vary from local treatments to the administration of systemic drugs with different mechanisms of action such as opiates, anti-inflammatory drugs and anticonvulsants employed to manage neuropathic pain (Ling and Larsson, 2011 and Bar Ad et al, 2010).
However, the real impact of dysphagia on HNC remains substantially misunderstood and underdiagnosed, consequently nowadays dysphagia results also improperly treated. Although, prompt diagnosis and adequate treatment of dysphagia are fundamental to correctly manage oncological patients, regretfully they still represent un unmet needs, considering also the limited evidence available to guide clinicians.
Correct nutrition is a major issue for HNC patients, since a number of cancer − and treatment-associated events are likely to impair food intake (Kang et al., 2016). On the other hand, malnourished HCN patients undergoing CCRT are, in turn, more susceptible to infections and mucositis. Overall, HNC patients with poor nutritional status are at higher risk of treatment interruptions.
Malnutrition resulting from lack of nutrient intake or damages to nutritional metabolism is characterized by some predominant symptoms such as progressive emaciation, weight loss or edema. In particular, severe hypoalbuminemia can cause multiple organ damage. The malnutrition prevalence rate on HNC patients depends on tumor location, type and disease stages and is around 75%. An adequate assessment of the nutritional status of HNC patients to evaluate the impact of malnutrition on therapeutic management and quality of life should be performed at the presentation of patients (Platek, 2012 and Prevost et al, 2014). In addition, nutritional counseling should be provided to HNC patients, to increase dietary intake and to prevent therapy-associated weight loss and interruption of radiotherapy (Bossola, 2015). Malnutrition could also be due to obstructing cancer and/or mucositis that interfere with swallowing; in these cases, nutrients are delivered by a feeding tube. However, the lack of strong evidence makes determination of the optimal enteral feeding method difficult. Prophylactic feeding through nasogastric tube (NGT) or percutaneous gastrostomy (PEG) to prevent weight loss, reduce dehydration and hospitalizations and avoid treatment breaks, have become relatively common. Compared to reactive feeding (patients are supported with oral nutritional supplements and, when the nutritional requirements become impossible to maintain, enteral feeding via a NGT or PEG is started), prophylactic feeding does not offer advantages in terms of nutritional outcomes, interruptions of radiotherapy and survival. A recent systematic review of 12 studies showed the beneficial effects of individualized dietary counseling on nutritional status and QoL, compared to no counseling or standard nutritional advice. However, the effects of oral nutritional supplements and feeding tube were inconsistent (Langius et al., 2013). In another recent randomized study including HCN patients treated with radiotherapy, the number of malnourished subjects at the end of treatment was lower among HCN patients who received concomitant intensive dietary counseling and nutritional therapy, compared to those who underwent standard dietary regimen (Kang et al., 2016).
Overall, further adequate prospective randomized studies are needed to correlate malnutrition with cancer- or treatment-related toxicities such as pain, and to define the better nutritional intervention in HNC patients undergoing CCRT.
In HNC, pain occurring before, during and after oncological treatments represents the major issue affecting several aspects of patients’ daily activities and negatively impacting on their quality of life. Several concurrent factors contribute to pain in HNC; they could be directly associated with the disease or represent treatment-related factors. In particular, the treatment-related toxicities here described, such as mucositis can dramatically exacerbate the oncological pain. Therefore, a prompt diagnosis and adequate management of these treatment-related toxicities could help to prevent or alleviate pain in HNC.
Educational activities may play a crucial role to promote the correct management of symptoms and potentially to increase treatment intensity. Those activities may be addressed either to the treating physicians or to patients (e.g. in cooperation with patients’ associations). In the HNC setting, it has been shown that educational programs and training are effective in increasing physicians' knowledge and positive attitudes towards prevention and treatment strategies (Odone et al, 2015 and Fung, 2015), while multi-modal information to patients on risk of therapies, importance of adherence and management of adverse events may result in improved outcomes (Platek, 2012, D'Souza et al, 2013, Wood, 2012, and González-Arriagada et al, 2013). In particular, Gonzales et al. (González-Arriagada et al., 2013), assessed the effect of an educational video on the improved understanding of treatment complications in HCN patients undergoing radiotherapy. In this controlled clinical study, a 6-min video about the side effects associated with radiotherapy was produced by a multidisciplinary oncology team. HCN patients that watched the video and received verbal information demonstrated better knowledge about radiotherapy complications than patients receiving only verbal information (González-Arriagada et al., 2013). Considering the variety of symptoms associated with these toxicities, a multidisciplinary approach with several types of expertise is needed to correctly identify the issue and provide the proper management.
In particular, with specific reference to the management of pain, pain specialists should draft and disseminate local guidelines, based on relevant valid evidence. Particularly, acute pain management is suitable for practice guidelines, while chronic pain is a more difficult area for such guidelines, due to frequent unclear diagnosis and, mostly, wide variability in outcome between patients. These guidelines should be valid, reliable, applicable, flexible and, most of all, clear and easy to use (Jacox et al., 1994). Pain management teams have to carry on programs of dissemination of the guidelines, bringing to health professionals (doctors, nurses) and patients, initial information (regular repetitions recommended to high turnover groups); moreover, specific educational interventions (e.g. study days and nursing competencies, based on leaflets and wall posters) could be really effective. Last, guidelines shall be available for ongoing references with interventions such as hospital handbooks and publication in the hospital intranet.
The management of the several unmet needs in HNC patients undergoing CCRT here identify could ultimately contribute to maintain the optimal treatment intensity, increase adherence to therapy and, consequently improve clinical outcome.
Conflicts of interest statement
The Authors have no conflicts of interest directly relevant to this manuscript.
We thank Sara Parodi, PhD, and Luca Giacomelli, PhD, who provided medical writing services, supported by CDPharma.
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a Department of Head and Neck Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
b Genitourinary Unit, Division of Medical Oncology, European Institute of Oncology, Milan, Italy
c Department of Radio-Oncology, IRCCS AOU San Martino, IST, National Institute for Cancer Research, Genoa, Italy
d Oncology Unit, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy
e Director of Division of Palliative Care and Pain Therapy, European Institute of Oncology, Milan, Italy
f Departement of Anesthesia & Intensive care, University of L' Aquila, L'Aquila, Italy
g Institute of Radiotherapy, Università Cattolica del Sacro Cuore, Rome, Italy
h Radiation Oncology Centre, “S. Maria” Hospital, Terni, Italy
⁎ Corresponding author.
© 2017 Elsevier B.V., All rights reserved.