Mind your elders: therapeutic implications of epidermal growth factor receptor inhibition in older patients with advanced non-small-cell lung cancer.
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Age Factors↗
Biomedical subjects
Corey J Langer
Publications and source records attributed to Corey J Langer.
A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC).
PURPOSE: To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin. PATIENTS AND METHODS: Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m(2) and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration. RESULTS: Seventy patients were enrolled and 68 patients were treated, 37 in phase 1 and 31 in phase 2 (14 with the combination and 17 with chemotherapy alone). Dose-limiting toxicity of CP-547,632 250 mg by mouth daily in combination with paclitaxel and carboplatin was grade 3 rash and grade 3 diarrhea despite medical intervention. CP-547,632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. No subject had CR. In phase I, seven subjects (22.6%) had a confirmed partial response. In phase II, four subjects (28.6%) receiving CP-547,632 plus chemotherapy had a confirmed partial response. In the phase II chemotherapy alone group, four subjects (25%) had a confirmed partial response. CONCLUSION: The combination of CP-547,632 and paclitaxel and carboplatin was well-tolerated at doses up to 200 mg by mouth daily. Dose-limiting toxicity of CP-547,632 at 250 mg consisted of diarrhea and rash. CP-547,632 did not increase the objective response rate to chemotherapy alone in patients with advanced non-small cell lung cancer.
Administration, Oral↗
Phase I trial of concurrent hyperfractionated split course radiotherapy (HFx RT), cisplatin (cDDP), and paclitaxel in patients with recurrent, previously irradiated, or treatment-naïve locally advanced upper aerodigestive malignancy.
PURPOSE: Phase I study to determine the maximally tolerated dose (MTD) of cisplatin (cDDP), paclitaxel (P), and concurrent split course hyperfractionated (BID) RT in advanced squamous cell carcinoma of the head and neck (SCCHN) and other upper aerodigestive tumors. MATERIALS AND METHODS: Eligibility stipulated ECOG performance status 0-2 and either Tx-naïve, locally advanced, or locally recurrent, previously radiated, surgically unresectable upper aerodigestive cancer. Metastases were permitted if disease was predominantly locoregional. RT-naïve patients received 150 cGy bid x 5 d Q 2 wks x 4. Previously radiated patients received 150 cGy bid x 5, wk 1; then 120 cGy bid x 5 Q 2 wk x 3 (later increased to 150 cGy BID for the entire treatment). Treatment fields included recurrent tumor only with 2 cm margins. Whenever possible, conventional and 3-D conformal techniques were used. Elective nodal radiation was not administered. Starting doses of cDDP and P were 12 mg/m2/d x 5 and 15 mg/m2/d x 5, respectively, Q 2 wk x 4, each given on RT days only. At dose level 2, cDDP was increased to 15 mg/m2/d x 5. At dose level 3, P was increased to 20 mg/m2/d x 5. Granulocyte colony stimulating factor (G-CSF) days 6-12 (off treatment week) was added if cumulative neutropenia precipitated treatment delays. RESULTS: Thirty-one patients (21 men, 10 women) were treated. Eight had received prior chemotherapy, 27 prior RT. At dose level three, regular treatment delays of >or=1 week due to slow neutrophil recovery occurred. Addition of G-CSF (dose level 3b) reduced treatment delays from 100 percent to 28 percent and decreased the incidence of Grade >or=2 neutropenia and mucositis. Six of 7 patients at this dose level completed all 4 cycles of treatment and all received full dose RT (60 Gy). No other dose-limiting toxicities occurred. Of 22 assessable patients with locally recurrent SCCHN, 12 (55 percent) responded. Median time to progression in this group was 6 months, with median and one-year survival of 9.5 mos and 41 percent, respectively. CONCLUSION: Concurrent daily cisplatin/paclitaxel and split course hyperfractionated RT (60 Gy) is feasible in previously radiated patients. G-CSF, administered between each cycle, reduces the incidence of treatment delays. Activity is promising and toxicity acceptable.
