Severity Of Rash Research Articles

Efficacy and safety of weekly paclitaxel combined with cetuximab in the treatment of pretreated recurrent/metastatic head and neck cancer patients.

5594 Background: The addition of cetuximab to weekly paclitaxel have shown high efficacy in the first-line treatment of patients with recurrent /metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, this combination has been widely extended to patients who present resistance to first line chemotherapy (CT) or those who are not candidate to platinum-based CT. Methods: We have retrospectively analyzed the efficacy of cetuximab in combination with weekly paclitaxel in patients with R/M-SCCHN who were not candidate to platinum-based CT or those who present disease progression after platinum schedules. Patients received weekly paclitaxel 80 mg/m2 and cetuximab 250 mg/m2 (initial dose of 400 mg/m2) till progression or unacceptable toxicity. Results: Twenty-one patients were included. Median age was 56 (43-72), ECOG PS (0/1/2): 6/10/5, 18 patients had received prior platinum-based treatment (9 patients were platinum-sensitive and 9 were platinum-refractory). With a median follow-up of 6.18 months (1.3-29.7), overall response rate (ORR) was 47.6% (95% IC 26.3-69%): 1 (4.7%) complete response and 9 (42.9%) partial responses. Median duration response was 10.23 months. There were no differences in response according to platinum sensitivity (55% sensitive vs. 45% refractory; P=0.74). Median progression free survival (PFS) and overall survival (OS) were 4.17 and 9.17 months, respectively. The main toxicity consisted of rash in 70% of patients (55% grade 2-3), with an association between rash severity and ORR (grades 0-1: 33% vs. grades 2-3: 55%; P=0.03) and a trend to better PFS and OS. Conclusions: Weekly paclitaxel in combination with cetuximab is a well tolerated and high active treatment in patients with R/M-SCCHN who experience disease progression after platinum-based CT, including those who present resistant disease. The efficacy of this combination is apparently higher than the published data on single agent cetuximab in this setting.

The relationship between the development of rash and clinical and quality of life outcomes by Kras mutation status in patients with colorectal cancer treated with cetuximab in NCIC CTG CO.17.

481 Background: The NCIC Clinical Trials Group CO.17 trial, conducted with the Australasian Gastrointestinal Trials Group, showed cetuximab monotherapy (CET vs. best supportive care [BSC]) improved overall (OS) and progression-free survival (PFS) and maintained quality of life (QoL) in patients previously treated for advanced colorectal cancer. Correlative analyses showed strong relationships between CET benefits and both rash development and Kras mutation status. Association between rash and CET benefits is now presented by Kras mutation status. Methods: Rash was graded weekly by NCI CTC 2.0 criteria. Landmark-type analyses (LTA) were performed by excluding patients who died within 28 days and then grouping by rash severity (gr 2+ vs. gr 0/1) based both on worst grade ever developed (LTA1) and worst grade on or before day 28 (LTA2). Multivariate Cox models were conducted separately for wild-type (WT) and mutated (MUT) Kras tumors. Results: More rash of severity gr 2+ was observed in WT than MUT patients treated with CET (57.3% vs. 44.4%; p = 0.08). The median OS, PFS, and HRs from LTA2 are presented for WT and MUT groups (see Table). Conclusions: Rash severity was positively correlated with PFS and OS in Kras WT patients who received CET, although only for gr 2+ rash did OS significantly exceed that of BSC patients. In Kras MUT patients, neither gr 0/1 nor gr 2+ rash was associated with either improved PFS or OS vs. BSC patients. Quality of life outcomes will also be reported by Kras mutation status. [Table: see text] [Table: see text]

Human epidermal growth factor receptor-2 (HER2) Ile655Val single nucleotide polymorphism (SNP) is associated with gender-specific outcome in patients with metastatic colorectal cancer (mCRC) treated with cetuximab in a phase II study (IMCL-0144).

