A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group.

BACKGROUND: Accurate grading of dermatologic adverse events (AE) due to epidermal growth factor receptor (EGFR) inhibitors (EGFRIs) is necessary for drug toxicity determinations, interagent comparisons, and supportive care trials. The most widely used severity grading scale, the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v4.0), was not designed specifically for this class of agents and may result in underreporting and poor grading of distinctive adverse events. We believe a class-specific grading scale is needed to help standardize assessment and improve reporting of EGFRI-associated dermatologic AEs. METHODS: The Multinational Association of Supportive Care in Cancer (MASCC) Skin Toxicity Study Group conducted an international multidisciplinary meeting that included 20 clinicians and researchers from academic centers and government agencies. Experts from different disciplines presented current information specific to EGFRI-induced dermatologic toxicities: grading scale development, pharmacovigilance safety reporting, health-related quality of life, patient reporting, and pharmacology. Group discussions, literature reviews, and professional expertise established the theoretical foundation for the proposed grading scale. RESULTS: A new grading system is proposed for the most common events associated with EGFRI-induced dermatologic AEs: papulopustular reaction or acneiform rash, nail changes, erythema, pruritus, xerosis, hair changes, telangiectasias, hyperpigmentation, mucositis, flushing, radiation dermatitis, hyposalivation, and taste changes. The proposed scale maintains consistency with the grading principles and language of the existing CTCAE version 4.0 and MedDRA terminology and includes relevant patient-reported health-related quality of life factors. CONCLUSIONS: A grading scale specific to EGFR inhibitor dermatologic AEs is presented for formal integration into future versions of CTCAE and for validation in clinical trial settings. The study group designed this scale to detect and report EGFRI-related toxicities with greater sensitivity, specificity, and range than the scales currently used. This scale should serve as a foundation for efforts to perform objective interdrug comparisons and assessments of supportive care treatment strategies more effectively than with current methods.

Expert consensus on the management of erlotinib-associated cutaneous toxicity in the u.k.

Rash has been reported in up to 76% of patients with lung cancer who have received the epidermal growth factor receptor inhibitor (EGFRI) erlotinib. It has also been observed in patients treated with other agents that have a similar mode of action. Erlotinib-associated skin toxicity typically presents as a papulopustular, follicular, acneiform rash. In most cases, it is mild, transient, and well tolerated, but in 8%-12% of patients, it may be sufficiently severe and persistent to necessitate intervention. Increasingly strong data suggest that the incidence and severity of skin toxicity may be predictive of response and survival in patients treated with erlotinib. This has prompted some clinicians to consider "treatment to rash" (i.e., increasing the dosage until a rash appears) as a rational management strategy. In 2007, an international consensus was developed for the management of EGFRI-associated skin toxicity. Subsequently, a multidisciplinary group (the U.K. Erlotinib Skin Toxicity Management Consensus Group) met to validate and modify the international recommendations for U.K. use, with specific reference to erlotinib. Although many aspects of the international consensus were approved by the group as being relevant for the U.K., certain parts were modified. The resulting expert opinion is a practical and workable version of the international proposal that considers all applicable national issues regarding the management of erlotinib-associated skin toxicity.

An interdisciplinary consensus on managing skin reactions associated with human epidermal growth factor receptor inhibitors.

The use of human epidermal growth factor receptor (HER1/EGFR) inhibitors, such as erlotinib, cetuximab, and panitumumab, often is accompanied by the development of a characteristic spectrum of skin toxicities. Although these toxicities rarely are life threatening, they can cause physical and emotional distress for patients and caregivers. As a result, practitioners often withdraw the drug, potentially depriving patients of a beneficial clinical outcome. These reactions do not necessarily require any alteration in HER1/EGFR-inhibitor treatment and often are best addressed through symptomatic treatment. Although the evidence for using such therapies is limited, an interdisciplinary HER1/EGFR-inhibitor dermatologic toxicity forum was held in October 2006 to discuss the underlying mechanisms of these toxicities and evaluate commonly used therapeutic interventions. The result was a proposal for a simple, three-tiered grading system for skin toxicities related to HER1/EGFR inhibitors to be used in therapeutic decision making and as a framework for building a stepwise approach to intervention.

Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC antiemesis tool.

