Comparative effectiveness of stereotactic radiosurgery versus whole-brain radiation therapy for patients with brain metastases from breast or non-small cell lung cancer.

BACKGROUND: The optimal treatment for patients with brain metastases remains controversial as the use of stereotactic radiosurgery (SRS) alone, replacing whole-brain radiation therapy (WBRT), has increased. This study determined the patterns of care at multiple institutions before 2010 and examined whether or not survival was different between patients treated with SRS and patients treated with WBRT. METHODS: This study examined the overall survival of patients treated with radiation therapy for brain metastases from non-small cell lung cancer (NSCLC; initially diagnosed in 2007-2009) or breast cancer (initially diagnosed in 1997-2009) at 5 centers. Propensity score analyses were performed to adjust for confounding factors such as the number of metastases, the extent of extracranial metastases, and the treatment center. RESULTS: Overall, 27.8% of 400 NSCLC patients and 13.4% of 387 breast cancer patients underwent SRS alone for the treatment of brain metastases. Few patients with more than 3 brain metastases or lesions ≥ 4 cm in size underwent SRS. Patients with fewer than 4 brain metastases less than 4 cm in size (n = 189 for NSCLC and n = 117 for breast cancer) who were treated with SRS had longer survival (adjusted hazard ratio [HR] for NSCLC, 0.58; 95% confidence Interval [CI], 0.38-0.87; P = .01; adjusted HR for breast cancer, 0.54; 95% CI, 0.33-0.91; P = .02) than those treated with WBRT. CONCLUSIONS: Patients treated for fewer than 4 brain metastases from NSCLC or breast cancer with SRS alone had longer survival than those treated with WBRT in this multi-institutional, retrospective study, even after adjustments for the propensity to undergo SRS. Cancer 2016;122:2091-100. © 2016 American Cancer Society.

Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.

Improvements in outcomes for patients with resectable lung cancers have plateaued. Clinical trials of resectable non-small-cell lung cancers with overall survival as the primary endpoint require a decade or longer to complete, are expensive, and limit innovation. A surrogate for survival, such as pathological response to neoadjuvant chemotherapy, has the potential to improve the efficiency of trials and expedite advances. 10% or less residual viable tumour after neoadjuvant chemotherapy, termed here major pathological response, meets criteria for a surrogate; major pathological response strongly associates with improved survival, is reflective of treatment effect, and captures the magnitude of the treatment benefit on survival. We support the incorporation of major pathological response as a surrogate endpoint for survival in future neoadjuvant trials of resectable lung cancers. Additional prospective studies are needed to confirm the validity and reproducibility of major pathological response within individual histological and molecular subgroups and with new drugs.

Association of Medicaid Insurance With Survival Among Patients With Small Cell Lung Cancer.

Importance: Small cell lung cancer (SCLC) is an aggressive neoplasm requiring rapid access to subspecialized multidisciplinary care. For this reason, insurance coverage such as Medicaid may be associated with oncologic outcomes in this disproportionately economically vulnerable population. With Medicaid expansion under the Affordable Care Act, it is important to understand outcomes associated with Medicaid coverage among patients with SCLC. Objective: To determine the association of Medicaid coverage with survival compared with other insurance statuses. Design, Setting, and Participants: This cohort study included adult patients with limited-stage (LS) and extensive-stage (ES) SCLC in the US National Cancer Database from 2004 to 2013. Data were analyzed in January 2019. Main Outcomes and Measures: Patients were analyzed with respect to insurance status. Associations of insurance status with survival were interrogated with univariate analyses, multivariable analyses, and propensity score matching. Results: A total of 181 784 patients with SCLC (93 131 [51.2%] female; median [interquartile range] age; 67 [60-75] years for patients with LS-SCLC and 68 [60-75] years for patients with ES-SCLC) were identified, of whom 70 247 (38.6%) had LS-SCLC and 109 479 (60.2%) had ES-SCLC. On univariate analyses of patients with LS-SCLC, Medicaid coverage was not associated with a survival advantage compared with being uninsured (hazard ratio, 1.02; 95% CI, 0.96-1.08; P = .49). Likewise, on multivariable analyses of patients with ES-SCLC, compared with being uninsured, Medicaid coverage was not associated with a survival advantage (hazard ratio, 1.00; 95% CI, 0.96-1.03; P = .78). After propensity score matching, median survival was similar between the uninsured and Medicaid groups both among patients with LS-SCLC (14.4 vs 14.1 months; hazard ratio, 1.05; 95% CI, 0.98-1.12; P = .17) and those with ES-SCLC (6.3 vs 6.4 months; hazard ratio, 1.00; 95% CI, 0.96-1.04; P = .92). Conclusions and Relevance: Despite of billions of dollars in annual federal and state spending, Medicaid was not associated with improved survival in patients with SCLC compared with being uninsured in the US National Cancer Database. These findings suggest that there are substantial outcome inequalities for SCLC relevant to the policy debate on the Medicaid expansion under the Affordable Care Act.