441 Background: HER2 pathway is an important growth-regulatory pathway in many malignancies. In-vitro data from various cell lines suggest that activation of HER family members predicts resistance to cetuximab. HER2 also interacts with hormone receptors and estrogen, promoting tumor proliferation in breast cancer models. We previously demonstrated that polymorphisms in HER1 and ER-β were associated with gender-specific survival in colorectal cancer patients. HER2 Ile655Val (rs1136201) SNP's functionality was shown in breast cell lines with Val-expressing cells exhibiting increase growth capacity. We tested whether this SNP may predict gender-specific clinical outcome in mCRC treated with cetuximab. Methods: Tissue samples of 130 patients, 64 males and 66 females, with mCRC, enrolled in a phase II trial of cetuximab monotherapy were analyzed. Genomic DNA was extracted from FFPE tumor tissue. K-Ras mutation status and HER2 Ile655Val (rs1136201) SNP were analyzed using direct DNA-sequencing and PCR-RFLP. 23 out of 130 patients were still alive at the time of data analysis with a median follow-up of 12.3 months. Results: Females with the low activity HER2 Ile/Ile (n = 41) genotype had better progression-free survival (PFS) when compared to Ile/Val or Val/Val (n = 21) genotypes (median PFS = 2.4 vs. 1.2 months; HR = 2.06 (95% CI: 1.08-3.92), p = 0.0281) based on the multivariable Cox regression model adjusting for KRAS, performance status and severity of skin rash and stratified by race. In KRAS wild-type females, 15 patients out of 20 (75%) with HER2 Ile/Ile genotype responded or had stable disease when compared to 4 out of 12 (33%) Ile/Val or Val/Val genotypes (exact conditional test p = 0.143). In males, HER2 Ile655Val SNP is not associated with outcome. HER2 Ile655Val SNP is not associated with gender-specific overall survival. Conclusions: Our data suggest that HER2 Ile655Val SNP may identify females with mCRC likely to experience better outcome when treated with cetuximab. Prospective biomarker-embedded clinical trials are needed to validate our results. [Table: see text]

Abstract P3-14-07: A Phase 1 Study To Assess the Safety, Tolerability and PK of ARRY-380 — An Oral HER2 Inhibitor

Abstract Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo. Methods: Patients (pts) with HER2+ MBC or other tumor types with published evidence of HER2 expression were treated with ARRY-380 as a single oral dose on C1 D1 followed by continuous dosing on C1 D3, in a BID schedule. Dose escalation was performed using standard DLT rules after all pts within a cohort completed the first cycle. Serial PK assessments were performed on D 1, 2, 3 and on D 15 of C1. Preliminary Results: As of 1 June, 2010, 30 pts have been treated at doses ranging from 25 mg to 800 mg BID. Pts had a median age of 57 years (range: 31-77 years). Cancer types included HER2+ MBC (n=23), CRC (n=6), and salivary gland (n=1). All HER2+ MBC pts had received prior trastuzumab and most (78%) had received prior lapatinib. The MTD (600 mg BID) has been determined in the dose escalation study. ARRY-380 was generally well-tolerated. One DLT of reversible grade 3 AST and one DLT of reversible grade 3 AST/ALT were noted at the 800 mg BID dose level. Other related AEs have been predominantly mild and include Grade 1 nausea, rash, and fatigue and Grade 2 fatigue. No treatment-related cardiac events have been reported. PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours, and a mean t1/2 of 5.3 hours across doses. Of the 15 HER2+ MBC pts evaluable for response at doses ≥200 mg BID, 1 (7%) pt had a confirmed PR and 8 (53%) had SD accompanied by regression of tumor lesions. Of the 8 pts with SD, 5 pts demonstrated SD for ≥4 months. The rate of PR + SD ≥4 months was 43%. The HER2+ MBC pt with a PR had complete regression of all target and non-target lesions and a change in CEA from 71.1 to 3.5 ng/mL [NR = 0.0-3.0 ng/mL]. This pt is currently in Cycle 5 and has received 6 prior lines of therapy for advanced disease with a best response of PD on lapatinib. Conclusions: ARRY-380 has demonstrated a generally well-tolerated safety profile with a low incidence and severity of rash and diarrhea. ARRY-380 has shown promising signs of antitumor activity in a heavily pretreated HER2+ MBC population (43% of pts with PR or SD ≥4 months). These safety and preliminary efficacy data compare favorably to historical data of other HER2-targeted agents. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-07.

