A systematic review of patient-reported outcome instruments of dermatologic adverse events associated with targeted cancer therapies.

PURPOSE: Dermatologic adverse events (dAEs) in cancer treatment are frequent with the use of targeted therapies. These dAEs have been shown to have significant impact on health-related quality of life (HRQoL). While standardized assessment tools have been developed for physicians to assess severity of dAEs, there is a discord between objective and subjective measures. The identification of patient-reported outcome (PRO) instruments useful in the context of targeted cancer therapies is therefore important in both the clinical and research settings for the overall evaluation of dAEs and their impact on HRQoL. METHODS: A comprehensive, systematic literature search of published articles was conducted by two independent reviewers in order to identify PRO instruments previously utilized in patient populations with dAEs from targeted cancer therapies. The identified PRO instruments were studied to determine which HRQoL issues relevant to dAEs were addressed, as well as the process of development and validation of these instruments. RESULTS: Thirteen articles identifying six PRO instruments met the inclusion criteria. Four instruments were general dermatology (Skindex-16©, Skindex-29©, Dermatology Life Quality Index (DLQI), and DIELH-24) and two were symptom-specific (functional assessment of cancer therapy-epidermal growth factor receptor inhibitor-18 (FACT-EGFRI-18) and hand-foot syndrome 14 (HFS-14)). CONCLUSIONS: While there are several PRO instruments that have been tested in the context of targeted cancer therapy, additional work is needed to develop new instruments and to further validate the instruments identified in this study in patients receiving targeted therapies.

Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses in patients with head and neck cancer receiving chemoradiation.

Treatment-related toxicities are common among patients with head and neck cancer, leading to poor clinical outcomes, reduced quality of life, and increased use of healthcare resources. Over the last decade, much has been learned about the pathogenesis of cancer regimen-related toxicities. Historically, toxicities were separated into those associated with tissue injury and those with behavioural or systemic changes. However, it is now clear that tissue-specific damage such as mucositis, dermatitis, or fibrosis is no longer the sole consequence of direct clonogenic cell death, and a relationship between toxicities that results in their presentation as symptom clusters has been documented and attributed to a common underlying pathobiology. In addition, the finding that patients commonly develop toxicities representing tissue injury outside radiation fields and side effects such as fatigue or cognitive dysfunction suggests the generation of systemic as well as local mediators. As a consequence, it might be appropriate to consider toxicity syndromes, rather than the traditional approach, in which each side effect was considered as an autonomous entity. In this paper, we propose a biologically based explanation which forms the basis for the diverse constellation of toxicities seen in response to current regimens used to treat cancers of the head and neck.

Strategies for non-resectable head and neck cancer.

OPINION STATEMENT: Treatment of unresectable, locally advanced head and neck cancer consists of many different options, all of them based on radiotherapy. The main variable is represented by chemotherapy, i.e., the way in which chemotherapy is combined with radiation. More recently, the combination of cetuximab and radiotherapy emerged as a new treatment opportunity and induction chemotherapy, with the combination of docetaxel, cisplatin, and 5-fluoruracil, gained a renewed interest. Concurrent chemoradiation is based on the most robust evidence and is regarded as the leading standard of care for unresectable locally advanced head and neck cancer. Unfortunately, chemoradiation is hampered by severe toxicity and patients must be selected carefully before treatment. The experience of the staff (medical oncologists, radiation oncologists, and nurses), and in particular its familiarity with toxicity management, as well the structural facilities, play an important role in the final outcome. When the patient is unfit for chemoradiation, or when experienced staff or adequate structures are unavailable, induction chemotherapy, cetuximab and radiotherapy, or radiotherapy alone are all evidence-based alternative options. The choice among them will be based on the clinical condition of the patient, the physician's experience, and the patient's preference. Whatever is the treatment of choice, it is important to involve a multidisciplinary staff in the management of these patients. Indeed, also unresectable patients may require supportive surgical interventions before or during treatment, or removal of residual disease after treatment.

The effects on pain and activity of daily living caused by crusted exudation in patients with head and neck cancer treated with cetuximab and radiotherapy.

