Biomedical subjects

Corey J Langer

Publications and source records attributed to Corey J Langer.

At least 37 records · Page 2Linked to original sources

PubMed2004

Outcome of elderly patients with recurrent or metastatic head and neck cancer treated with cisplatin-based chemotherapy.

PURPOSE: To evaluate the outcome of elderly patients with head and neck cancer undergoing palliative chemotherapy. PATIENTS AND METHODS: We analyzed combined data from two mature phase III randomized trials conducted by the Eastern Cooperative Oncology Group (ECOG; trial E1393, which compared cisplatin plus paclitaxel at two dose levels, and trial E1395, which compared cisplatin plus fluorouracil to cisplatin plus paclitaxel) to evaluate the toxicity, objective response rates, and survival of patients 70 years or older versus their younger counterparts. All patients had previously untreated recurrent or metastatic squamous cell carcinoma of the head and neck and ECOG performance status 0 or 1. RESULTS: Fifty-three elderly patients were enrolled from a total of 399 eligible participants (13%). Elderly patients had similar objective response rates (28% v 33%) and median time to progression (5.25 v 4.8 months) compared with younger patients. The median survival was 5.3 v 8 months (Wilcoxon P =.06; log-rank P =.17) and the 1-year survival 26% v 33% for elderly and younger patients, respectively. Elderly patients had a significantly higher incidence of severe nephrotoxicity, diarrhea, and thrombocytopenia. A higher rate of toxic deaths was noted in the elderly but did not reach statistical significance (13% v 8%; P =.29). CONCLUSION: Elderly patients were underrepresented in these studies. Fit elderly patients with recurrent or metastatic head and neck cancer sustained increased toxicities with cisplatin-based doublets but had comparable survival outcomes compared with younger patients. Strategies to ameliorate toxicities should be pursued in the elderly.

Adult↗

PubMed2004

The role of HER2/neu expression and trastuzumab in non-small cell lung cancer.

Research over the past decade has led to an increased understanding of the pathophysiology of lung cancer. The HER2/neu receptor is a member of the ErbB family of signaling-transduction receptors and appears to play a major role in the development of lung cancer as well as many other solid tumors. HER2/neu is overexpressed in 16% to 57% of patients with non-small cell lung cancer (NSCLC) and studies have shown that HER2/neu overexpression imparts a poor prognosis in both resected and advanced NSCLC, as it does in breast cancer. Trastuzumab, a humanized monoclonal antibody that recognizes the HER2/neu protein receptor, has been approved by the US Food and Drug Administration for patients with HER2/neu-positive metastatic breast cancer. In NSCLC preclinical studies, marked synergistic growth inhibition occurred when standard cytotoxic chemotherapy was combined with trastuzumab in HER2/neu-expressing cell lines. In the clinical setting, trastuzumab has proven safe and feasible in combination with cytotoxic chemotherapy in both single-institution and multi-institutional cooperative group studies. Unlike the experience in advanced breast cancer, cardiac toxicity is a marginal concern in this population. However, to date, clinical studies with trastuzumab in patients with NSCLC have not shown a demonstrable advantage for the majority of patients.