There is a lack of clinical tools to facilitate communication between clinicians and patients about chemotherapy-induced nausea and vomiting (CINV). The Multinational Association of Supportive Care in Cancer (MASCC) has developed such a tool, which is an eight-item scale for the assessment of acute and delayed nausea and vomiting, and is completed once per cycle of chemotherapy. The aim of the current study was to assess its psychometric properties, specifically reliability and validity, cultural transferability and equivalence, and congruence with proxy assessments, as well as to determine if accuracy of recall of CINV events using the MASCC Antiemesis Tool (MAT) differed over time from chemotherapy. A prospective study was carried out with adult cancer patients and their informal carers from two hospitals, one each in the United Kingdom (UK) and United States of America (U.S.). Patients completed the Rhodes Index for nausea, vomiting and retching (INVR) daily for the first five days after chemotherapy and were then asked to complete the MAT at one week, two weeks, or three weeks after chemotherapy. Carers completed an adapted MAT concurrently with patients. The sample consisted of 87 patients and 22 informal carers. The internal consistency reliability of the scale was high, with Cronbach alphas of 0.77 (patient sample) and 0.82 (carer sample). Responses were similar between the UK and U.S. samples in terms of nausea and vomiting, and both samples found the scale easy to use. Contrasted-groups validity (using age as a grouping variable) and concurrent validity (MAT compared with INVR) suggested that the scale is sensitive to detect the different dimensions of CINV and performed well against a daily assessment of nausea/vomiting (total score correlation r=0.86, P<0.001). Recall of events was high even three weeks after chemotherapy (correlations with INVR of 0.44-0.99, all P<0.01). Factor analysis clearly identified three factors, namely vomiting, acute nausea, and delayed nausea. Proxy assessments by carers were congruent with the patients' responses, especially in relation to vomiting. The MAT is a reliable, valid, clear, and easy-to-use clinical tool that could facilitate discussion between clinicians and patients about their nausea and vomiting experience, thereby potentially aiding treatment decisions. Regular assessment of nausea and vomiting after chemotherapy has the potential to significantly improve CINV management.

Carboplatin/pemetrexed/bevacizumab in the treatment of patients with advanced non-small-cell lung cancer: a single-institution experience.

PURPOSE: The purpose of this study was to determine the efficacy and tolerability of carboplatin, pemetrexed, and bevacizumab in patients with advanced, nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: The charts of consecutive patients with stage IIIB/IV nonsquamous NSCLC were reviewed. All patients receiving at least 1 cycle of the 3-drug regimen (pemetrexed 500 mg/m2, carboplatin area under the curve of 5-6, bevacizumab 15 mg/kg intravenously), were included for assessment of response, safety, and toxicity. RESULTS: A total of 27 patients received this regimen between February 2008 and July 2009; 63% were women. Median follow-up was 6.3 months (range, 1.6-21.1 months). Median number of cycles was 6 (range, 1-6 cycles); 67% completed 6 cycles; 83% went on to receive maintenance bevacizumab/pemetrexed. Among those who received maintenance, the median number of cycles administered was 4.5 (range, 1-18 cycles). Response rate was 52%; stable disease was observed in another 40%. On the basis of Kaplan-Meier analysis, actuarial overall survival was 83% at 12 months; actuarial progression-free survival was 83% and 63% at 6 and 12 months, respectively. Clinical improvement was noted in 41% of the patients, with clinical stability in another 48%. Grade 2 and 3 toxicities from the regimen included anemia (11% and 15%), fatigue (37% and 7.4%), febrile neutropenia (7.4%; grade 3 only), thrombocytopenia (7.4% and 0), and thromboembolic disorders (3.7% and 3.7%). Bevacizumab-induced side effects (any grade) included headaches (22.2%), epistaxis (30%), hemoptysis (3.7%), and hypertension (11%). No grade 4 or 5 toxicities were seen. CONCLUSION: Combination carboplatin/pemetrexed and bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab is effective, with response rates > 50%, acceptable toxicity, and promising early survival in patients with advanced nonsquamous NSCLC.

Adjuvant cisplatin and docetaxel for non-small cell lung cancer: the Hospital of the University of Pennsylvania experience.