Prophylactic tetracycline does not diminish the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash: results from the North Central Cancer Treatment Group (Supplementary N03CB)

Previous studies suggest tetracycline and other antibiotics lessen the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash. This study sought to confirm such findings. Patients starting an EGFR inhibitor were eligible for this randomized, double-blinded, placebo-controlled study and had to be rash-free. They were then randomly assigned to tetracycline 500 mg orally twice a day for 28 days versus a placebo. Rash development and severity (monthly physician assessment and weekly patient-reported questionnaires), quality of life (SKINDEX-16), and adverse events were monitored during the 4-week intervention and then for an additional 4 weeks. The primary objective was to compare the incidence of grade 2 or worse rash between study arms; 32 patients per group provided a 90% probability of detecting a 40% difference in incidence with a type I error rate of 0.05 (two-sided). Sixty-five patients were enrolled, and groups were balanced on baseline characteristics. During the first 4 weeks, healthcare provider-reported data found that 27 tetracycline-treated patients (82%) and 24 placebo-exposed patients (75%) developed a rash. This rash was a grade 2+ in 17 (52%) and 14 (44%), respectively (p = 0.62). Comparable grade 2+ rash rates were observed during weeks 5 through 8 as well as with patient-reported rash data throughout the study period. Quality of life was comparable across study arms, and tetracycline was well tolerated. Although previous studies suggest otherwise, this randomized, double-blinded, placebo-controlled study did not find that tetracycline lessened rash incidence or severity in patients who were taking EGFR inhibitors.

Herpes zoster-related pain in aged individuals: How to manage it safely

Varicella-Zoster virus, an exclusively human herpes virus is responsible for chickenpox and herpes zoster. After the primary infection, the virus becomes permanently latent in the dorsal-root sensory ganglias and may be reactivated several decades later causing a vesicular dermatomal rash, traditionally metameric. Old adults can present severe pain during the acute phase, and late complications, such as postherpetic neuralgia that can be trying and crippling. Initiated within the first 72 hours of the rash, antivirals accelerate rash healing, reducing both rash and acute pain severity as well as avoiding the onset of other complications. The combination of antivirals and corticosteroids may further alleviate short-term zoster pain, increasing the risk of serious adverse effects, especially among older adults. Recently, some therapeutic recommendations focused on analgesic treatments (NSAIDs, opioid agonists, antidepressive drugs, calcium channel α2-δ ligands, corticosteroids and even antiviral agents) were published. However, their applications in old, frail, comorbid and often polymedicated patients have to be consciously pondered and are sometimes contraindicated (as tricyclic antidepressants). Specific recommendations for the therapeutic management of acute and post herpes zoster-related neuralgias, in older adults are proposed.

Does Sunscreen Prevent Epidermal Growth Factor Receptor (EGFR) Inhibitor–Induced Rash? Results of a Placebo-Controlled Trial from the North Central Cancer Treatment Group (N05C4)

Rash occurs in >50% of patients prescribed epidermal growth factor receptor (EGFR) inhibitors. This study was undertaken to determine whether sunscreen prevents or mitigates these rashes. This placebo-controlled, double-blinded trial enrolled rash-free patients starting an EGFR inhibitor. Patients were randomly assigned to sunscreen with a sun protection factor of 60 applied twice a day for 28 days versus placebo. They were then monitored for rash and quality of life (Skindex-16) during the 4-week intervention and for an additional 4 weeks. Fifty-four patients received sunscreen, and 56 received placebo; the arms were balanced at baseline. During the 4-week intervention, physician-reported rash occurred in 38 (78%) and 39 (80%) sunscreen-treated and placebo-exposed patients, respectively (p = 1.00); no significant differences in rash rates emerged over the additional 4 weeks. There were no significant differences in rash severity, and patient-reported outcomes of rash yielded similar conclusions. Adjustment for sun intensity by geographical zone, season, and use of photosensitivity medications did not yield a significant difference in rash across study arms (p = .20). Quality of life scores declined but remained comparable between arms. Sunscreen, as prescribed in this trial, did not prevent or attenuate EGFR inhibitor-induced rash.