PURPOSE: To date, the specific role of "in-field" crusting exudation on pain and on activity of daily living (ADL) in head and neck cancer (HNSCC) patients undergoing treatment with cetuximab and radiochemotherapy has been neglected. The purpose of the study was to evaluate the role of crusting exudation on the severity of pain and ADL METHODS: Thirty-seven of the 45 HNSCC patients enrolled in the alternating radiotherapy, chemotherapy, and cetuximab trial were evaluated in this study. The main radiodermatitis signs (the intensity of erythema, the extension of dry, and moist desquamation and of necrosis)--including crusting exudation severity--pain, ADL, and radiodermatitis scores were registered at least weekly during and after treatment. The correlation between crusting exudation and pain or ADL was evaluated. RESULTS: The "in-field" crusting exudation score seemed to have the strongest correlation with pain (Spearman's rho = 0.897; p < 0.001) and the most intense influence on it (Co-B = 0.715; 95% C.I. = 0.643-0.787). However, it seemed to have a weaker correlation with ADL than the other clinical radiodermatitis signs. CONCLUSIONS: Crusts have the strongest correlation with pain in patients with Cetuximab-related radiation dermatitis. Moreover, the presence of crusts can lead operators to misclassify dermatitis as score 4, causing unnecessary delays or interruptions in treatment.

Postoperative therapy in head and neck cancer: state of the art, risk subset, prognosis and unsolved questions.

Head and neck cancer may be easily controlled at early stages, but resectable locally advanced disease often relapses at T and N sites. Therefore, adequate adjuvant treatment is of crucial importance for improving local control and/or survival. Unfortunately, little data are available on the adjuvant setting. Adjuvant radiotherapy is regarded as a standard approach for patients with locally advanced radically resected head and neck cancer, while postoperative chemotherapy alone cannot be considered outside of clinical trials. However, chemoradiotherapy is widely considered superior to radiotherapy in patients at a high risk of relapse and may be considered the standard treatment in this population. In this respect, in the last few decades, there has been a growing interest due to the emerging data on both tumor biology and clinical trials. Several pathological and molecular factors, affecting behavior and head and neck cancer prognosis, could allow for a better selection of postoperative treatment. More recently, new prognostic and predictive factors were identified, including biomolecular aspects, human papillomavirus infection and lifestyle. The integration of these new factors deserves dedicated clinical studies, but the available knowledge already allows some deductive hypotheses. We performed a review of the literature to analyze the role of therapy in the postoperative setting and to discuss both the possibility of a different approach to each class of risk and the unsolved question for which randomized trials are warranted.

Survival prediction and frequency of anticancer treatment in cancer patients hospitalized due to acute conditions. Role of clinical parameters and PaP score.

PURPOSE: Survival prediction is useful in selecting patients for palliative care or active anticancer therapy. The palliative and prognostic (PaP) score was shown to predict 1-month survival in terminally ill patients. Its application to patients with less advanced disease is a subject of debate. We assessed the value of the PaP score and of other clinical parameters in predicting survival in patients admitted in an oncological ward due to acute conditions. We also evaluated the frequency of active anticancer treatment in the last weeks of life. METHODS: All the 208 patients, consecutively admitted in a department of medical oncology and radiotherapy in a 9-month period, were included. Patients and disease features together with the PaP score were assessed and included in a multivariable model for survival prediction. RESULTS: Overall, median survival was 19 weeks and 12-week survival was 59.6%. The PaP score accurately predicted 4-week survival. Among the 39 patients who died within 4 weeks, 36% were on active treatment. The reason of admission, disease control, treatment, and PaP score were independently related to 12-week survival in the multivariate analysis; however patients with a 12-week survival lower than 30% were a minority. CONCLUSIONS: Although the PaP score accurately predicts life expectancy, its use in the setting of acute conditions seems not straightforward, due to the overall good prognosis of these patients. Active treatment in the last period of life is common. The potential reversibility of acute conditions makes prognostic measures inadequate for the purpose of treatment choices.

Predictive value of Prostate Specific Antigen variations in the last week of salvage radiotherapy for biochemical recurrence of prostate cancer after surgery: A practical approach.

BACKGROUND: About a third of patients who underwent radical prostatectomy for prostate cancer (Pca) develop a biochemical failure (BF) within 10 years from surgery, and about a half of them receive salvage radiation therapy (SRT). Factors to predict risk to relapse after SRT are still lacking. Dynamic models, based on the assessment of changes in Prostate Specific Antigen (PSA) postsurgery seem to show good reliability. AIMS: The goal of the study was to identify a simple analytical method for the postsalvage radiation therapy biochemical failure (post-SRTBF) prediction before the end of the SRT, regardless of the PSA value at the beginning of the treatment (PSA start), measuring the PSA values at the start and 1 week before the end of SRT. METHODS: In a series of 83 patients treated with SRT for BF of Pca we measured PSA values at the first day and 1 week before the end of SRT. These values were used to define an analytical method for the post-SRTBF prediction. RESULTS: PSA value in patients without post-SRTBF show a significant difference in term of difference during the SRT with respect to patients with post-SRTBF. Starting from this difference, we identified a simple and practical analytical method for the post-SRTBF prediction before the end of the SRT. The data corresponds with the model and the analytical method is highly predictive (Sensitivity = 81%, Specificity = 85%, Accuracy = 83%). CONCLUSION: This study offers a new tool to early predict Pca relapse overtime and to select patients who can benefit from an early additional systemic treatment.