Adult↗
Laryngeal cancer in the United States: changes in demographics, patterns of care, and survival.
BACKGROUND: Survival has decreased among patients with laryngeal cancer during the past 2 decades in the United States. During this same period, there has been an increase in the nonsurgical treatment of laryngeal cancer. OBJECTIVE: The objectives of this study were to identify trends in the demographics, management, and outcome of laryngeal cancer in the United States and to analyze factors contributing to the decreased survival. STUDY DESIGN: The authors conducted a retrospective, longitudinal study of laryngeal cancer cases. METHODS: Review of the National Cancer Data Base (NCDB) revealed 158,426 cases of laryngeal squamous cell carcinoma (excluding verrucous carcinoma) diagnosed between the years 1985 and 2001. Analysis of these case records addressed demographics, management, and survival for cases grouped according to stage, site, and specific TNM classifications. RESULTS: This review of data from the NCDB analysis confirms the previously identified trend toward decreasing survival among patients with laryngeal cancer from the mid-1980s to mid-1990s. Patterns of initial management across this same period indicated an increase in the use of chemoradiation with a decrease in the use of surgery despite an increase in the use of endoscopic resection. The most notable decline in the 5-year relative survival between the 1985 to 1990 period and the 1994 to 1996 period occurred among advanced-stage glottic cancer, early-stage supraglottic cancers, and supraglottic cancers classified as T3N0M0. Initial treatment of T3N0M0 laryngeal cancer (all sites) in the 1994 to 1996 period resulted in poor 5-year relative survival for those receiving either chemoradiation (59.2%) or irradiation alone (42.7%) when compared with that of patients after surgery with irradiation (65.2%) and surgery alone (63.3%). In contrast, identical 5-year relative survival (65.6%) rates were observed during this same period for the subset of T3N0M0 glottic cancers initially treated with either chemoradiation or surgery with irradiation. CONCLUSIONS: The decreased survival recorded for patients with laryngeal cancer in the mid-1990s may be related to changes in patterns of management. Future studies are warranted to further evaluate these associations.
Antineoplastic Agents↗
Neglected and underrepresented subpopulations: elderly and performance status 2 patients with advanced-stage non-small-cell lung cancer.
Elderly patients and those with performance status (PS) of 2 with non-small-cell lung cancer (NSCLC) have been habitually underrepresented in clinical trials. Therapeutic neglect and legitimate concerns about toxicity are responsible. Yet randomized phase III data in the elderly have demonstrated a survival benefit for single-agent chemotherapy compared with best supportive care, and retrospective analyses of fit elderly patients enrolled on platinum agent-based trials have shown similar survival rates, albeit more toxicity, compared with younger counterparts. To date, however, there are no phase III trials specific to the elderly population demonstrating a survival benefit for platinum agent-based combinations compared with the constituent nonplatinum single agent; such efforts are ongoing. Performance status is a critical prognostic factor in advanced-stage NSCLC. Retrospective analyses of multiple trials conducted before 1995 suggested that patients with advanced-stage NSCLC and compromised PS experienced substantial toxicity and virtually no benefit from systemic chemotherapy, leading most cooperative groups to suspend research in this cohort. But this trend has changed. A subset analysis of patients with a PS of 2 enrolled on a recent Cancer and Leukemia Group B trial showed a significant survival benefit for carboplatin in combination with paclitaxel compared with paclitaxel alone, and recent randomized phase II efforts evaluating platinum agent-based combinations have yielded median survival times of > 6 months with acceptable toxicity rates. Although the Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reaction trials testing polyglutamated paclitaxel failed to show a survival advantage compared with standard agents, interest in testing new, less toxic agents continues. Future efforts will need to differentiate the reasons for compromised PS, be it tumor burden, comorbidity, or both.
Age Factors↗
Non-small cell lung cancer clinical practice guidelines in oncology.
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Humans↗
Small cell lung cancer clinical practice guidelines in oncology.