Adjuvant chemotherapy in completely resected non-small-cell lung cancer.

Surgery alone has long been the standard treatment for patients with operable non-small-cell lung cancer (NSCLC). However, despite complete resection, 5-year survival rates have been disappointing, with about 50% of patients eventually suffering relapse and death from disease. Randomized trials conducted in the 1980s hinted at a survival benefit for postoperative cisplatin-based regimens, but they were underpowered. A meta-analysis published in 1995 found a nonsignificant 13% reduction in the risk of death associated with cisplatin-based chemotherapy, with an increase of survival of 5% at 5 years. This led to renewed interest in adjuvant chemotherapy in resected NSCLC. Thousands of patients have been included in a new generation of randomized trials in the last 10 years. Most of these recent studies have now been reported and several have demonstrated a clear survival advantage for patients treated with platin-based adjuvant therapy. These results also suggest a greater benefit with modern two-drug regimens. In view of the most recent data, postoperative platin-based chemotherapy can now be considered the standard of care for completely resected NSCLC patients with good performance status.

Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy.

PURPOSE: We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer. EXPERIMENTAL DESIGN: Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32. RESULTS: Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment. CONCLUSIONS: Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.

Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease.

The purpose of this study was to evaluate the feasibility, efficacy, safety, and pharmacokinetics of trastuzumab plus cisplatin and gemcitabine in patients with Her2-overexpressing stages IIIB or IV non-small cell lung cancer (NSCLC) and to study the relationship between results from the two methods for determining levels of Her2 overexpression. Chemonaive patients were eligible if they had stages IIIB or IV NSCLC with either a Her2 score of at least 1+ by immunohistochemical (IHC) analysis or a serum Her2 shed antigen level of at least 15 ng/ml by enzyme-linked immunosorbent assay (ELISA). Treatment consisted of cisplatin 75 mg/m(2) day one plus gemcitabine 1250 mg/m(2) days one and eight plus trastuzumab 4 mg/kg day one and 2 mg/kg weekly thereafter on a 21-day cycle for six cycles followed by weekly maintenance trastuzumab therapy. Of the 21 patients enrolled, 8 (38%) patients had a partial response. The 1-year survival rate was 62% (13/21). Median time to progression was 36 weeks. Pharmacokinetic studies revealed no interaction between trastuzumab and gemcitabine plus cisplatin. In patients screened for this study, Her2 expression was zero in 283/360 (79%); 1+ in 32/360 (9%); 2+ in 27/360 (8%); and 3+ in 18/360 patients (5%). Serum Her2 shed antigen was >15 ng/ml in 27/ 288 (9%) patients. Of patients who had both Her2 assays, 24% (4/17) with ELISA scores >15 ng/ml had IHC scores of 3+, compared with only 2% (3/145) of the patients <15 ng/ml and 4% (7/162) of all patients. The addition of trastuzumab to cisplatin and gemcitabine was well tolerated, but further study will be required to determine whether this combination is superior to chemotherapy alone. This may be demonstrated if only those patients with Her2, having a score of IHC 3+ were eligible. Since IHC 3+ is rare in NSCLC, performing IHC in only those patients with serum Her2 shed antigen >15 ng/ml would greatly increase the efficiency of IHC screening though at the cost of excluding nearly half the patients with Her2 scores of 3+ on IHC analysis. Thus, if sequential screening consisting of serum ELISA followed by IHC analysis is implemented, it may make a trastuzumab trial feasible but should ultimately be supplanted by another screening system if trastuzumab is shown to be beneficial to some patients with IHC Her2 scores of 3+.

Adjuvant chemotherapy for non-small-cell lung cancer.

Survival rates following complete resection for patients with non-small-cell lung cancer are disappointing. Only 60-70% of patients with stage I disease (no lymph node involvement) are expected to survive 5 years. Attempts to improve survival have included the use of chemotherapy, radiation, or both before or after surgery. The majority of randomized trials examining the use of postoperative therapies have not found a survival benefit. Many of these trials have enrolled small numbers of patients and have been underpowered to detect small, but significant, survival differences. Recent data from large, randomized international trials have yielded conflicting results. The use of postoperative therapy should continue to be studied in clinical trials and a new meta-analysis incorporating results from recently completed randomized trials should be conducted.