Lactobacillus brevis CD2 for Prevention of Oral Mucositis in Patients With Head and Neck Tumors: A Multicentric Randomized Study.

BACKGROUND: Oropharyngeal mucositis occurs in virtually all patients with head and neck cancer receiving radiochemotherapy. The manipulation of the oral cavity microbiota represents an intriguing and challenging target. PATIENTS AND METHODS: A total of 75 patients were enrolled to receive Lactobacillus brevis CD2 lozenges or oral care regimen with sodium bicarbonate mouthwashes. The primary endpoint was the incidence of grade 3 or 4 oropharyngeal mucositis during radiotherapy treatment. RESULTS: There was no statistical difference in the incidence of grade 3-4 oropharyngeal mucositis between the intervention and control groups (40.6% vs. 41.6% respectively, p=0.974). The incidence of pain, dysphagia, body weight loss and quality of life were not different between the experimental and standard arm. CONCLUSION: Our study was not able to demonstrate the efficacy of L. brevis CD2 lozenges in preventing radiation-induced mucositis in patients with head and neck cancer. Although modulating homeostasis of the salivary microbiota in the oral cavity seems attractive, it clearly needs further study.

Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial): Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide.

INTRODUCTION AND BACKGROUND: Second-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in overall survival and quality of life of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited.This study aims to test the hypothesis that attacking the tumor microenvironment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors. METHODS/DESIGN: In this open label, multi-center, single-arm, Phase Ib/II, R/M-HNC patients pretreated with at least one line of therapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8. DISCUSSION: The treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell reactivation owing to the inhibition of the PD-1-PD-L1 axis by avelumab.The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile.Finally, an ancillary translational study will be extended to all the patients' population. TRIAL REGISTRATION: EudraCT n. 2017-000353-39.

Gemcitabine and cisplatin in a concomitant alternating chemoradiotherapy program for locally advanced head-and-neck cancer: a pharmacology-guided schedule.

PURPOSE: Administration of gemcitabine together with cisplatin at cytotoxic doses in a chemoradiotherapy regimen is hampered by a high degree of local toxicity. Using the pharmacologic properties of the drug we designed a modified schedule aimed at reducing toxicity while preserving activity. METHODS AND MATERIALS: Patients with squamous cell carcinomas of the oral cavity, pharynx and larynx, bulky T4, and/or N2 to N3 were eligible. Gemcitabine was administered at a dose of 800 mg/m2 on Days 1 and 12 and cisplatin at a dose of 20 mg/m2 on Days 2 to 5, every 21 days for 3 courses. Radiotherapy, delivered with standard fractionation, was given on Days 8 to 12 and 15 to 19 and was repeated 3 times up to a total dose of > or = 60 Gy. RESULTS: A total of 28 patients were selected. Grade 3 to 4 stomatitis was recorded in 25 patients (89%). Thirteen patients (46%) experienced Grade 3 to 4 neutropenia. Febrile neutropenia occurred in 8 patients (29%) and in 2 was complicated by infection and death. The overall complete response rate was 79%. At a median follow up of 71 months, 11 patients had a locoregional relapse (3-year locoregional control, 64%); 6 patients had distant metastases, among whom only 2 were without locoregional recurrence. The 3-year progression-free survival is 39% and 3-year overall survival has been 43%. CONCLUSION: The schedule modification did not attenuate local toxicity. Moreover, infections and especially pneumonia, were a major problem. The high activity of gemcitabine when combined with radiotherapy would most likely be better exploited in the context of modified radiation schemes.

Management of Skin Reactions During Cetuximab Treatment in Association With Chemotherapy or Radiotherapy: Update of the Italian Expert Recommendations.