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Humans↗
Current management of brain metastases, with a focus on systemic options.
Brain metastases are an important sequelae of many types of cancer, most commonly lung cancer. Current treatment options include whole-brain radiation therapy (WBRT), surgical resection, stereotactic radiosurgery, and chemotherapy. Corticosteroids and antiepileptic medications are commonly used for palliation of mass effect and seizures, respectively. The overall median survival is only 4 months after WBRT. Combined-modality strategies of WBRT with either chemotherapy or novel anticancer agents are under clinical investigation. Promising results have been obtained with several experimental agents and confirmatory phase III trials are underway. Although improvement in overall survival has not been seen universally, reduction in death due to progression of brain metastases and prolongation of the time to neurologic and neurocognitive progression have been reported in selected series. On the basis of these findings, it might be possible to identify new agents that may enhance the efficacy of WBRT.
Adrenal Cortex Hormones↗
Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience.
PURPOSE: To determine whether overall treatment time affects outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small-cell lung carcinoma (NSCLC). METHODS AND MATERIALS: Data were analyzed from 3 prospective Radiation Therapy Oncology Group trials (RTOG 91-06, 92-04, and 94-10) in which immediate concurrent chemoradiation (cisplatin-based) was the primary therapy for good-performance status Stage III (and selected inoperable Stage II) NSCLC. "Short" overall treatment time (per protocol) was defined as completing treatment within 5 days of plan; other patients were considered to have had "prolonged" treatment time (protocol violation); treatment time was also analyzed as a continuous variable in a multivariate model. Actuarial analysis was performed for overall survival, progression-free survival, freedom from local-regional progression, and toxicity. RESULTS: A total of 474 patients were analyzed. Median follow-up for surviving patients was 6.1 years. Treatment time was delivered per protocol in 387 (82%), whereas 87 patients (18%) had a prolonged treatment time. Long treatment time was significantly associated with severe acute esophagitis. Median survival was slightly better in patients completing treatment on time (19.5 months vs. 14.8 months), but this did not reach statistical significance (p = 0.15) in the univariate analysis. However, in the multivariate analysis of treatment time as a continuous variable, prolonged treatment time was significantly associated with poorer survival (p = 0.02), indicating a 2% increase in the risk of death for each day of prolongation in therapy. Histology (squamous fared worse) and performance status were also significant in the multivariate model. CONCLUSIONS: This retrospective analysis demonstrates a correlation between prolonged overall radiotherapy treatment time and survival in patients with locally advanced NSCLC, even when concurrent chemotherapy is used. Further study of novel radiation-chemotherapy dose/fractionation regimens is warranted.
Actuarial Analysis↗
Toxicity and outcome analysis of patients with recurrent head and neck cancer treated with hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy from two prospective phase I and II studies.
BACKGROUND: Patients with local recurrences or new head and neck primary tumors in previously irradiated tissues have few options for salvage treatment. One option for select patients is to undergo reirradiation with concurrent chemotherapy. The purpose of this study is to report the initial clinical results of the Fox Chase phase I and II prospective reirradiation and chemotherapy studies. METHODS: Between July 1996 and January 2002, 38 patients with locally recurrent unresectable squamous cell carcinoma of the head and neck were treated with concurrent chemotherapy and reirradiation on two prospective trials. All patients had received prior radiation therapy to the head and neck region (median dose, 64.2 Gy). Patients received cisplatin and paclitaxel along with hyperfractionated external beam radiation therapy to the site of recurrence. RESULTS: The median follow-up was 10 months. The median survival was 12.4 months, with actuarial rates of overall survival of 50% and 35% at 1 and 2 years, respectively. During follow-up, 63% of patients experienced local progression of disease, all in the irradiated field. Actuarial progression-free survival at 1 year was 33%, with a median time to progression of 7.3 months. Acute grade 3 to 4 toxicity included neutropenia, nausea, emesis, and mucositis. CONCLUSIONS: Hyperfractionated split-course reirradiation and concurrent cisplatin and paclitaxel chemotherapy demonstrates durable locoregional control in select patients, although late toxicity may occasionally be significant. Only sites of disease recurrence need to be covered in the reirradiation fields.
