Intravenous and topical intranasal bevacizumab (Avastin) in hereditary hemorrhagic telangiectasia.

Current treatment of severe epistaxis in patients with hereditary hemorrhagic telangiectasia is not durable in reducing the frequency and severity of bleeds. Recent reports have demonstrated marked improvement of epistaxis with administration of either intravenous or topical bevacizumab. We present the long-term outcome of a patient who received repeated treatments of intravenous bevacizumab followed by maintenance intranasal bevacizumab. We demonstrate durable control of epistaxis with intranasal bevacizumab. This allows delivery of bevacizumab effectively, reduces cost, and obviates the risk of systemic adverse effects related to bevacizumab.

EphA2 mutation in lung squamous cell carcinoma promotes increased cell survival, cell invasion, focal adhesions, and mammalian target of rapamycin activation.

Non-small cell lung cancer (NSCLC) has a poor prognosis and improved therapies are needed. Expression of EphA2 is increased in NSCLC metastases. In this study, we investigated EphA2 mutations in NSCLC and examined molecular pathways involved in NSCLC. Tumor and cell line DNA was sequenced. One EphA2 mutation was modeled by expression in BEAS2B cells, and functional and biochemical studies were conducted. A G391R mutation was detected in H2170 and 2/28 squamous cell carcinoma patient samples. EphA2 G391R caused constitutive activation of EphA2 with increased phosphorylation of Src, cortactin, and p130(Cas). Wild-type (WT) and G391R cells had 20 and 40% increased invasiveness; this was attenuated with knockdown of Src, cortactin, or p130(Cas). WT and G391R cells demonstrated a 70% increase in focal adhesion area. Mammalian target of rapamycin (mTOR) phosphorylation was increased in G391R cells with increased survival (55%) compared with WT (30%) and had increased sensitivity to rapamycin. A recurrent EphA2 mutation is present in lung squamous cell carcinoma and increases tumor invasion and survival through activation of focal adhesions and actin cytoskeletal regulatory proteins as well as mTOR. Further study of EphA2 as a therapeutic target is warranted.

Phase II study of sunitinib malate in head and neck squamous cell carcinoma.

BACKGROUND: Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor of RET, VEGFR, PDGFR, and c-KIT. We conducted a phase II trial to evaluate the tolerability and efficacy of sunitinib in metastatic and/or recurrent SCCHN patients. METHODS: Patients who had received no more than two prior chemotherapy regimens were eligible and, depending on ECOG performance status (PS), were entered into either Cohort A (PS 0-1) or Cohort B (PS 2). Sunitinib was administered in 6-week cycles at 50 mg daily for 4 weeks followed by 2 weeks off. Primary endpoint for Cohort A was objective tumor response. A Simon two-stage design required twelve patients to be enrolled in the first stage and if 1 or fewer responses were observed, further study of this cohort would be terminated due to lack of treatment efficacy. Primary endpoint of Cohort B was to determine the feasibility of sunitinib in patients with ECOG performance status 2. RESULTS: Twenty-two patients were accrued (Cohort A - 15 patients, Cohort B - 7 patients). Median age in cohort A and B was 56 and 61 years, respectively. Grade 3 hematologic toxicities encountered were lymphopenia (18%), neutropenia (14%) and thrombocytopenia (5%). There was only one incidence of grade 4 hematologic toxicity which was thrombocytopenia. Fatigue and anorexia were the most common non-hematologic toxicities. Grade 3 fatigue occurred in 23% of patients. The only grade 4 non-hematologic toxicity was one incidence of gastrointestinal hemorrhage. Non-fatal hemorrhagic complications occurred in 8 patients: epistaxis (3 patients), pulmonary hemorrhage (2 patients), gastrointestinal hemorrhage (2 patients) and tumor hemorrhage (1 patient). Four patients were not evaluable for tumor response (Cohort A - 3patients, Cohort B - 1 pt). One partial response was observed in the entire study. Dose reduction was required in 5 patients (Cohort A - 3 patients for grd 3 fatigue, grd 3 mucositis and recurrent grd 3 neutropenia; Cohort B - 2 patients for grd 3 fatigue and grd 3 nausea). Median time to progression for cohort A and B were 8.4 and 10.5 weeks, respectively. Median overall survival for cohort A and B was 21 and 19 weeks, respectively. CONCLUSIONS: Sunitinib had low single agent activity in SCCHN necessitating early closure of cohort A at interim analysis. Sunitinib was well tolerated in PS 2 patients. Further evaluation of single agent sunitinib in head and neck is not supported by the results of this trial.