Antibodies, Monoclonal↗

PubMed2004

Phase II evaluation of 96-hour paclitaxel infusion in advanced (recurrent or metastatic) squamous cell carcinoma of the head and neck (E3395): a trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Paclitaxel (24-hour infusion) has yielded activity in advanced squamous cell carcinoma of the head and neck (SCCHN). Protracted exposure to paclitaxel may overcome resistance observed by using shorter infusions. Therefore we sought to evaluate paclitaxel by 96-hour infusion in both treatment-naïve and previously treated patients with SCCHN. MATERIALS AND METHODS: Eligibility stipulated bi-dimensionally measurable, biopsy-documented, incurable SCCHN, Eastern Cooperative Oncology Group performance status (PS) 0-1, and adequate physiological indices. Patients were divided into three cohorts: 1) chemotherapy-naïve; 2) chemotherapy-exposed, paclitaxel-naïve; and 3) chemotherapy and paclitaxel exposed. Paclitaxel was dosed at 140 mg/m2 (96-hour infusion) every 3 weeks in treatment-naïve patients and at 120 mg/m2 (96 hours) every 3 weeks in previously treated patients. RESULTS: Fifty patients were accrued between February 1997 and July 2000. The study was terminated because of low response rate. Eighty percent of patients were male, 75% PS 1. Nearly half the patients had oropharyngeal or hypopharyngeal primary sites. There was one treatment-related death due to neutropenic fever/pneumonia. Grade 4 toxicities included granulocytopenia in eight patients (20%), thrombocytopenia, and stomatitis in one patient each. Grade 3 or greater anemia occurred in 10 patients. There was no grade 2 or 3 peripheral sensory neuropathy. In 15 chemotherapy-naïve patients, two responses (13%) were observed. There were no responses in treatment-exposed patients. The overall median survival was 5.5 months, and 1-year survival rate 10%. Treatment-naïve patients had a median survival of 8.2 months and 1-year survival rate of 20%. CONCLUSIONS: Paclitaxel by 96-hour infusion at a dose of 120-140 mg/m2/96 hours is only marginally active in the treatment of SCCHN. This dose and schedule cannot be recommended for further evaluation.

Adult↗

PubMed2004

CT-2103: emerging utility and therapy for solid tumours.

CT-2103 (XYOTAX, Cell Therapeutics, Inc.) is a conjugate of paclitaxel to a polyglutamate polymer. Its macromolecular nature exploits enhanced permeability and retention in tumour tissues. This compound is stable and inactive in aqueous solution and undergoes predominantly intracellular metabolism at the site where active paclitaxel is released. Because it does not require a Cremophor EL vehicle, it can be administered by short infusion into peripheral veins. In preclinical models, compared with the same dose of unconjugated paclitaxel in Cremophor EL-ethanol, CT-2103 yields >or= 12-fold increase in area under the curve in both plasma and tumour tissue. This alteration in drug pharmacokinetics and biodistribution is attributable to the ability of macromolecules to concentrate in areas of vascular leakiness, such as tumour tissue. CT-2103 is taken up by both tumour cells and normal phagocytic cells and is transported to lysosomes, where it is released by specific proteases through enzymatic action. In syngeneic and xenogeneic tumour models, at the maximally tolerated dose, CT-2103 appears to be more active than the standard doses of paclitaxel. It has also demonstrated activity in paclitaxel-resistant tumour models. Its potential enhancement of efficacy and decrease in drug-related toxicities make this agent an attractive option for therapeutic investigation. In Phase I trials it has been relatively well-tolerated, with acceptable toxicity at doses <or= 225 mg/m(2) every 3 weeks. In combination with carboplatin the maximum tolerated dose is 235 mg/m(2) and the recommended Phase II dose 210 mg/m(2). Activity has been demonstrated in both non-small cell lung carcinoma (NSCLC) and in ovarian cancer, Phase III studies are currently testing this agent versus standard paclitaxel as maintenance therapy for first-line treatment-naive ovarian cancer. In addition, CT-2103 at a dose of 210 mg/m(2) (performance status [PS] 0 - 1) or 175 mg/m(2) (PS 2) is being compared with docetaxel (75 mg/m(2)) for the second-line treatment of NSCLC. In front-line PS 2 NSCLC patients, this agent in combination with carboplatin is undergoing comparison with paclitaxel/carboplatin; in a separate effort, single-agent CT-2103 is being compared with either gemcitabine or vinorelbine. These studies will determine whether the preclinical and early clinical promise of this agent can be realised in the clinical treatment of solid tumours.

Animals↗

PubMed2004

Dilemmas in management: the controversial role of chemotherapy in PS 2 advanced NSCLC and the potential role of CT-2103 (Xyotax).