Antineoplastic Combined Chemotherapy Protocols↗
The surgical management of superior sulcus tumors: a retrospective review with long-term follow-up.
BACKGROUND: We reviewed our experience with multimodality therapy for superior sulcus tumors to identify aspects of treatment that impact survival. METHODS: We retrospectively analyzed the records of 39 consecutive patients who underwent surgical resection in a single institution between 1993 and 2000. RESULTS: Median age at presentation was 59 years (range, 40 to 77). Twenty-five patients (64%) were men. At presentation, 36 patients (92%) had clinical T3 tumors and 3 (8%) had clinical T4 tumors. Mediastinoscopy was negative in all patients. Thirty-one patients (79%) received preoperative radiotherapy (median dose, 4500 cGy). Chemotherapy was administered concurrently with radiotherapy in 27 patients (69%). Complete surgical resection was performed in 34 patients (87%). There were 2 (5%) postoperative deaths. Of the 31 patients who received preoperative therapy, 14 (45%) had their tumors downstaged and 9 (29%) demonstrated a complete pathologic response. Median follow-up (100%) was 69 months. Overall 5-year survival was 47.9%. Five-year survival was 52.1% in patients with negative resection margins (p = 0.005), and 60.6% in patients who demonstrated a response to induction chemoradiation therapy (p = 0.008). Independently, margin status and response to induction therapy are predictors of overall survival (p = 0.01 and p = 0.02, respectively). Multivariable analysis identified margin status as the only factor significantly associated with overall survival. Negative margins strongly correlated with the response to preoperative therapy (p = 0.004). Disease-free survival correlated well with the response to induction therapy (p = 0.03). The chemotherapy regimen, T status, operative procedure, and complete pathologic response did not correlate with survival. CONCLUSIONS: The use of chemoradiation induction therapy may downstage tumors, enhance the ability to obtain a complete surgical resection, and prolong survival.
Adult↗
Patterns of care survey (PCS) in lung cancer: how well does current U.S. practice with chemotherapy in the non-metastatic setting follow the literature?
BACKGROUND: In LD-SCLC, combined modality therapy has emerged as the standard of practice in good performance status (PS) patients (pts). Pignon's meta-analysis [N Engl J Med 1992;327:1618-24] showed that combination chemotherapy (CT) and thoracic radiation (XRT) in LD-SCLC yielded an absolute 5.4% increase in 3-year survival versus chemotherapy alone. Concurrent chemoradiation upfront has generated the highest survival rates [Murray. J Clin Oncol 1993;11:336-44; Jeremic. J Clin Oncol 1996;15:893-900; Takada. J Clin Oncol 2002;20:3054-60]. In stage III NSCLC, multiple studies have shown therapeutic superiority for combination chemotherapy and XRT versus RT alone; and recent literature suggests a therapeutic advantage for concurrent chemoradiation versus chemotherapy followed by XRT [Curran. ASCO 2000;19:484a; Furuse. JCO 1999;17:2692-9; Zatloukal. ASCO 2002;A-1159]. Data are less secure regarding the role of chemotherapy in stage I and II NSCLC. MATERIAL AND METHODS: A stratified two-step cluster sampling technique was used for data collection. Five hundred and forty-one individuals diagnosed between 1998 and 1999 with lung cancer, either LD-SCLC or stages I-III NSCLC were sampled from 58 institutions featuring radiotherapy facilities, giving a weighted sample size (wss) of 42,335 patients. All pts had Karnofski performance status (KPS) >or=60. We determined the percentage who received chemotherapy; the nature of chemotherapy and its timing with respect to XRT. SUDAAN statistical software was used to allow the incorporation of the design elements and weights to reflect the relative contribution of each institution and each patient in the analysis RESULTS: Of 72 (wss=6138) pts with LD-SCLC, 100% received XRT and 95% received chemotherapy (CT); 66% received concurrent (con) CT and XRT, of whom 29% also received CT pre XRT; 22% received CT post XRT as well, and 23% received both: 63% received sequential