Response and Resistance in a Non–Small-Cell Lung Cancer Patient With an Epidermal Growth Factor Receptor Mutation and Leptomeningeal Metastases Treated With High-Dose Gefitinib

Abstract

HIV and human papillomavirus (HPV) coinfected patients are at high risk of developing precancerous anal lesions (anal intraepithelial neoplasia) and anal malignancies. 1 The natural history (that is, progression and persistence) of HPV-associated lesions is accelerated by HIV-related immunosuppression, which may result in the reactivation of previously acquired HPV infection and loss of control of HPV viral replication. 2 The longer life expectancy of these coinfected patients in the era of HAART provides an opportunity for invasive anal carcinoma to develop from its dysplastic precursor. The prognosis of anal squamous cell carcinoma is poor in HIV-positive patients, who often present with advanced tumors. 3 The appropriate treatment of patients with advanced anal cancer and HIV infection is uncertain. 4 Concomitant radiation therapy and chemotherapy (fluorouracil and mitomycin-C) is the current standard of care for HIV-negative patients with invasive anal carcinoma, and that approach has been investigated and applied successfully in HIV-positive patients with similar anal cancers, particularly those with CD4ϩ T-lymphocyte counts greater than 200 cells/L. 5,6 HIV-positive patients with anal cancer treated with HAART tend to fare better than those patients who are not receiving HAART. 7 It is prudent to point out that our patient never had an anal Papanicolaou (Pap) test (Fig 3, high-grade dysplastic squamous cells; ThinPrep, Cytyc Corporation, Marlborough, MA). HIV-associated anal carcinoma appears to mirror cervical carcinoma in unscreened women, presenting late in the course of the disease and having a protracted, ultimately fatal, course. 8 Screening of HIV-positive patients for anorectal dysplasia and/or malignancy by means of an anal Pap test could save lives. 9

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

“…This drug level would be grossly insufficient to inhibit the phosphorylation and activation of H870R+L858R double mutant as shown in this study. Although some clinical reports have shown that small molecule EGFR tyrosine kinase inhibitor can pass through the blood-brain barrier and cause shrinkage of brain metastasis (23)(24)(25)(26), other reports have suggested that tyrosine kinase inhibitor penetration into the brain could be incomplete (5,22), and brain metastasis was strongly associated with the emergence of acquired resistance in NSCLC patients treated with gefitinib (27). As shown in Fig.…”

“…According to our results, this drug level could be marginally sufficient for controlling tumor cells in the lung. However, the gefitinib drug concentration attainable in the cerebrospinal fluid could be as low as 18 nmol/L for an oral dose of 500 mg/d and 42 nmol/L for 1,000 mg/d (22). This drug level would be grossly insufficient to inhibit the phosphorylation and activation of H870R+L858R double mutant as shown in this study.…”

Gefitinib Alone or with Concomitant Whole Brain Radiotherapy for Patients with Brain Metastasis from Non-small-cell Lung Cancer: A Retrospective Study

“…With the concept of the disruption of blood brain barrier (BBB) by BM and radiation therapy, gefitinib with small molecular weight may have the ability to penetrate the BBB (Fidler et al, 2002;Van et al, 2002;Jackman et al, 2006). Furthermore, gefitinib might enhance radiosensitivity (Bianco et al, 2002;Huang et al, 2002;Bonner et al, 2006;Shimato et al, 2006;Das et al, 2007;Park et al, 2010).…”

Erlotinib May be More Effective for Central Nervous Metastasis of Lung Adenocarcinoma Than Gefitinib Because of the Difference in the Clinical Regimes

“…The symptoms had improved and no cancer cells were detected. Jackman DM et al [6] found the 50% inhibitory concentration (IC 50 ) of gefi tinib in a cancer cell line obtained from the pleural effusion of a patient with EGFR gene exon 19 deletions who developed brain metastasis during oral gefi tinib (250 mg) treatment to be 10-50 nmol/L. Then they compared the gefi tinib concentration in the CSF with the gefi tinib dosage.…”