Combined modality therapy of early stage nonsmall cell lung cancer.

Therapy for locally advanced NSCLC has evolved into a multidisciplinary effort. Patients who are considered for this approach should undergo rigorous testing to accurately stage their disease. Patients with pleural effusions (with rare exception) are not candidates for intensive combined modality therapy. Appropriate patients for combined modality therapy should have a good performance status (generally Zubrod 0 or 1), adequate pulmonary function, absence of significant heart, lung, or other medical diseases, and be appropriate candidates for combination chemotherapy and thoracic surgery or thoracic radiotherapy. Several lessons can be learned from looking broadly at the phase II and phase III combined modality experience. The available data do not support the routine use of postoperative therapy in patients with completely resected disease. Treatment with chemotherapy before surgery or radiation has demonstrated survival benefit in patients with stage III disease. The French phase III trial of induction chemotherapy in patients with early stage disease found an 11-month improvement in overall survival (P = 0.15) and a significant increase in the risk of death for patients with stage I and II disease. The ongoing U.S. intergroup trial (SWOG 9900) and European trials will help to further define the role of chemotherapy in patients with clinical stage IB, II and IIIA NSCLC. Clinical trials should be conducted to compare preoperative chemoradiotherapy with preoperative chemotherapy. The recently completed intergroup 0139 trial (chemoradiation followed by surgery or not) should help to define whether surgery and radiation are required in the management of stage IIIA NSCLC. Finally, further improvement in survival with the use of "newer" cytotoxic agents seems unlikely as phase III trials in metastatic NSCLC have not demonstrated marked superiority over cispiatin-based regimens. Ongoing trials are assessing the incorporation of newer, biologic-based "targeted" therapies. Despite the dismal findings of trials of postoperative therapy, many patients continue to have surgery as their initial treatment followed by postoperative therapy. In contrast, trials with induction treatment seem to offer improved survival. It is time for a true multidisciplinary approach to the treatment of locally advanced NSCLC. Pulmonary physicians, thoracic surgeons, medical oncologists, and radiation oncologists should meet before the initiation of treatment to plan the most appropriate therapy for the individual patient.

Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220.

BACKGROUND: Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy. METHODS: Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility. RESULTS: Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%. CONCLUSIONS: Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.

Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer: Southwest Oncology Group Trial S9900, an intergroup, randomized, phase III trial.

PURPOSE Patients with early-stage non-small-cell lung cancer (NSCLC) have a poor prognosis even after complete resection. Earlier studies of preoperative (induction) chemotherapy in resectable NSCLC demonstrated feasibility and encouraging survival data. This randomized phase III trial compared overall survival (OS) for preoperative paclitaxel and carboplatin followed by surgery with surgery alone in patients with early-stage NSCLC. PATIENTS AND METHODS Patients with clinical stage IB-IIIA NSCLC (excluding superior sulcus tumors and N2 disease) were eligible. Patients were randomly assigned to surgery alone or to three cycles of paclitaxel (225 mg/m(2)) and carboplatin (area under curve, 6) followed by surgical resection. The primary end point was OS; secondary end points were progression-free survival (PFS), chemotherapy response, and toxicity. RESULTS The trial closed early with 354 patients after reports of a survival benefit for postoperative chemotherapy in other studies. The median OS was 41 months in the surgery-only arm and 62 months in the preoperative chemotherapy arm (hazard ratio, 0.79; 95% CI, 0.60 to 1.06; P = .11.) The median PFS was 20 months for surgery alone and 33 months for preoperative chemotherapy (hazard ratio, 0.80; 95% CI, 0.61 to 1.04; P = .10.) Major response to chemotherapy was seen in 41% of patients; no unexpected toxicity was observed. CONCLUSION This trial closed prematurely after compelling evidence supporting postoperative chemotherapy emerged. Although OS and PFS were higher with preoperative chemotherapy, the differences did not reach statistical significance. At present, stronger evidence exists for postoperative chemotherapy in early-stage NSCLC.

Dose escalation of gemcitabine is possible with concurrent chest three-dimensional rather than two-dimensional radiotherapy: a phase I trial in patients with stage III non-small-cell lung cancer.