CT-->XRT+/-con CT; and 38% received some CT after XRT. Fifty-two percent received cisplatin (DDP), and 38% received carboplatin (CBDCA); 73% received etoposide (VP-16), while 10% received paclitaxel. Of 469 pts (wss=36,197) with NSCLC, 52% received CT, including 30% with stage I disease, 48% with stage II NSCLC, 60% with stage III NSCLC, and 50% with unknown stage. Thirty-nine percent received sequential CT-->XRT+/-CT, of whom 49% received CT pre XRT only. Seventy-four percent received con CT and XRT; and 27% received posterior CT, of whom 84% also received con CT/XRT. Forty-five received some CT in the pre-op setting and 15% in the post-op setting. Twelve percent received DDP-based therapy, while only 13% and 7% received VP-16 or vincas, respectively; 67% received CBDCA. Seventy-two percent received taxanes, of whom 96% received paclitaxel. Gemcitabine was administered to 3% of NSCLC pts. CONCLUSIONS: Combined modality therapy is typically employed in the therapy of LD-SCLC and LA-NSCLC. The majority of those treated for SCLC receive concurrent CT/XRT, while nearly 3/4 of those treated with CT and XRT for LA-NSCLC received concurrent CT/XRT. Current practice in the US generally matches evidence-based literature, although a significant percentage of practitioners substitute CBDCA for DDP in both venues and use paclitaxel in lieu of vincas or etoposide in NSCLC.
Adult↗
The emerging role of vascular endothelial growth factor receptor tyrosine kinase inhibitors.
In the United States, non-small cell lung cancer (NSCLC) constitutes 85% of all newly diagnosed lung cancers. Over the past 40 years, the 5-year survival rates in NSCLC have improved from 6% to 15%, with surgery remaining the most curative approach. However, resection is feasible in less than 35% of patients at diagnosis, and 40% to 50% of newly diagnosed patients present with metastatic disease. Platinum-based combination chemotherapy is standard treatment for these patients, but improvement beyond platinum doublets has not been achieved. Therefore, a clear-cut need exists for new treatment approaches for NSCLC. Targeted therapies, particularly angiogenesis inhibitors, are hoped to facilitate therapeutic progress. Neovascularization not only allows for the continued growth of the primary tumor, but also provides migrating tumor cells access to the systemic circulation, facilitating metastasis. A number of studies have shown a clear correlation between vascular endothelial growth factor (VEGF) expression, microvessel density, and impaired prognosis. Monoclonal antibodies directed against the VEGF and VEGF receptor have been studied in depth in advanced NSCLC. A randomized phase III trial evaluated the role of the anti-VEGF-A antibody bevacizumab in combination with paclitaxel and carboplatin versus chemotherapy alone in NSCLC. Based on toxicity observations from a phase II study, this trial excluded patients with squamous histology, brain metastases, or an ongoing need for therapeutic anti-coagulation or non-steroidal anti-inflammatory agents. Preliminary data confirmed a survival advantage of 12.5 months for patients in the bevacizumab arm compared with 10.2 months in the control arm (P = .0075), which showed that antiangiogenic therapies can be effective in NSCLC. Antiangiogenic therapies, including antibodies against VEGF, and, in particular, new small-molecule inhibitors of the VEGF receptor, are reviewed and discussed in detail.
Angiogenesis Inhibitors↗
Role of zoledronic acid in the setting of bone metastases from non-small-cell lung cancer.
Bone metastases are major sequelae of non-small-cell lung cancer and are associated with poor survival, skeletal-related events (SREs), and economic burden. In recent phase III trials, zoledronic acid has demonstrated a potential to prevent or delay SREs, although this has not yet translated into a survival benefit. Zoledronic acid is the first and only bisphosphonate with proven efficacy in the treatment of bone metastases associated with a broad range of tumors, including lung cancer. We report herein a case study that highlights the clinical benefit of zoledronic acid in a patient with squamous cell carcinoma of the lung.