Impact of a Pre-Emptive Skin Treatment Regimen on Skin Toxicities of Anti–Epidermal Growth Factor Receptor Monoclonal Antibodies: More Questions Than Answers

TO THE EDITOR: The Skin Toxicity Evaluation Protocol With Panitumumab (STEPP) study 1 adds to our increasing knowledge of how best to manage the sometimes troubling dermatologic adverse effects of anti– epidermal growth factor receptor monoclonal antibodies. However, it also raises numerous new questions that need to be addressed before a prophylactic treatment approach becomes a standard of care. As an example, many patients have only mild to no skin toxicity with these drugs. Is preventive therapy really needed in all? Also, the pre-emptive strategy involves four separate interventions. Could just one or two have sufficed? In addition, only one patient (2%) in the reactive treatment group received all four components of the skin treatment regimen when the patient developed a rash. Had these patients received the same protocol as the prophylactic group, would we have seen the same result? The modified Common Terminology Criteria for Adverse Events version 3.0, which was used in this study for the assessment of panitumumab-related skin adverse effects, is a subjective scale. As such, one could question if it is the most appropriate tool to quantify skin toxicity in this unblinded study setting. Finally, severity of rash is highly correlated with the efficacy of these agents. 2-4 Can we be certain this effect will remain in the face of a prophy

Effects of pregabalin on acute herpetic pain and postherpetic neuralgia incidence

Acute zoster pain usually disappears with regression of the rash but may be of significant intensity and prolonged duration leading to postherpetic neuralgia. We evaluated the effect of pregabalin on alleviation of acute zoster pain and onset of postherpetic neuralgia. The prospective randomized double-blind placebo-controlled study included 29 outpatients who had had acute zoster pain for a period of 7-14 days. Patients were treated for three weeks with 150-300 mg pregabalin daily or with a placebo. Pain was treated with naproxen, tramadol or oxycodone, as necessary. During the treatment we assessed pain, allodynia, hyperalgesia, severity of burning, prickling and tingling sensations, quality of sleep, physical activity, consumption of analgesics, manifestation of adverse events and postherpetic neuralgia. There were no statistically significant differences with respect to patients' demographic data, dermatomal distribution and severity of rash, use of antiviral therapy or duration of acute zoster pain. Standard statistical analyses found no significant differences between the two treatment groups in intensity of pain, allodynia, hyperalgesia, burning, prickling and tingling sensations, consumption of analgesics, or the quality of sleep and physical activity; there was also no significant difference in development of postherpetic neuralgia. However, there were statistically significant differences between the groups in the occurrence of dizziness and somnolence in relation to pregabalin. The study did not prove any statistically significant effect of pregabalin in pain relief in patients with acute zoster pain or in the onset of postherpetic neuralgia in comparison with the placebo. The use of pregabalin was related to a statistically significant increase in the appearance of adverse effects.

Abstract 3588: Personalized medicine for non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib

Abstract Erlotinib is an oral available, selective inhibitor of EGFR tyrosine kinase activity for the treatment of patients with NSCLC. Side effects, commonly seen as skin rash and diarrhea, occurred in 75% of patients. About 20% of patients needed erlotinib dose reduction from the standard dose of 150mg/day due to these toxicities. Since the severity of skin rash is strongly associated with improved clinical outcome, skin rash may be a surrogate marker of favorable clinical outcome. Erlotinib is a substrate for ABC transporters such as ABCB1 and ABCG2. However, it is unknown whether these polymorphisms affect the pharmacokinetics of erlotinib and influence the inter-individual variability in erlotinib toxicity. The purpose of this study is to evaluate the effects of ABC transporter polymorphism on erlotinib pharmacokinetics and the development of side effects, skin rash and diarrhea in Japanese patients with NSCLC. Methods: Thirty-one Patients were orally administered 150 mg erlotinib as a single treatment. Plasma levels of erlotinib were measured by high-performance liquid chromatography on days 1(D1), 8(D8), and stable phase. DNA from plasma was screened for SNPs in the ABCB1 and ABCG2 genes using TaqMan assay or direct nucleotide sequencing. Results: The mean Cmax of D1 and D8 were 1.7 and 3.1 µg/ml, respectively. Trough concentration at D1, D8 and steady state were 0.7, 1.2 and 1.4 µg/ml, respectively. Skin rash occurred in 95% of patients. One patient (Cmax, 3.0 µg/ml at D1) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The Cmax and AUC on D1 was correlated with the severity of skin rash, however, Cmin were not correlated. Patients with homozygous variant for ABCB1 1236C>T, 2677 G>(T/A), and 3435C>T genotype as compared to patients carrying the wild-type and heterozygous were associated with higher AUC and Cmin at D1 (31 vs 21, p=0.07; 1.1 vs 0.6 µg/ml, p=0.007). AGCG2 421C>A genotype were not associated with any pharmacokinetic parameters. ABCB1 polymorphism was associated with decreased ABCB1 function, resulting in the increased concentration of erlotinib. All five patients with homozygous variant for ABCB1 1236TT-2677TT-3435TT developed higher grade 2 toxicity by day 7. Patients homozygous variant for ABCB1 developed toxicity significantly faster than those with at least one T allele (p=0.002). On the other hand, all three patients carrying without T allele had not experience toxicity. Conclusions: The present study suggests that ABCB1 polymorphism affects the pharmacokinetics of erlotinib and also influence the development of erlotinib toxicity. We proposed that prior to the Erlotinib treatment, the measuring of ABCB1 polymorphism may help to identify patients with NSCLC who can develop a severe toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3588.

Escalating weekly doses of cetuximab and correlation with skin toxicity: A phase I study

Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m² intravenously (IV) followed by a weekly maintenance dose of 250 mg/m². It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods Four dose levels were tested: Cetuximab 400 mg/m² IV loading dose and 250, 300, 350, 400 mg/m² weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m²). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m²) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. Cetuximab administered at 400 mg/m² IV as a loading dose with weekly maintenance dose of 400 mg/m² is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.

The role of anti-epidermal growth factor receptor monoclonal antibody monotherapy in the treatment of metastatic colorectal cancer

Despite the introduction of newer chemotherapeutic agents such as irinotecan, capecitabine and oxaliplatin, patients with metastatic colorectal cancer (mCRC) still have a poor prognosis. More effective and better-tolerated treatment strategies are needed to improve patient outcomes, particularly in subsequent lines of treatment following chemotherapy failure. The favourable efficacy and acceptable safety profiles of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have led to the approval of panitumumab and cetuximab monotherapy for the treatment of patients with EGFR-expressing mCRC whose tumours express non-mutated (wildtype) KRAS, after failure of standard chemotherapy. Cetuximab is also approved in combination with chemotherapy for the treatment of mCRC in this patient population. In phase III monotherapy studies, panitumumab and cetuximab demonstrated significant improvements in progression-free survival when administered with best supportive care (BSC) vs. BSC alone in chemotherapy-refractory mCRC patients. A planned retrospective analysis of the panitumumab monotherapy trial was the first large-scale clinical demonstration that efficacy was confined to patients with tumours expressing wild-type KRAS. It is now recognised that anti-EGFR mAb therapy should only be used in patients whose tumours express wild-type KRAS. While generally well tolerated, anti-EGFR mAb monotherapy is associated with skin toxicity, and severity of the skin rash has been proposed as an early marker of response to treatment. BRAF, PTEN, and PI3K are also emerging as future potential predictive markers of response; however, further clinical studies are warranted to define the role of these biomarkers.