PURPOSE: To determine in a Phase I study the maximum tolerated dose of weekly gemcitabine concurrent with radiotherapy in locally advanced non-small-cell lung cancer (NSCLC), as well as the relationship between the volume of the esophagus irradiated and severe esophagitis. METHODS AND MATERIALS: Twenty-one patients with Stage III NSCLC received gemcitabine initially at 150 mg/m(2)/wk over 7 weeks concurrently with chest radiotherapy to 63 Gy in 34 fractions. The first 9 patients underwent treatment with two-dimensional (2D) radiotherapy; the remaining 12 patients, with three-dimensional conformal radiotherapy (3D-CRT) and target volume reduced to clinically apparent disease. Consolidation was 4 cycles of gemcitabine at 1000 mg/m(2)/wk and cisplatin 60 mg/m(2). RESULTS: In the 2D group, the dose-limiting toxicity, Grade 3 esophagitis, occurred in 3 of 6 patients in the 150-mg/m(2)/wk cohort and 2 of 3 patients in the 125-mg/m(2)/wk cohort. No cases of Grade 3 esophagitis occurred at these doses in the 3D group. At gemcitabine 190 mg/m(2)/wk, 2 of 6 patients in the 3D cohort had Grade 3 esophagitis. The mean percentages of esophagus irradiated to 60 Gy were 68% in the 2D cohort and 18% in the 3D cohort. CONCLUSIONS: We could not escalate the dose of gemcitabine with concurrent radiotherapy when using 2D planning because of severe acute esophagitis. However, we could escalate the dose of gemcitabine to 190 mg/m(2)/wk when using 3D planning. The Phase II dose is 150 mg/m(2)/wk. Three-dimensional CRT permitted the use of higher doses of gemcitabine.

Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline.

PURPOSE: To determine the role of adjuvant chemotherapy and radiation therapy in patients with completely resected stage IA-IIIA non-small-cell lung cancer (NSCLC). METHODS: The Cancer Care Ontario Program in Evidence-Based Care and the American Society of Clinical Oncology convened a Joint Expert Panel in August 2006 to review the evidence and draft recommendations for these therapies. RESULTS: Available data support the use of adjuvant cisplatin-based chemotherapy in completely resected NSCLC; however, the strength of the data and consequent recommendations vary by disease stage. Adjuvant radiation therapy appears detrimental to survival in stages IB and II, with a possible modest benefit in stage IIIA. CONCLUSION: Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease. Although there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use. To date, very few patients with stage IA NSCLC have been enrolled onto RCTs of adjuvant therapy; adjuvant chemotherapy is not recommended in these cases. Evidence from RCTs demonstrates a survival detriment for adjuvant radiotherapy with limited evidence for a reduction in local recurrence. Adjuvant radiation therapy appears detrimental to survival in stage IB and II, and may possibly confer a modest benefit in stage IIIA.

Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma.

BACKGROUND: The authors evaluated the safety, tolerability, and efficacy of treatment using lonafarnib, a novel farnesyltransferase inhibitor (FTI), in combination with paclitaxel in patients with metastatic (Stage IIIB/V), taxane-refractory/resistant nonsmall cell lung carcinoma (NSCLC). METHODS: Patients with NSCLC who experienced disease progression while receiving previous taxane therapy or who had disease recurrence within 3 months after taxane therapy cessation were treated with continuous lonafarnib 100 mg orally twice per day beginning on Day 1 and paclitaxel 175 mg/m(2) intravenously over 3 hours on Day 8 of each 21-day cycle. RESULTS: A total of 33 patients were enrolled, 29 of whom were evaluable for response. Partial responses (PR) and stable disease (SD) were observed in 3 (10%) and 11 patients (38%), respectively. Thus, 48% (14 of 29) experienced clinical benefit (PR or SD). The updated and final median overall survival time was 39 weeks and the median disease progression-free survival time was 16 weeks. The combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Grade 3 toxicities included fatigue (9%), diarrhea (6%), and dyspnea (6%). Grade 3 neutropenia occurred in only 1 patient (3%). Grade 4 adverse events included respiratory insufficiency in 2 patients (6%) and acute respiratory failure in 1 patient (3%). CONCLUSIONS: Lonafarnib plus paclitaxel demonstrated clinical activity in patients with taxane-refractory/resistant metastatic NSCLC. In addition, the combination of lonafarnib and paclitaxel was well tolerated with minimal toxicity. Evaluation of this combination therapy in additional clinical trials is warranted.

Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced nonsmall cell lung cancer.