Platinum-based chemotherapy improves long-term survival in patients with advanced non-small cell lung cancer (NSCLC). Meta-analyses have demonstrated an improvement in median and 1-year survival times as well as quality of life. However, these benefits are largely confined to patients with a good performance status (PS), one of the most critical determinants influencing outcome. Several clinical trials that initially included PS 2 patients ultimately discontinued their enrollment due to a high propensity of adverse reactions to treatment. The advent of more active, less toxic agents has revitalized investigator interest in treating PS 2 patients. CT-2103 is a novel paclitaxel conjugate undergoing investigation in the treatment of advanced NSCLC. The median survival for PS 2 patients treated with single-agent CT-2103 in one small trial proved similar to that reported for paclitaxel/carboplatin in NSCLC patients and was associated with an improved safety profile compared with conventional taxanes. Phase III studies comparing CT-2103 as a single agent and in combination with carboplatin to current standards of care are in progress. Unlike a well-defined population with good PS, the therapeutic index in PS 2 patients is narrower and not as clearly defined. These and other efforts will determine the optimal mode of therapy in PS 2 individuals with NSCLC.

Antineoplastic Agents↗

PubMed2004

CT-2103: a novel macromolecular taxane with potential advantages compared with conventional taxanes.

CT-2103 (Xyotax) is a polymer-drug conjugate designed to improve upon the therapeutic index and tolerability of conventional taxanes. Because standard chemotherapy drugs distribute randomly in the body, both tumor and normal tissues are exposed to the cytotoxic effects of these drugs. In contrast, conjugation of low molecular weight drugs, such as paclitaxel, to a polymer results in significant passive tumor targeting by the enhanced permeability and retention effect. Moreover, appropriately designed polymer-drug conjugates form polymeric prodrugs that are inert during transport. The release of the active drug is dependent on cleavage of the polymer backbone following endocytic uptake of the conjugate into tumor cells. Preclinical studies show that CT-2103 accumulates in the tumor tissue and that paclitaxel is slowly and progressively released from the polymer. Clinical pharmacokinetics data show that CT-2103 is stable in plasma; data are consistent with prolonged tumor exposure and reduced systemic exposure to active drug. Based on the promising results in phase I/II studies, 3 phase III trials of CT-2103 were initiated in advanced non-small-cell lung cancer (NSCLC). These Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reaction (STELLAR) trials represent the largest randomized phase III programs in patients with NSCLC and a poor performance status.

Antineoplastic Agents↗

PubMed2004

Irinotecan in advanced lung cancer: focus on North American trials.

New agents with improved systemic activity are needed for the treatment of lung cancer. Irinotecan (Camptosar) is a promising agent in advanced non-small-cell (NSCLC) and small-cell lung cancer (SCLC). In a Japanese phase III trial of advanced NSCLC, irinotecan or irinotecan/cisplatin demonstrated a significant survival advantage compared to the standard of vindesine/cisplatin. Similar North American phase III trials focusing on irinotecan's role in NSCLC are under way. Ongoing trials have also been launched to corroborate the significant survival advantage reported by a Japanese phase III trial for irinotecan/cisplatin vs standard etoposide/cisplatin in extensive SCLC. Current and planned trials in NSCLC with irinotecan in combination with gemcitabine (Gemzar), the taxanes, and other new agents, and thoracic radiotherapy should also provide useful clinical data. Moreover, trials in SCLC are investigating the rationale of combining irinotecan with a platinum agent as a component of chemoradiotherapy regimens. Promising data from these and other studies will further elucidate a role for irinotecan in the management of lung cancer.

Antimetabolites, Antineoplastic↗

PubMed2003

Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies.

The Erb-B family of receptors plays an important role in lung carcinogenesis and tumor development, and EGFR and HER2 are highly expressed in bronchial preneoplasia. In invasive tumors, EGFR are expressed in 50-90%, and mostly in squamous cell carcinomas, but also in adenocarcinomas and large cell carcinomas, while HER2 is less frequently expressed (20-30%) and mostly expressed in adenocarcinomas. Bronchioloalveolar cell carcinomas may present a distinct EGFR profile compared to the other NSCLCs and evidence and consequences are discussed. The genetic mechanisms responsible for overexpression of EGFR and HER2 proteins might be numerous, including gene dosage (overrepresentation or amplification) as well as translational and post-translational mechanisms. However, for EGFR and HER2 there is a positive correlation between gene copy numbers and level of protein expression demonstrated by fluorescence in situ hybridization analysis and immunochemistry. Gene amplification for EGFR and HER2 is demonstrated in only 5-10% of the tumors. The treatment status and therapeutic limitation with trastuzumab (Herceptin) in lung cancer compared to breast cancer is discussed.

