ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial.

BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rßγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS: In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 µg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 µg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.

Imaging in Advanced Non-Small Cell Lung Cancer: A Medical Oncology Perspective.

Treatment advances have improved outcomes in patients with lung cancer, with a number of targeted therapies and immunotherapies now approved for patients with metastatic disease. Along with longer survival, modern treatment paradigms have increased therapeutic decision-making complexity underscoring informative imaging as paramount in guiding clinical care. In this review, we summarize challenges the thoracic oncologist encounters in common clinical settings. In addition, we explore unmet needs for future investigations with particular focus on positron emission tomography technology and immunotherapies.

Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib.

BACKGROUND: Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-positive patients remains poorly understood as these patients have been routinely excluded from clinical trials. METHODS: We describe four ALK-positive patients with LM who were treated with the next-generation ALK inhibitor alectinib through single-patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors--crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily. RESULTS: Four ALK-positive NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clinical and radiographic improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 months before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose reduction due to grade 2 hyperbilirubinemia. CONCLUSIONS: Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Additional prospective studies of alectinib in ALK-positive patients with LM are warranted.

The role of molecular analyses in the era of personalized therapy for advanced NSCLC.

Platinum-based doublet chemotherapy is the traditional treatment of choice for advanced non-small cell lung cancer (NSCLC); however, the efficacy of these regimens has reached a plateau. Increasing evidence demonstrates that patients with sensitizing mutations in the epidermal growth factor receptor (EGFR) experience improved progression-free survival and response rates with first-line gefitinib or erlotinib therapy relative to traditional platinum-based chemotherapy, while patients with EGFR-mutation negative tumors gain greater benefit from platinum-based chemotherapy. These results highlight the importance of molecular testing prior to the initiation of first-line therapy for advanced NSCLC. Routine molecular testing of tumor samples represents an important paradigm shift in NSCLC therapy and would allow for individualized therapy in specific subsets of patients. As these and other advances in personalized treatment are integrated into everyday clinical practice, pulmonologists will play a vital role in ensuring that tumor samples of adequate quality and quantity are collected in order to perform appropriate molecular analyses to guide treatment decisions. This article provides an overview of clinical trial data supporting molecular analysis of NSCLC, describes specimen acquisition and testing methods currently in use, and discusses future directions of personalized therapy for patients with NSCLC.

Toxicity, response rates and survival outcomes of induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy for locally advanced esophageal cancer.

OBJECTIVE: Cisplatin-based chemoradiotherapy is standard treatment for locally advanced esophageal and gastroesophageal cancers; however, the optimal chemotherapy regimen remains to be defined. METHODS: Retrospective single institution analysis of toxicities, response rates and survival outcomes in patients with cT3-4 or N1/M1a esophageal squamous cell or adenocarcinoma treated with induction cisplatin and irinotecan followed by concurrent cisplatin, irinotecan and radiotherapy. Secondary analysis for association of disease control and outcomes with demographic, tumor and treatment factors (including histology). RESULTS: Fifty-three patients were eligible for the present analysis. All patients underwent endoscopic ultrasonography and were either cT3-4 and/or cN1 disease. Fifty patients completed radiotherapy as planned (median dose 50.4 Gy, range 0-61.2), and 35 patients completed four cycles of chemotherapy as planned (range 1-4). Severe acute toxicities included Grade ≥ 3 neutropenia and esophagitis in 13 and 12 patients, respectively. There were no Grade 5 (fatal) toxicities noted. At mean survivor follow-up of 24.5 months (range 2.7-63), 17 patients were alive (8 without disease) and 36 deceased. Forty patients experienced disease recurrence, with initial loco-regional, distant or both failures in 28, 9 and 3 patients, respectively. Estimated 2-year overall survival and freedom from failure were 42 and 9%, respectively, without significant difference by histology. CONCLUSIONS: Cisplatin/irinotecan chemoradiotherapy is tolerable, demonstrating similar efficacy for squamous cell and adenocarcinoma esophageal cancers.

Involved-field radiotherapy with concurrent chemotherapy for limited-stage small-cell lung cancer: disease control, patterns of failure and survival.