OBJECTIVES: Cetuximab was shown in phase III clinical trials to improve chemotherapy efficacy in patients with advanced colorectal and head-neck cancer. Appropriate management of skin reactions associated with epidermal growth factor receptor inhibitor therapy is necessary to allow adequate drug compliance and to improve patient quality of life and outcomes. METHODS: The RAND/UCLA Appropriateness Method was used by a group of experts to produce new Italian recommendations on the management of skin reactions in this setting. Statements were generated on the basis of an updated systematic review of the literature and rated twice by a panel of 38 expert physicians. A meeting of the panel was held after the first rating session. RESULTS: Skin reactions included acneiformic rash, skin dryness (xerosis), pruritus, paronychia, hair abnormalities, mucositis, and increased growth of eyelashes or facial hair. Updates of the previous recommendations on the prevention and treatment of each type of reaction were proposed. CONCLUSIONS: This updated Expert Opinion focuses on how to assess and correctly grade skin reactions according to the latest National Cancer Institute Common Terminology Criteria for Adverse Events and on how to manage these adverse events in clinical practice.

Extreme hypofractionation for early prostate cancer: Biology meets technology.

The aim of this review is to present the available radiobiological, technical and clinical data about extreme hypofractionation in primary prostate cancer radiotherapy. The interest in this technique is based on the favourable radiobiological characteristics of prostate cancer and supported by advantageous logistic aspects deriving from short overall treatment time. The clinical validity of short-term treatment schedule is proven by a body of non-randomised studies, using both isocentric (LINAC-based) or non-isocentric (CyberKnife®-based) stereotactic body irradiation techniques. Twenty clinical studies, each enrolling more than 40 patients for a total of 1874 treated patients, were revised in terms of technological setting, toxicity, outcome and quality of life assessment. The implemented strategies for the tracking of the prostate and the sparing of the rectal wall have been investigated with particular attention. The urinary toxicity after prostate stereotactic body irradiation seems slightly more pronounced as compared to rectal adverse events, and this is more evident for late occurring events, but no worse as respect to conventional fractionation schemes. As far as the rate of severe acute toxicity is concerned, in all the available studies the treatment was globally well tolerated. While awaiting long-term data on efficacy and toxicity, the analysed studies suggest that the outcome profile of this approach, alongside the patient convenience and reduced costs, is promising. Forty-eight ongoing clinical trials are also presented as a preview of the expectation from the near future.

Mucositis in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus statements.

BACKGROUND: Oral mucositis (OM) due to radiotherapy and systemic therapies in head and neck cancer treatment represents a major problem causing a wide spectrum of clinical signs and symptoms. This adverse event may reduce quality of life, resulting from debilitating oral pain, bleeding, dysphagia, infections, impairment of food intake, high rate of hospitalization and may interfere with the delivery of programmed treatment plans, ultimately jeopardizing patient outcome. Globally, there is a lack of evidence on effective measures for the prevention and treatment of OM, and only scant uniform conclusions and recommendations can be derived from the existing literature and guidelines. A multidisciplinary team of Italian head and neck cancer experts met in Milan 17-18 February 2013 with the aim of reaching consensus on prophylaxis and management of mucositis. The results of the literature review and the statements that achieved consensus are reported and discussed in this paper. MATERIAL AND METHODS: The Delphi Appropriateness Method was used as a structured communication method for achieving consensus. Subsequently, external expert reviewers evaluated the conclusions carefully according to their area of expertise. RESULTS: This paper presents 13 clusters of statements on prophylaxis and treatment of mucositis that achieved consensus. CONCLUSIONS: OM represents a very stressful situation for head and neck cancer patients submitted to chemo-radiation or exclusive radiation treatment. A multidisciplinary approach is mandatory, but there is still no gold-standard protocol that is prominently better than others.

Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Xerostomia and trismus (Part 2). Literature review and consensus statement.

Radiotherapy alone or in combination with chemotherapy and/or surgery is a well-known radical treatment for head and neck cancer patients. Nevertheless acute side effects (such as moist desquamation, skin erythema, loss of taste, mucositis etc.) and in particular late toxicities (osteoradionecrosis, xerostomia, trismus, radiation caries etc.) are often debilitating and underestimated. A multidisciplinary group of head and neck cancer specialists from Italy met in Milan with the aim of reaching a consensus on a clinical definition and management of these toxicities. The Delphi Appropriateness method was used for this consensus and external experts evaluated the conclusions. The paper contains 20 clusters of statements about the clinical definition and management of stomatological issues that reached consensus, and offers a review of the literature about these topics. The review was split into two parts: the first part dealt with dental pathologies and osteo-radionecrosis (10 clusters of statements), whereas this second part deals with trismus and xerostomia (10 clusters of statements).

Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: Dental pathologies and osteoradionecrosis (Part 1) literature review and consensus statement.