Carcinoma, Non-Small-Cell Lung↗

PubMed2003

Targeted molecular mechanisms of epoetin alfa.

Despite therapeutic improvements and ongoing efforts to develop more efficacious therapies, the majority of lung cancer patients face a poor prognosis. Therefore, the primary goal of current treatment is palliation, improvement and maintenance of quality of life (QOL), and (modest) prolongation of survival. Anemia frequently occurs in lung cancer patients and has been associated with decreased QOL, impaired treatment outcomes, and shortened survival time. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of chemotherapy and radiotherapy. Thus, correction of even mild anemia seems to have a beneficial effect on QOL and cancer treatment outcomes. The current article describes the basis and mechanism for the use of recombinant human erythropoietin (rHuEPO, epoetin alfa), a molecular targeted therapy, for the treatment of cancer-related anemia, with a focus on lung cancer. Epoetin alfa has proven efficacy and safety in correcting anemia and improving QOL based on numerous clinical studies and over a decade of clinical practice. In addition, emerging data show that epoetin alfa may offer potential benefits beyond treating anemia, specifically in terms of treatment outcomes and cognitive function. Future research needs to be conducted to explore the potential for epoetin alfa to improve survival time in lung cancer patients.

Anemia↗

PubMed2003

The role of radiation therapy and chemotherapy in the management of airway tumors other than small-cell carcinoma and non-small-cell carcinoma.

In rare pulmonary tumors, the choice of local and systemic therapy is frequently dictated by the histologic cell type and (generally) by extrapolation from the existing therapeutic literature for that cell type's more common presentation; however, this approach might change. We are in the midst of a new biological and technological era in how approach and treat cancer. In a phase I trial for non-small-cell lung cancer, Hayman et al safely treated with radiation doses as high as 102.9 Gy (to limited volumes) using three-dimensional, conformal radiation [100]. Such techniques facilitate radiation dose escalation for thoracic neoplasms while minimizing normal tissue toxicity, potentially enhancing the therapeutic ratio. Furthermore, the entire human genome has been sequenced recently, and scientists are now in the process of discovering the functions of previously unknown sequences and their protein products. DNA microarrays can be used to analyze small tissue samples for the presence of gene variations or mutations (genotyping), performing the equivalent of several thousand "Southern blot" experiments in only a few days. In the future, patients might receive individually tailored therapy based upon unique molecular-genetic alterations of the tumor.

Bronchial Neoplasms↗

PubMed2003

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar), vinorelbine (Navelbine) and irinotecan (Campto), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20-30% and 1-year survival rates of 30-40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-alpha. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.

Antineoplastic Agents↗

PubMed2003

The emerging role of gemcitabine in combination with radiation in locally advanced, unresectable non-small-cell lung cancer.

The median survival for patients with locally advanced non-small-cell lung cancer (NSCLC) remains 18 months, at best, in cooperative group efforts. Integrating new agents into the standard combined modality treatment paradigm is a daunting challenge. Gemcitabine has activity in advanced NSCLC and is a potent radiosensitizer, but preclinical trials did not delineate an optimal dose or schedule, and early attempts to graft full-dose gemcitabine (1000 mg/m2/week) onto standard radical thoracic radiation therapy (RT) were marked by significant grade 4 and 5 toxicity. More recent trials, however, have shown that attenuated doses of 150-300 mg/m2/week during radiation (XRT) are safer and potentially efficacious. Higher doses produce dose-limiting esophageal and pulmonary toxicities. Using a twice-weekly schedule, the maximum tolerated dose is 35 mg/m2. The use of 3 dimensional conformal RT may enable significant dose escalations while substantially reducing esophageal exposure and minimizing toxicity. The cooperative oncology groups are just beginning to evaluate gemcitabine in this setting. Cancer and Leukemia Group B, in a randomized phase II study, assessed combination gemcitabine and cisplatin in both the induction and radiosensitizing setting. During the induction phase, gemcitabine was given 1250 mg/m2 on days 1 and 8 every 3 weeks for 2 cycles in combination with cisplatin 80 mg/m2 every 3 weeks, and then reduced to 600 mg/m2 days 1 and 8 every 3 weeks during XRT. The overall response rate was 63% with median survival of 18.3 months and 1-year and 3-year survival rates of 68% and 28%, respectively. Radiation Therapy Oncology Group is currently spearheading a phase I study of concurrent radiation and weekly gemcitabine in combination with either weekly carboplatin or paclitaxel. Ongoing efforts will also evaluate the role of gemcitabine either alone or in combination with docetaxel in the consolidation setting after definitive chemoradiation has been completed. Whether gemcitabine in combination with radiation, with or without other agents, will ultimately prove superior to standard chemoradiation regimens remains to be determined.