Key signaling pathways and targets in lung cancer therapy.

Despite the use of chemotherapy, radiation therapy, and surgery, the overall outcome for lung cancer continues to be disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics need to be developed. The molecular mechanisms of carcinogenesis in lung cancer are complex and involve multiple oncogenes, tumor suppressor genes, receptor tyrosine kinases, cytoplasmic enzymes, and tumor interstitial elements, among other cellular proteins. In this review, the authors discuss key signaling pathways and molecular targets in the treatment of lung cancer. Through understanding molecular targets and the utilization of specific inhibitors, hopefully, a dramatic impact will be made in the biology and therapy of lung cancer.

Epidermal growth factor receptor directed therapy in head and neck cancer.

Squamous cell head and neck cancer (SCCHN) is the seventh most common cause of cancer death worldwide and its incidence is rising rapidly in developing countries. Despite recent advances in managing locally advanced SCCHN, patients with recurrent and metastatic SCCHN have a poor prognosis and little progress has been made its management. Epidermal growth factor receptor (EGFR) has been implicated in the pathogenesis of SCCHN and is a marker of poor prognosis. Recent advances in targeted therapeutics against EGFR are being investigated clinically. In this article, we review the different modalities utilized to inhibit EGFR signaling in SCCHN, including small molecule tyrosine kinase inhibitors, monoclonal antibodies, anti-sense therapy and immunotoxin conjugates. Monotherapy with EGFR inhibitors has demonstrated response rates between 5 and 15% in advanced SCCHN. However, combining EGFR inhibitors with cytotoxic chemotherapy or radiation therapy appears to augment response rates and survival. With the foundation for the use of EGFR inhibitors laid in these studies, future studies will need to optimize the delivery of these agents in combination with conventional therapies.

Adjuvant and neoadjuvant therapy for early-stage non-small-cell lung cancer.

Early-stage non-small-cell lung cancer (NSCLC) carries with it an unfavorable prognosis even in patients who have undergone surgical intervention. Efforts to improve the outcome of patients with early-stage NSCLC have focused on adjuvant or neoadjuvant chemotherapy. The role of adjuvant therapy in NSCLC has been clarified by the recent publication of several large randomized trials. The International Adjuvant Lung Trial was the first prospective trial to report that adjuvant chemotherapy following complete surgical resection of NSCLC improved absolute overall survival by approximately 5% at 5 years. This result has subsequently been confirmed by several other trials. As a result, adjuvant chemotherapy following complete resection of stage IB-III NSCLC can now be considered the standard of care. Neoadjuvant chemotherapy, which has long been investigated for stage III NSCLC, was also recently explored in stage I/II NSCLC. Although neoadjuvant chemotherapy seems promising, more work is needed to comprehensively evaluate and optimize this approach. The current evidence for adjuvant and neoadjuvant therapy in early-stage NSCLC is reviewed in this article.

Long-term outcome of a phase II study of docetaxel-based multimodality chemoradiotherapy for locally advanced carcinoma of the esophagus or gastroesophageal junction.

We performed a phase II trial to evaluate a docetaxel-based regimen in locoregionally advanced esophageal cancer. Untreated stage II-IVa esophageal cancer patients with performance status 0-2 were included. Tumor resectability was determined prior to initiation of study. Induction docetaxel (75 mg/m(2)) and cisplatin (75 mg/m(2)) day 1 with prophylactic filgrastim was delivered every 21 days for 3 cycles. Subsequent concomitant chemoradiotherapy (CRT) utilized weekly docetaxel (20 mg/m(2)) and concurrent radiotherapy (2 Gy/day) in resectable/resected patients (50 Gy) and in unresectable patients (66 Gy). A total of 78 patients (15 squamous cell carcinoma, 60 adenocarcinoma, 3 mixed/undifferentiated; 68 men, 10 women; median age 61 years) were accrued. The regimen was administered to 59 (76%) potentially resectable patients and 13 (17%) unresectable patients; 6 patients (8%) received the regimen post-operatively. Response rate in 66 evaluable patients following induction chemotherapy was 30%. Sixty-nine patients underwent CRT. Ten patients had disease progression during CRT. Forty-five out of 59 potentially resectable patients underwent esophagectomy after CRT, and 42 patients had complete tumor resection with negative margins. Eighteen out of 59 patients who were potentially resectable patients had pathologic complete response (pCR-31%). Grade 3/4 toxicity during induction chemotherapy included leucopenia, neutropenia, vomiting, and neuropathy. Esophagitis was the predominant toxicity during CRT. Median overall survival was 11.4 months for unresectable patients, 14.3 months for resectable patients and 10.4 months for patients who received the regimen post-operatively (log-rank P = 0.2492). Docetaxel-based CRT regimen is active and tolerable in esophageal cancer. The observed pCR in the potentially resectable group indicates good local control.