Improvements in physical wellbeing over the first two years on antiretroviral therapy in western Kenya

Improvements in physical wellbeing during the first six months on antiretroviral therapy (ART) are well known, but little is known regarding long-term follow-up. We conducted a prospective cohort study among 222 HIV-positive adult tea plantation workers in western Kenya to assess wellbeing over their first two years on ART. Study subjects completed a standardized questionnaire during repeat ART clinic visits. A 30-day recall period was used to elicit the number of days when subjects experienced poor health and the number of days that pain made it difficult to complete usual activities at home and work. A seven-day recall period was used to assess the severity of bodily pain, nausea, fatigue, and rash. Prevalence of most symptoms declined over time. A median of seven days poor health during the first month on ART declined to three days in the 24th month (p=0.043). For pain making usual activities difficult, a median of seven days during the first month on ART fell to zero by 12 months (p≤0.0001) but increased to three days by two years. Any bodily pain (range 59–83%) and fatigue (range 51–84%) over the past seven days were common through two years. However, pain and fatigue often over the past seven days declined over two years (from 24–10% (p=0.067) and 41–15% (p=0.002)). Skin rash was rare at all times, though higher at two years (8.6%) than any other time. Initial improvements in physical wellbeing were sustained over two years, however, increased pain and skin rash at year two may indicate problems as treatment programs mature. These improvements in physical wellbeing will be important in sustaining the long-term success of HIV treatment programs.

A case of rheumatoid arthritis presenting with postherpetic neuralgia and abdominal-wall pseudohernia

Postherpetic neuralgia is a common complication, while the postherpetic abdominal-wall pseudohernia (AWP) is a quite rare complication of herpes zoster (HZ). We report a patient >45years of age with a history of rheumatoid arthritis (RA) who presented with two chronic HZ complications. A 75-year-old woman was admitted with neuralgia following cutaneous herpes zoster 6weeks before. She was on long-term glucocorticoid, antimalarial and non-steroidal anti-inflammatory treatment. Confluent ulcers began to fill with granulation tissue, crusts, scars and skin discoloration in the area of the left T12-L2 dermatomes and reducible, painless swelling of the left flank, 20×20cm, without palpable defect in abdominal-wall. There were typical joint deformity and positive rheumatoid factor. On neurological examination superficial abdominal reflexes were diminished in the left side, with hypesthesia of the overlying skin. Needle electromyography revealed denervational changes limited to the left-side muscles (on affected dermatomes T12-L2). Thoracoabdominal CT did not reveal the presence of existing hernia. There was an abdominal distension, the left abdominal-wall was thinner than the right side. The patient was treated with an oral preparation containing benfotiamine and vitamins B6 and B12, carbamazepine, amitriptyline, gabapentin, and local lidocaine. Skin rash left with scarring and pigmentary changes and the abdominal-wall swelling resolved within 8months, however, the pain still persisted. To our best knowledge, this is the first observation of RA-associated postherpetic AWP. This rare motor complication appears to be self-limited with a good prognosis for recovery, while postherpetic neuralgia may require a combination of treatments for adequate pain relief. Older age, female sex, greater rash and acute pain severity are considered as risk factors associated with severe postherpetic neuralgia. In addition, patients with RA, mainly those treated with oral corticosteroids, are also at increased risk of HZ complications.

PARASITES OF THE BRUSH-TAILED ROCK-WALLABY (PETROGALE PENICILLATA)

The brush-tailed rock-wallaby (Petrogale penicillata) is listed as vulnerable on the International Union for Conservation of Nature (IUCN) Red List of Threatened Species. Parasitic diseases have been proposed as possible contributing factors to the decline of the species, but very little is known about the effects of parasites on this host. This study determined the antibody prevalence of the protist Toxoplasma gondii in a wild brush-tailed rock-wallaby population from three neighboring colonies in southeast Queensland, Australia. Fecal egg and oocyst count, tick count, severity of skin rash, and presence of lice and microfilariae were also monitored during four or five trapping periods over 1 yr. Antibodies against T. gondii were detected in 5% of animals (3/64). Fecal egg and oocyst counts were highly variable, but fecal egg counts were lower in subadult animals relative to adults. Neither fecal egg count nor oocyst count was associated with variation in blood variables or condition index, but a negative association between fecal egg count and oocyst count was observed. Microfilariae (Breinlia spelaea), lice (Heterodoxus octoseriatus), and skin lesions were seen more frequently during the November trapping period. A mite, Thadeua sp., was more likely to be detected in these skin lesions than in skin of unaffected wallabies. Tick (Ixodes holocyclus and Haemaphysalis bancrofti) counts also varied between trapping periods and were lowest in the April/May trapping period. This study provides the most detailed account to date of parasite burdens in a vulnerable macropodid, but no clear evidence emerged linking parasites to adverse impact on the host.