Radiotherapy alone or in combination with chemotherapy and/or surgery is the typical treatment for head and neck cancer patients. Acute side effects (such as oral mucositis, dermatitis, salivary changes, taste alterations, etc.), and late toxicities in particular (such as osteo-radionecrosis, hypo-salivation and xerostomia, trismus, radiation caries etc.), are often debilitating. These effects tend to be underestimated and insufficiently addressed in the medical community. A multidisciplinary group of head and neck cancer specialists met in Milan with the aim of reaching a consensus on clinical definitions and management of these toxicities. The Delphi Appropriateness method was used for developing the consensus, and external experts evaluated the conclusions. This paper contains 10 clusters of statements about the clinical definitions and management of head and neck cancer treatment sequels (dental pathologies and osteo-radionecroses) that reached consensus, and offers a review of the literature about these topics. The review was split into two parts: the first part dealt with dental pathologies and osteo-radionecroses (10 clusters of statements), whereas this second part deals with trismus and xerostomia.

Paclitaxel, cisplatin, 5-fluorouracil and radiotherapy in the management of advanced squamous cell carcinoma of the head and neck: a phase II trial.

Aim of the present study was to test, activity and toxicity of a rapidly alternating chemoradiation (paclitaxel based) in 31 patients with unresectable, locally advanced or recurrent after surgery, head and neck cancer. Three-year overall survival and progression-free survival were 61.4 and 73.7%, respectively. Main side effects remain a major problem.

Facial Basal Cell Carcinomas in Elderly Frail Patients Treated with Low Total-dose Radiotherapy.

AIM: A retrospective analysis was performed in our two Institutions in order to evaluate the feasibility and reliability of a hypofractionated-radiotherapy regimen in the treatment of frail elderly patients with facial basal cell carcinomas (BCCs). PATIENTS AND METHODS: The records of elderly patients (age >75 years) with histologically-confirmed BCC, T1-2, treated to a total radiation dose of 25-30 Gy over 5-6 weeks, were retrospectively analyzed. RESULTS: From February 2007-December 2010, 134 ambulatory patients with 159 BCCs were treated. Their median age was 82.5 years (range=75-103). Grade 1-2 skin acute toxicities were observed in 30.6% of patients (41/134). Complete responses were observed in 157 tumors in 132 patients. At the last follow-up, June 2014, no late toxicities had been noted; three patients had local recurrent disease. CONCLUSION: Our results seem to demonstrate both the feasibility and efficacy of curative hypofractionated radiation therapy in elderly patients with BCCs unfit for daily irradiation.

Acute skin toxicity management in head and neck cancer patients treated with radiotherapy and chemotherapy or EGFR inhibitors: Literature review and consensus.

The adverse effects of radiation therapy, often integrated with chemotherapy and/or targeted therapies, on the skin include severe acute and chronic dermatitis associated with pain, discomfort, itching, and burning, and may heavily affect patients' quality of life. The management of these skin adverse effects in head and neck cancer patients (HNCPs) are very heterogeneous due to the lack of shared rigorous classification systems and evidence based treatments. A multidisciplinary group of head and neck cancer specialists from Italy met with the aim of reaching a consensus on a clinical definition and management of dermatitis in HNCPs treated with radiotherapy with or without systemic therapies in order to improve skin toxicity management. The Delphi Appropriateness Method was used. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. This paper offers contains seven clusters of statements about the management of dermatitis in HNCPs and a review of recent literature on these topics.

Dysphagia in head and neck cancer patients treated with radiotherapy and systemic therapies: Literature review and consensus.

BACKGROUND: Head and neck cancer (HNC) and its therapy are associated with acute and late swallowing dysfunction. Consensus guidelines regarding evaluation and management are lacking. To address this gap, a multidisciplinary team of experts (oncologists, practitioners, deglutologists, etc.) met in Milan 17-18 February 2013 with the aim of reaching a consensus on the management of swallowing difficulties in HNC patients treated with radiotherapy with or without systemic therapies (such as chemotherapy and targeted agents). The consensus was focused particularly on those statements with limited evidence. The results of the literature review and the statements that obtained a consensus are reported and discussed in this paper. MATERIALS AND METHODS: The Delphi Appropriateness Method was used for this consensus. External expert reviewers then evaluated the conclusions carefully according to their area of expertise. RESULTS: This paper contains 6 clusters of statements about the management of swallowing problems in radio-treated HNC patients and a review of the recent literature on these topics. CONCLUSIONS: Dysphagia assessment and its management are difficult and require a multi-team cooperation (ENT specialists, radiation and medical oncologists, deglutologists, etc.).