Complete and durable response of choroid metastasis from non-small cell lung cancer with systemic bevacizumab and chemotherapy.

Ocular metastasis from lung cancer is uncommon. We report a patient with metastatic non-small cell lung cancer who was found to have a metastatic lesion in the choroid at the time of presentation. The patient was treated with carboplatin, gemcitabine, and bevacizumab. After three cycles of chemotherapy, radiologic imaging and ophthalmologic examination demonstrated complete resolution of the choroid lesion. This case report demonstrates the durable response of choroidal metastasis from non-small cell lung cancer to systemic bevacizumab and chemotherapy.

Phase I study of induction chemotherapy and concomitant chemoradiotherapy with irinotecan, carboplatin, and paclitaxel for stage III non-small cell lung cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer. METHODS: Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m2, carboplatin AUC 5, and paclitaxel 175 mg/m2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen. RESULTS: Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to

Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer.

INTRODUCTION: This Phase I trial aimed to determine the maximum-tolerated-dose of erlotinib administered with two standard chemoradiotherapy regimens for non-small cell lung cancer. METHODS: Unresectable stage III non-small cell lung cancer patients were enrolled in this 2-arm dose-escalation study. Erlotinib, given only during chemoradiotherapy, was escalated from 50 to 150 mg/d in 3 to 6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m IV days 1, 8, 29, 36), etoposide (50 mg/m IV days 1-5, 29-33) and chest radiotherapy (66 Gy, 2 Gy/d) followed by docetaxel (75 mg/m IV Q21 d) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m) for two 21-d cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/wk) and paclitaxel (50 mg/m/wk). RESULTS: Seventeen patients were treated in each arm. PATIENT CHARACTERISTICS: performance status 0 to 24 patients, 1 to 10 patients, median age 63 years, adenocarcinoma 21% and female 14 patients. Dose-escalation of erlotinib to 150 mg/d was possible on both chemoradiotherapy regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 chemoradiotherapy toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); and arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on Arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash were 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference. CONCLUSION: Addition of standard-dose erlotinib to chemoradiotherapy is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach.

Forthcoming receptor tyrosine kinase inhibitors.

Receptor tyrosine kinases play a significant role in carcinogenesis and have been successfully targeted with monoclonal antibodies and small-molecule inhibitors. There have been recent developments in the understanding of receptor tyrosine kinase signal transduction which have enabled better drug development. The use of receptor tyrosine kinase inhibitors in clinical practice has expanded the knowledge on cancer biology, in particular the understanding of resistant mutations and strategies to overcome such resistance. This has driven drug development from single kinase inhibitors to multi-kinase inhibitors and high-affinity kinase inhibitors. Finally, as the use of receptor tyrosine kinase inhibitors grows in clinical practice, more is learned about appropriate patient selection for such therapies. This is an exciting time in cancer therapeutics, highlighted by the advent of effective targeted therapy with receptor tyrosine kinase inhibitors.

Gefitinib response of erlotinib-refractory lung cancer involving meninges--role of EGFR mutation.

BACKGROUND: A 70-year-old Japanese-American woman who had never smoked was diagnosed with stage IV non-small-cell lung cancer with rib metastases. She had previously been well and she had no family history of malignancy. While receiving treatment with erlotinib, an epidermal growth factor receptor small-molecule inhibitor, she progressed and developed new brain metastases. She failed further chemotherapy treatments and subsequently developed extensive symptomatic leptomeningeal carcinomatosis associated with diplopia, hemiparesis, weight loss, and incontinence. INVESTIGATIONS: Chest X-ray, head and chest CT scan, R2 lymph-node biopsy, histopathology, immunohistochemistry, MRI of head and spine, lumbar puncture, laser microdissection and EGFR genomic DNA sequencing of the R2 lymph node and cerebrospinal fluid tumor cells. DIAGNOSIS: Erlotinib-refractory stage IV lung adenocarcinoma and end-stage symptomatic leptomeningeal metastases with a novel double L858R + E884K somatic mutation of the EGFR. MANAGEMENT: Carboplatin, paclitaxel and erlotinib, whole-brain radiotherapy, temozolomide with and without irinotecan, and gefitinib.