A 9 year follow up of post herpetic neuralgia and predisposing factors in elderly patients following herpes zoster

To characterise predisposition to post herpetic neuralgia following herpes zoster. Late follow up of patients originally admitted with acute zoster to a double blind randomised placebo controlled study of oral acyclovir over 60 years of age. Two UK cities of 1.5 million population. 158 of the 298 patients from the original study were available for evaluation at a mean follow up of 9 years. Thirty four (21%) described experiencing pain from the zoster within the previous 12 months. Pain at follow up was associated with characteristics at the time of acute zoster of: moderate or severe acute pain (p = 0.006), prodromal pain >72 h before rash (p = 0.006), severity of rash (p = 0.033) and female gender (p = 0.046). There was no association between pain at 9 year follow up and use of placebo or aciclovir nor with the presence or absence of pain at the point of discharge from the original study. Further analysis of 17 of the 34 patients with long term pain who have full data available, the median pain score was 4 out of 10 and more than 50% described persistent pain and interference with sleep. Long term pain in the elderly following zoster is associated with identifiable characteristics during the acute illness.

Evidence-Based Treatment Options for the Management of Skin Toxicities Associated with Epidermal Growth Factor Receptor Inhibitors

To compile evidence from randomized controlled trials, case series, and case reports to identify the effectiveness of various therapeutic agents for the treatment and prevention of dermatologic effects secondary to epidermal growth factor receptor inhibitor (EGFRI) administration. Literature was accessed through PubMed (2002-May 2009) and Scopus (2002-March 2009), using the terms epidermal growth factor receptor inhibitor, cetuximab, erlotinib, gefitinib, panitumumab, management, skin toxicity, and cutaneous effects. In addition, reference citations from publications identified were reviewed. An evaluation of published clinical trials, case series, case reports, and clinical management guidelines that studied the treatment options for EGFRI-induced skin toxicities was performed. Studies that reported dosing regimens and treatment outcomes were included in this review. Management of EGFRI-induced skin toxicities has been documented in 2 randomized controlled trials, 3 case series, and 10 case reports in a total of 156 patients. There is strong evidence for the use of topical antibiotics to manage EGFRI skin toxicities. Controversy exists regarding the use of corticosteroids and retinoids for the management of EGFRI-induced rash. Several variables are noted among the number of case series and case reports, such as follow-up duration of the intervention, making any comparisons difficult. Overall, antibiotics are the most common treatment option and have the potential to reduce the severity of skin rash. Well-designed clinical studies with proper recording of relevant data on the management of EGFRI-induced dermatologic effects are needed to properly evaluate the use of various therapeutic agents. Apart from randomized controlled trials, comprehensive case reports are also important for clinical evaluation on a case-by-case basis.

A prospective randomized trial of topical pimecrolimus for cetuximab-associated acne-like eruption

Clinical trials addressing the acneiform rash associated with epidermal growth factor receptor inhibitors are lacking. We evaluated the ability of topical pimecrolimus to reduce the severity of cetuximab-related facial rash. In all, 24 patients with metastatic colorectal cancer with cetuximab facial rash received twice daily pimecrolimus application for 5 weeks to half of the face. At baseline, week 2, and week 5, a dermatologist performed facial lesion counts, patients reported perceived severity of rash-related symptoms, and standardized facial photographs were obtained for blinded evaluation of global rash severity. Treatment sides had greater decrease in lesion counts than observation sides of face at weeks 2 (P < .001) and 5 (P = .02). However, there were no significant differences in patients' assessment of symptoms and in review of facial photographs for rash severity between treatment and observation sides. This study was not placebo controlled. Pimecrolimus application did not translate into clinically meaningful benefit for patients with cetuximab-related facial rash.