Antineoplastic Combined Chemotherapy Protocols↗
Response to temozolomide in second-line treatment of recurrent nonsmall cell lung carcinoma: case report.
Almost all patients with stage IV nonsmall cell lung cancer (NSCLC) who show an initial response to chemotherapy will eventually relapse. For patients with a good performance status at relapse, second-line chemotherapy is a standard treatment option. A case of recurrent NSCLC described herein profiles a patient previously treated with cisplatin, irinotecan, and radical thoracic radiation for stage IIIb NSCLC. The patient showed a complete response to first-line therapy that lasted for approximately 17 months. When new adenopathy was discovered, therapy with the oral chemotherapeutic agent temozolomide was initiated. After 2 treatment cycles, a near complete response was obtained and she remained free from disease progression during all subsequent treatment cycles with temozolomide. The patient remained free from disease progression for a total of 15 months when she was treated for dehydration and a computed tomography (CT) scan showed new small bilateral pleural effusions and enlarging subcarinal, right hilar, and left infrahilar lymph nodes. The patient died 21 months after her first treatment cycle with temozolomide, most likely because of progressive disease.
Administration, Oral↗
Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.
PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.
Antibodies, Monoclonal↗
Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC.
Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which to test these compounds. Both gefitinib and erlotinib have shown clinical activity in pretreated, advanced non-small-cell lung cancer, but placebo-controlled randomized Phase III studies evaluating gefitinib in combination with standard cytotoxic therapy, to our chagrin, have failed to demonstrate a survival advantage compared with chemotherapy alone.
Antibodies, Monoclonal↗
Trastuzumab in the treatment of advanced non-small-cell lung cancer: is there a role? Focus on Eastern Cooperative Oncology Group study 2598.
PURPOSE: Multiple non-small-cell lung cancer (NSCLC) cell lines and 20% to 50% of pathologic specimens express HER-2/neu, the target of trastuzumab, and HER-2/neu expression has proven to be an independent, unfavorable prognostic factor in resected patients with NSCLC. Trastuzumab, in vitro, has demonstrated growth-inhibiting synergy with platinating agents, and additivity with paclitaxel. The Eastern Cooperative Oncology Group therefore launched a phase II study evaluating combination carboplatin, paclitaxel, and trastuzumab in patients with advanced NSCLC. MATERIALS AND METHODS: Eligibility stipulated the following: measurable tumor, HER-2/neu positivity (1+ to 3+ by Herceptest [Dako Corp, Carpinteria, CA], confirmed by central review), Eastern Cooperative Oncology Group PS 0 to 1, adequate marrow, hepatic and renal function, and left ventricular ejection fraction >or= 45%. Patients received paclitaxel 225 mg/m(2)/3 hours, and carboplatin (area under the curve, 6) every 3 weeks, and trastuzumab 4 mg/kg intravenously on day 1, then 2 mg/kg weekly for or= 3 neutropenia and thrombocytopenia was 57% (34%) and 16% (2%), respectively. Asymptomatic grade <or= 2 reduction in left ventricular ejection fraction occurred in 7%. Other nonhematologic toxicities, including nausea, fatigue, arthralgias, and peripheral sensory neuropathy, were mild to moderate and matched those expected with carboplatin and paclitaxel alone. Eighteen patients (35%) received maintenance trastuzumab. Median progression-free survival was 3.3 months; median survival was 10.1 months, and 1-year survival rate was 42%. CONCLUSION: Combination paclitaxel, carboplatin, and trastuzumab is feasible. Toxicity appears no worse than cytotoxic therapy alone. Overall survival is similar to historical data using carboplatin and paclitaxel alone. However, patients with 3+ HER-2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of NSCLC. Critical assessment of trastuzumab's role in advanced NSCLC will require phase III trials.
Adult↗