Phase II trial of temozolomide and irinotecan as second-line treatment for advanced non-small cell lung cancer.

BACKGROUND: This study was performed to evaluate the tolerability and efficacy of temozolomide and irinotecan as a second-line regimen in recurrent/metastatic non-small cell lung cancer (NSCLC). METHODS: Patients with recurrent/metastatic NSCLC, including those with treated brain metastases, following one prior platinum-based regimen received temozolomide 75 mg/m daily on days 1 through 15 and irinotecan 100 mg/m on days 8 and 15 every 21 days. RESULTS: The authors treated 46 patients, of whom more that 90% had a performance status of 0 or 1. Four patients (8.7%) attained partial response and 17 (37.0%) had disease stabilization as their best response. The median time to progression was 1.8 months, median overall survival was 9.8 months, and 1-year overall survival was 34%. Grade 1/2 fatigue (63%), anemia (61%), nausea (52%), and diarrhea (44%) were the most common toxicities. Grade 3/4 leukopenia and diarrhea were each observed in 9% of patients. One unexpected death occurred, possibly related to the regimen. CONCLUSION: Second-line treatment with temozolomide and irinotecan showed tolerable toxicities. The response rates, median survival times, and 1-year survival rates were comparable to other active NSCLC agents.

Therapeutic targeting of receptor tyrosine kinases in lung cancer.

Lung cancer is a difficult illness with a poor overall survival. Even though combination strategies with chemotherapy, radiation therapy and surgery have all been utilised, the overall outcome for this disease continues to be relatively disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics will have to be developed. Through basic biological studies, a number of receptor tyrosine kinases have been implicated in the pathogenesis and progression of lung cancer. In this review, the authors summarise the mechanisms of several major receptor tyrosine kinases in lung cancer, especially epidermal growth factor receptor, Her2/neu, MET, vascular endothelial growth factor and KIT. The biology associated with these receptors is described, and the various novel therapeutic inhibitory strategies that are ongoing in preclinical and clinical studies for lung cancer are detailed. Through understanding of receptor tyrosine kinases and the utilisation of specific inhibitors, it is hopeful that a dramatic impact will be made on the biology and therapy for lung cancer.

Small cell carcinoma of the urinary bladder. The Mayo Clinic experience.

BACKGROUND: Small cell carcinoma (SCC) of the urinary bladder accounts for 0.35-0.70% of all bladder tumors. There is no standard approach to the management of SCC of the urinary bladder. METHODS: The authors performed a retrospective study at Mayo Clinic (Rochester, MN) to characterize the clinical and pathologic features of patients with SCC of the urinary bladder diagnosed between 1975 and 2003 with emphasis on management. RESULTS: Forty-four patients were identified who had primary bladder SCC, 61.4% of whom had pure SCC. The male:female ratio was 3:1, the mean age was 66.9 years, and the mean follow-up was 3.2 years. Twelve patients (27.3%) had Stage II disease, 13 patients (29.6%) had Stage III disease, and 19 patients (43.2%) had Stage IV disease. The overall median survival was 1.7 years. The 5-year survival rates for patients with Stage II, III, and IV disease were 63.6%, 15.4%, and 10.5%, respectively. Six of eight patients with Stage II bladder SCC achieved a cure with radical cystectomy. Five patients with Stage IV disease had obvious metastases and received chemotherapy. Fourteen patients underwent radical cystectomy and were diagnosed later with locally advanced disease (T4b) or lymph node metastasis (N1-N3; Stage IV disease). Only 2 of 19 patients with Stage IV disease who received adjuvant chemotherapy were alive at 5 years. CONCLUSIONS: Patients with bladder SCC should undergo radical cystectomy except when metastatic disease is present (M1), in which case, systemic chemotherapy is indicated. Adjuvant treatment is not indicated for patients with Stage II disease after radical cystectomy but should be considered for patients with Stage III and IV disease. Chemotherapy should be a platinum-based regimen.