Journal Article↗

PubMed2003

The global role of irinotecan in the treatment of lung cancer: 2003 update.

Lung cancer is the most lethal malignancy in the United States. In light of its natural history, new agents with improved systemic activity are needed. Irinotecan (CPT-11, Camptosar) is a promising agent in the treatment of advanced non-small-cell and small-cell lung cancer. In subgroup analysis of a Japanese phase III trial, irinotecan or irinotecan/cisplatin demonstrated a significant survival advantage compared with standard vindesine (Eldisine)/cisplatin in advanced non-small-cell lung cancer. Similar North American phase III trials focusing on irinotecan's role in non-small-cell lung cancer are planned. Ongoing trials have also been inaugurated to corroborate the significant survival advantage reported by a Japanese phase III trial of irinotecan/cisplatin vs standard etoposide/cisplatin in extensive small-cell lung cancer. Current and planned trials in patients with non-small-cell lung cancer will investigate treatment using irinotecan in combination with gemcitabine (Gemzar), the taxanes, and other new agents, as well as with thoracic radiotherapy. Moreover, trials in small-cell lung cancer are investigating the utility of irinotecan in combination with a platinum agent when incorporated in chemoradiotherapy regimens. It is hoped that data from these and other studies will help investigators to more clearly delineate a role for irinotecan in the management of lung cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2002

Standards of care for anemia management in oncology: focus on lung carcinoma.

BACKGROUND: Anemia is common in patients with lung carcinoma, particularly among those undergoing platinum-based cytotoxic chemotherapy. Evidence is growing that anemia can have a profound impact on the patient's quality of life, often manifested as the patient's inability to function normally. METHODS: A literature review was conducted to provide a current picture of the incidence and impact of anemia in patients with lung carcinoma and the usage and limitations of current treatment. RESULTS: The incidence of anemia (a hemoglobin [Hb] level < 11g/dL) in lung carcinoma patients is approximately 50-60%, varying according to treatment regimen. However, despite evidence supporting the treatment of anemia, many clinicians only intervene when Hb levels fall below 8 g/dL. This may be because of a lack of awareness of the incidence and impact of anemia on cancer patients, but most likely is because of limitations of current treatment options (blood transfusion and recombinant human erythropoietin [epoetin-alpha]). Darbepoetin-alpha represents a new generation of erythropoiesis-stimulating proteins. Biochemically distinct from epoetin-alpha, darbepoetin-alpha has a greater sialic acid content and biologic half-life than epoetin-alpha, but stimulates erythropoiesis in the same manner. Clinical trials involving patients with cancer-related anemia have shown that darbepoetin-alpha has a threefold longer half-life than epoetin-alpha, which may allow less frequent dosing. The results from an ongoing clinical trial dedicated to testing the clinical benefits of darbepoetin-alpha in treating anemia in lung carcinoma patients will provide a valuable insight into its full potential in this setting. CONCLUSIONS: Anemia is common but is reported to be undertreated in patients with lung carcinoma. The introduction of darbepoetin-alpha into clinical practice may overcome some of the limitations of current treatments and facilitate improvement in the management of cancer-related anemia.

Anemia↗

PubMed2002

Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial.