INTRODUCTION: Cisplatin and docetaxel (Doc) are commonly used for adjuvant therapy for non-small cell lung cancer based on extrapolation from the metastatic setting. Nevertheless, essentially no data have been published on this regimen in the adjuvant context, leading to controversy, particularly surrounding feasibility. METHODS: Using a tumor database augmented with chart reviews, we retrospectively evaluated treatment outcomes of all patients receiving postoperative cisplatin (75 mg/m) and Doc (75 mg/m) between August 2003 and November 2008. During this period, this regimen was considered to be the first choice regimen for sufficiently fit patients at the University of Pennsylvania. RESULTS: The database captured 54 patients. Overall, 85.2% received all four planned cycles (83.3% at full dose). Chart review allowed definitive assessment of toxicity in 47 patients. A single patient (2%) died of grade 5 febrile neutropenia. There was no grade 4 toxicity, and 8.5% experienced grade 3 febrile neutropenia. No febrile neutropenia was observed in 26 patients given prophylactic peg-filgrastim. The incidence was 23.8% in the 21 patients not given peg-filgrastim during the first cycle; 6.4% each experienced grade 3 gastritis, anorexia, nausea, and fatigue, and 2.1% experienced grade 3 diarrhea. Median progression-free survival was 17.9 months, and median overall survival has not been reached. CONCLUSION: Cisplatin and Doc are feasible in the adjuvant setting with superior dose delivery and convenience compared with historic data with cisplatin and vinorelbine.

Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management.

Epidermal growth factor receptor inhibitors (EGFRIs) have demonstrated improved overall survival in patients with non-small cell lung cancer, pancreatic cancer, and colorectal cancer; however, their use is associated with dermatologic reactions of varying severity. The similar spectrum of events observed with monoclonal antibodies and tyrosine kinase inhibitors suggests such toxicities are a class effect. While such reactions do not necessarily require any alteration in EGFRI treatment, being best addressed through symptomatic treatment, there is limited evidence on which to base such therapies. In October 2006, at an international and interdisciplinary EGFRI dermatologic toxicity forum, the underlying mechanisms of these toxicities were discussed and commonly used therapeutic interventions were evaluated. Our aim was to reach a current consensus on management strategies. A three-tiered, EGFRI-focused toxicity grading system is suggested for the purposes of therapeutic decision making, and as a framework on which to build a stepwise approach to intervention. This approach to successful management is specifically tailored to accurately categorize dermatologic toxicity associated with EGFRIs, and can be easily applied by all health care professionals. The goal is to maximize quality of life in patients who are being treated with these agents--many of whom will be on these drugs for several months or even years.

Gefitinib in patients with advanced non-small cell lung cancer (NSCLC): the expanded access protocol experience at the University of Pennsylvania.

Gefitinib (Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE) is an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with favorable toxicity and antitumor activity in pretreated patients with non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the toxicity and efficacy of gefitinib in patients with advanced NSCLC treated at our institution as part of an expanded access protocol; 112 patients with advanced NSCLC were entered. All patients had failed at least one previous chemotherapy regimen, or were not suitable for any systemic chemotherapy because of poor performance status (PS), or were ineligible for other clinical trials. Therapy consisted of gefitinib 250 mg orally once daily; 10.5% (95% CI 5.3-17.9%) of patients achieved partial/minimal response (PR/MR) and 29.5% (95% CI 21.0-39.2%) had stable disease (SD), resulting in a disease control rate (PR/MR+SD) of 40% (95% CI 31-50%). The median duration of treatment for all patients was 12 weeks (range 2-116 weeks) and for patients achieving disease control 28 weeks (range 8-116). Nine patients received gefitinib for more than 1 year. Median survival was 30 weeks. Symptoms were improved in 36% of evaluable patients, and 64% of patients who achieved disease control experienced improvement of their disease related symptoms. Adverse events were generally mild and consisted mostly of skin rash (48%) and diarrhea (38%). A statistically significant association was observed between disease control and skin rash (p = < 0.001), nonsmoking status (p = 0.048), and symptom improvement (p = 0.001). The disease control rate was not statistically associated with histology, PS, gender, or number of prior treatments. In addition, longer survival was significantly associated with skin rash (p = < 0.001) and symptom improvement (p = < 0.001). Gefitinib demonstrated relevant clinical activity and a favorable toxicity profile in pretreated patients with advanced NSCLC. The development of toxicity was associated with a favorable response. In addition, a history of never having smoked seems to predict a higher efficacy of gefitinib.