Clinical efficacy of erlotinib in patients previously treated for advanced non‐small cell lung cancer

Erlotinib is one of the standard second/third line treatments for patients with advanced non-small cell lung cancer (NSCLC). This study investigated the efficacy of erlotinib in a Chinese population with advanced NSCLC and compared the predictive value of serum vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-alpha for the efficacy of erlotinib. Patients with advanced, previously treated NSCLC received 150 mg of erlotinib once daily orally until disease progression or intolerable toxicity. Serum levels of VEGF and TGF-alpha were measured by ELISA at baseline and 1 month after treatment commenced. There were 112 patients enrolled during the period October 2005 to February 2008 and followed until July 2008. Serum samples were available in 50 patients. Tumour response to erlotinib was partial in 35.7% of patients and 41.1% of patients had stable disease. The severity of skin rash (P < 0.001) had a significant positive correlation with the response to erlotinib. Median progression-free survival (PFS) and overall survival were 6.3 months and 12.5 months, respectively. After erlotinib treatment, serum VEGF levels did not change significantly, while serum TGF-alpha levels increased in patients who had partial response (P = 0.075) or stable disease (P = 0.055), but not in patients with progressive disease (P = 0.155). In patients with measurable serum TGF-alpha levels at baseline the PFS and median survival were 5 and 9.9 months respectively, and in patients with no measurable TGF-alpha at baseline the PFS and median survival were 11 and 21 months, respectively. Overall survival was significantly longer in patients with negative baseline serum TGF-alpha (P = 0.002). Oral erlotinib was effective as a second/third line treatment for patients with advanced NSCLC. Baseline serum TGF-alpha levels may be a predictor for the efficacy of erlotinib treatment.

Association of pharmacokinetics and germ-line mutations in EGFR and ABC transporters with erlotinib toxicity in patients with non-small cell lung cancer (NSCLC)

2506 Background: Erlotinib demonstrates substantial inter-individual differences in response and the development of skin rash (grade≥2) was correlated with efficacy. Erlotinib interacts with its target EGFR and the efflux transporter ABCB1 and ABCG2. EGFR CA repeat is associated with incidence of skin rash. A 421C&gt;A SNP in ABCG2 and 1236C&gt;T, 2677 G&gt;(T/A), and 3435C&gt;T SNPs in ABCB1 are associated with reduced protein expression. The aim of this study was to evaluate the effects of these variants and pharmacokinetics of erlotinib on toxicity grade in Japanese patients treating single agent erlotinib. Methods: Twenty-two patients with NSCLC received erlotinib orally at 150 mg/day and plasma levels of erlotinib were measured on days 1(D1), 8(D8), and stable phase (&gt;day 14) by high-performance liquid chromatography. DNA from plasma was screened for SNPs in the EGFR, ABCB1, and ABCG2 genes using direct nucleotide sequencing or TaqMan assay. Eligibility criteria included: performance status (PS) &lt; 3, age &lt; 75, stage IIIB-IV, and written informed consent. Results: The mean Cmax (±SD) of D1 and D8 were 1.8 ± 1.0 and 3.1 ± 1.4 μg/ml, respectively. Trough concentration (Cmin) at D1 and steady state were 0.9 and 1.7 μg/ml, respectively. Grade 1–2 skin rash or diarrhea occurred in 95% of patients. One patient (Cmax at D1, 3.0 μg/ml) developed interstitial lung disease after continuous treatment with erlotinib for 3 days. The area under curves and Cmax on D1 were correlated with the severity of skin rash (p=0.05 and 0.01), however, Cmin were not correlated. Patients with homozygous variant and heterozygous for ABCB1 1236C&gt;T, 2677 G&gt;(T/A), and 3435C&gt;T genotype as compared to patients carrying the wild-type were associated with higher Cmin at steady state (2.4 vs 1.2 μg/ml, p=0.01). EGFR CA repeat and AGCG2 421C&gt;A genotype were not associated with any pharmacokinetic parameters. All Patients (n=4) with homozygous variant for ABCB1 1236TT- 2677TT/TA/AA-3435TT developed grade≥2 skin rash or diarrhea. Conclusions: The present study suggests that ABCB1 gene polymorphism is associated with the variable toxicity and pharmacokinetics to erlotinib treatment. No significant financial relationships to disclose.