BACKGROUND: Older patients, even if fit, are often considered incapable of tolerating platinum-based systemic therapy. We performed a retrospective analysis of Eastern Cooperative Oncology Group (ECOG) 5592, a phase III randomized trial of platinum-based chemotherapy regimens for non-small-cell lung cancer (NSCLC), and compared outcomes in enrollees 70 years of age and older with those in younger patients. METHODS: ECOG carried out a randomized phase III trial of cisplatin plus either etoposide or paclitaxel in chemotherapy-naïve NSCLC patients with stages III(B) or IV disease. Toxic effects, response rates, and survival rates were compared between age groups. All P values were two-sided. RESULTS: A total of 574 patients enrolled from August 1993 through December 1994 were evaluable. Eighty-six (15%) were 70 years old or older. Older patients had a higher incidence of cardiovascular (P =.009) and respiratory (P =.04) comorbidities and nonanalgesic medication use (P =.02). Leukopenia (P<.001) and neuropsychiatric toxicity (P =.002) were more common in elderly men than in younger men. Elderly women lost more weight than younger women (P =.006). Other toxic effects were similar in older and younger patients. The proportions with clinical partial or complete response (21.5% versus 23.3%; Fisher's exact test, P =.66), median time to progression (4.37 versus 4.30 months; log-rank test, P =.29), and survival distribution (log-rank test, P =.29; median survival, 9.05 versus 8.53 months; 1-year survival, 38% versus 29%; and 2-year survival, 14% versus 12%) were similar in patients younger than 70 years and 70 years old or older. Baseline quality-of-life and treatment-outcome indices were similar. Equivalent declines over time in functional well-being occurred in both groups. CONCLUSION: Response rate, toxicity, and survival in fit, elderly NSCLC patients receiving platinum-based treatment appear to be similar to those in younger patients, although patients 70 years old or older have more comorbidities and can expect more leukopenia and neuropsychiatric toxicity. Advanced age alone should not preclude appropriate NSCLC treatment.

Aged↗

PubMed2002

Elderly patients with lung cancer: biases and evidence.

Although 60% of those diagnosed with non-small-cell lung cancer are 60 years of age or older, the elderly are often undertreated. Furthermore, those older than age 70 are under-represented in clinical research trials. Tremendous bias exists against treating the elderly; therapeutic nihilism and constrained societal/financial resources conspire to maintain the status quo. In limited stage small cell carcinoma of the lung (SCLC), a pivotal meta-analysis by Pignon et al. showed no obvious benefit for chemoradiation over chemotherapy alone in patients older than 70 years of age. However, more recent trials have revealed a clear-cut benefit for fit elderly patients to receive combined modality therapy versus chemotherapy alone, even though outcome generally remains superior for younger patients. For patients with locally advanced non-small-cell lung cancer, conflicting results exist. Individual trials evaluating combined modality therapy have shown no impairment in survival for older patients, but retrospective analyses of the Radiation Therapy Oncology Group database have demonstrated that increased therapeutic intensity does not translate into improved outcome compared with standard, single daily fraction radiation alone. Weighted survival analyses that deduct time spent with progressive disease or significant toxicity have reinforced this notion. In advanced non-small-cell lung cancer, fit elderly patients who receive platinum-based regimens do as well, or nearly as well, as patients younger than age 70, although the incidence of neutropenia and fatigue is often higher. Platinum doses above 75 mg/m2 every 3 weeks to 4 weeks are relatively more toxic in the elderly than are lower doses. Three separate studies from Italy have formally assessed the elderly. One showed superiority for single-agent vinorelbine versus best supportive care regarding survival rates and quality of life. A second showed a marked survival advantage for combination vinorelbine and gemcitabine versus vinorelbine alone. However, a much larger, more credible study demonstrated no benefit for combination vinorelbine and gemcitabine versus the constituent single agents. To date, no elderly-specific trials have addressed the role of taxanes or of platinum-based combination therapy versus non-platinum monotherapy or doublets. Comprehensive evaluation of comorbidities and their influence on outcome have not been conducted, and there are virtually no data for patients older than age 80.

Age Factors↗

PubMed2002

Epidermal growth factor receptors as a target for cancer treatment: the emerging role of IMC-C225 in the treatment of lung and head and neck cancers.