BACKGROUND: The primary objectives of this study were to determine the efficacy and tolerability of a pemetrexed-carboplatin combination as first-line therapy in patients with advanced nonsmall cell lung cancer. METHODS: Eligibility criteria included Zubrod performance status of 0 or 1, Stage IIIB (malignant effusion) or IV disease, and no prior chemotherapy. Treatment was pemetrexed 500 mg/m2 given intravenously and carboplatin area under the serum concentration-time curve = 6 given intravenously on Day 1 every 3 weeks for six cycles; patients could receive additional cycles at the discretion of the treating physician and patient. All patients received folic acid, vitamin B12, and dexamethasone prophylaxis. RESULTS: Fifty patients (31 men and 19 women) were treated. The median age was 62 years. Ninety-six percent of patients had Stage IV disease, and 88% had a performance status of 1. The median number of cycles was 6; 15 patients received 8 or more cycles. There was Grade 3/4 neutropenia in 11 (22%) and 2 (4%) patients, respectively; Grade 3/4 thrombocytopenia in 1 (2%) and 0 patients, respectively. Three patients (6%) experienced Grade 3 nonhematologic side effects (diarrhea, neutropenic pneumonia, and fatigue). No patients had sensory neuropathy or alopecia >Grade 1. The partial response rate was 24%, median time to progression 5.4 months, 1-year survival 56.0%, and median survival 13.5 months. CONCLUSIONS: This is an active, very well-tolerated regimen. Trials focused on how to integrate this doublet with novel agents are warranted.

The novel and effective nonplatinum, nontaxane combination of gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: potential for decreased toxicity and combination with biological therapy.

BACKGROUND: Gemcitabine and vinorelbine are two of the most active third-generation agents for the treatment of advanced nonsmall cell lung carcinoma (NSCLC). The authors conducted a formal Phase II trial to evaluate the efficacy of this combination in both untreated and previously treated patients with Stage IIIB (with pleural effusion) or Stage IV NSCLC. METHODS: A total of 78 patients were treated on the current Phase II trial of front-line or second/third-line therapy with gemcitabine and vinorelbine in NSCLC. Eligible patients manifested either untreated disease (n = 42) or had received at least one but not more than two prior chemotherapy regimens (n = 36). The median age was 57.5 years (range, 33-79) with 57 men (73%) and 21 women (27%). The median performance status was one (range, one to two). The initial eight patients (four untreated and four previously treated) were treated at a previously established maximum tolerated dose of vinorelbine (30 mg/m(2)) and gemcitabine (1000 mg/m(2)) on Days 1, 8, and 15, with significant myelosuppression seen in five out of eight patients requiring dose omission in the first cycle. The next 70 patients received a reduced dose of vinorelbine (25 mg/m(2)) followed by gemcitabine (900 mg/m(2)) on Days 1, 8, and 15. RESULTS: Seventy eight patients were treated. Fifteen (36%) of the 42 evaluable patients who received front-line therapy had objective responses and 14 (33%) had stable disease. In the patients with prior treatment, 6 (17%) of 36 patients had partial response and 18 patients (50%) had stable disease. Median survival time for the previously untreated patient group was 10.1 months, with a one year survival of 43% and a two year survival rate of 32%. For the previously treated patients, the median survival time was 8.5 months, with a one year survival rate of 30%. Toxic effects were notable for significant myelosuppression, with > or =Grade 3 granulocytopenia seen in 55% of the patients on the untreated arm and 67% of the patients on the previously treated arm. Additionally, 9.5% and 13.9% (untreated and previously treated), respectively, of these patients experienced Grades 3 and 4 thrombocytopenia at some point in their treatment. A full dose delivery analysis showed that this myelosuppression resulted in Course 1, Day 15 skipped doses (even at the reduced dose level) in 42% of previously untreated patients and 47% of pretreated patients. Other side effects seen at Grades 3 and 4 in previously untreated and treated patients included anemia (9.5% and 2.8%), asthenia (4.8% and 5.5%), infection (14.3% and 5.6%), pain (9.5% and 19.4%), and pulmonary complications (4.8% and 13.8%). CONCLUSIONS: Gemcitabine/vinorelbine is an active, well-tolerated combination in both front-line and second/third-line therapy for Stage IIIB/IV NSCLC. The response rate, median survival rate, and one year survival rate compare favorably with platinum-based regimens. The toxicity profile of the gemcitabine/vinorelbine combination was quite favorable, with minimal Grade 3 and 4 toxic effects aside from granulocytopenia, which resulted in numerous Day 15 skipped doses but no significant febrile neutropenia or infection. The combination of gemcitabine and vinorelbine could be a useful regimen in standard clinical practice and has the potential for efficient combination with biologic/targeted therapy. Multiple randomized trials of this combination versus platinum combinations are now ongoing [corrected].