Epidermal growth factor receptor is one of four receptors critical to cellular proliferation, differentiation, and survival, and is widely expressed in malignant tissue, particularly in squamous cell carcinoma of the head and neck. Expression has been associated with malignant progression, inhibition of apoptosis, neoplastic angiogenesis, enhanced metastatic potential, and both chemoresistance and radioresistance. IMC-C225 is a chimeric monoclonal antibody that targets extracellular epidermal growth factor receptor; it has shown both in vitro and in vivo antitumor activity in tumor cells lines expressing epidermal growth factor receptor, including heightened radiation response in vitro in cultured human squamous cell carcinoma and enhancement of taxane- and platinum-induced cytotoxicity in non-small cell lung cancer xenografts. In A431 head and neck squamous cell xenografts, IMC-C225 administered both before and after radiation therapy yields a radiation enhancement factor of 3.62, attributable to both tumor necrosis and antiangiogenesis. In phase I pharmacokinetic studies, IMC-C225 has a long half-life, lending itself to convenient weekly administration. It has shown a favorable toxicity profile, limited primarily to allergic and dermatologic reactions, the latter characterized by a self-limited, sterile, acneiform rash. Anaphylaxis is rare. Standard treatment entails a loading dose of 400 mg/m(2) at week 1, followed by a maintenance dose of 250 mg/m(2) weekly. An ongoing phase III international multicenter, randomized study in locally advanced squamous cell carcinoma of the head and neck is evaluating therapeutic radiation therapy, either alone or in conjunction with IMC-C225. In a pilot trial, six of nine patients with platinum-exposed squamous cell carcinoma of the head and neck exhibited objective response. In an ongoing phase II trial in patients with stable or progressive disease on platinum-based therapy, the preliminary response rate is approximately 20%, far higher than one would expect with standard salvage regimens. The Eastern Cooperative Oncology Group has completed a placebo-controlled phase III registration trial assessing cisplatin 100 mg/m(2) every 4 weeks with or without IMC-C225. Three separate phase II trials in non-small cell lung cancer have been launched: one trial tests IMC-C225 in combination with standard paclitaxel/carboplatin; another integrates IMC-C225 into the gemcitabine/carboplatin combination in treatment-naive patients; and a third trial evaluates IMC-C225 in combination with docetaxel 75 mg/m(2) every 3 weeks in the second-line setting.

Antibodies, Monoclonal↗

PubMed2002

Temozolomide in non-small-cell lung cancer: preliminary results of a phase II trial in previously treated patients.

Virtually all patients with advanced non-small-cell lung cancer (NSCLC) relapse. Docetaxel has an established, Food and Drug Administration-approved role as salvage therapy in previously treated, platinum-exposed patients. However, the response rate in phase III studies is < 15%, and median survival is only 6-8 months. Temozolomide, a novel triazene derivative with activity in melanoma and anaplastic astrocytoma, has demonstrated activity in C26 adenocarcinoma, Lewis lung cancer, and in phase I studies. A phase II trial was mounted using a unique schedule of oral temozolomide 75 mg/m2 daily for 6 weeks every 8-10 weeks, in patients with previously treated, advanced, incurable NSCLC. Eligibility stipulated an Eastern Cooperative Oncology Group performance status (PS) of 0-2, adequate end organ function, up to 1 prior chemotherapy for advanced (relapsed or metastatic) disease, and up to 1 prior regimen in the context of radiosensitization, adjuvant therapy, or induction. From March 2000 through January 2002, 47 patients (24 male, 23 female) were enrolled. The median age was 67 years. Sixteen patients had a PS of 2, 22 had a PS of 1, and 9 had a PS of 0. It was too early to evaluate 9 patients. Toxicity, with the exception of mild nausea and thrombocytopenia, was negligible. Three patients had a delayed recovery of platelets prompting discontinuation of treatment. Of the 38 evaluable patients, 1 patient had a complete response, 2 patients had a partial response, 12 had stable disease, and 19 had disease progression. Four patients were not evaluable. Six patients died within 30 days of taking temozolomide; 5 of these deaths were not related to treatment upon review by an independent data safety monitoring committee. Temozolomide, using a unique 6-week continuous schedule, has demonstrated activity in the salvage therapy of advanced NSCLC. Toxicity is modest, and accrual to this study continues.

Journal Article↗