INTRODUCTION: Major randomised trials have employed elective nodal irradiation as part of combined modality therapy for limited-stage small-cell lung cancer (SCLC). The present investigation describes patterns of failure, disease control, and survival outcomes for involved-field radiotherapy with concurrent chemotherapy, without elective irradiation of uninvolved mediastinal nodal regions. METHODS: Retrospective analysis of SCLC patients treated with curative-intent accelerated, twice-daily radiotherapy and concurrent platinum-based chemotherapy at an academic institution. Treatment fields were reviewed, and patients who completed ≥42 Gy in 1.5 Gy twice-daily fractions to involved fields (without elective irradiation of uninvolved mediastinal lymphatic regions) were included in the present analysis. Initial patterns of failure, disease control and overall survival were recorded. RESULTS: Fifty-two patients fulfilled study criteria and were included in the present analysis. All but one patient completed three to four cycles of chemotherapy, and 10 patients experienced grade 3 acute esophagitis. At a median survivor follow-up of 35 months (range 5.5-91.9), 22 patients were alive (15 without recurrence) and 30 had died (23 of/with disease, four of unknown cause, two of other cause and one of treatment toxicity). Initial site(s) of disease failure were loco-regional only (11 patients), distant only (14) and loco-regional plus distant (3). There were no cases of isolated out-of-field mediastinal recurrence in the absence of supraclavicular or more distant disease. The estimated 3-year disease-free and overall survivals were 36% and 44%, respectively. CONCLUSIONS: Involved-field radiotherapy did not appear to have an adverse impact on the anticipated patterns of failure, disease control, or overall survival in this population of limited-stage SCLC patients.

Once-daily radiotherapy to > or =59.4 Gy versus twice-daily radiotherapy to > or =45.0 Gy with concurrent chemotherapy for limited-stage small-cell lung cancer: a comparative analysis of toxicities and outcomes.

PURPOSE: The aim of this study was to compare toxicities, disease control, survival outcomes, and patterns of failure between groups of limited-stage small-cell lung cancer patients treated with once-daily versus twice-daily radiotherapy and concurrent chemotherapy. MATERIALS AND METHODS: This single-institution retrospective analysis included a comparison of two of radiotherapy regimens to planned doses of (1) > or =59.4 Gy at 1.8-2.0 Gy per once-daily fraction or (2) > or =45 Gy at 1.5 Gy per twice-daily fractions with concurrent platinum-based chemotherapy. Comparative analyses of toxicities and disease control were performed. RESULTS: A total of 71 patients were included in the present study (17 once-daily, 54 twice-daily). Patient, tumor, staging, and treatment factors were similar between the two treatment groups. Median planned radiotherapy doses were 60 Gy (range 59.4-70.0 Gy) and 45 Gy (range 45-51 Gy) for the once-daily and twice-daily groups, respectively. Acute toxicities were similar between the groups ( approximately 20% grade 3 esophagitis). At a median survival follow-up of 26.2 months (range 3.4-85.5 months), 42 patients had died. The 2-year overall survival estimates were similar at 43% and 49% for the once-daily versus twice-daily groups, respectively. Isolated in-field failures were similar between the two groups ( approximately 17%). CONCLUSION: The present analysis did not detect a statistically significant difference in acute toxicities, disease control, or survival outcomes in limited-stage small-cell lung cancer patients treated with concurrent chemotherapy and once-daily versus twice-daily radiotherapy.

Cisplatin/Irinotecan versus carboplatin/paclitaxel as definitive chemoradiotherapy for locoregionally advanced esophageal cancer.

OBJECTIVE: To compare toxicities, disease control, and survival outcomes for patients treated with either cisplatin/irinotecan versus carboplatin/paclitaxel concurrent chemoradiotherapy for locally advanced esophageal cancer. METHODS: Single-institution retrospective comparison between treatment groups: the cisplatin/irinotecan group was treated with 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy, whereas the carboplatin/paclitaxel group began with chemoradiotherapy followed by 2 additional cycles of chemotherapy. Acute toxicities, response rates, disease control, survival outcomes, and patterns of failure were compared between the groups. RESULTS: Between January 2000 and December 2007, 57 patients were identified for inclusion in the present study (38 cisplatin/irinotecan and 19 carboplatin/paclitaxel). Groups were well-balanced by clinical-, pathologic-, staging-, and treatment-related factors. Thirty-five patients (92%) in the cisplatin/irinotecan group and 18 patients (95%) in the carboplatin/paclitaxel group completed the concurrent phase of chemoradiotherapy. There were no significant differences in hematologic or nonhematologic toxicities between the groups. At a median survivor follow-up of 37.6 months (range: 7.3-59.3 months) for the entire population, 22 patients were alive (16 without evidence of disease). The 3-year overall survival estimates was 19.7% for the cisplatin/irinotecan group versus 56.1% for the carboplatin/paclitaxel group (P = 0.022). Estimated 3-year cancer-specific survivals were 24.6% for the cisplatin/irinotecan group versus 59.3% for the carboplatin/paclitaxel group (P = 0.033). CONCLUSION: Concurrent chemoradiotherapy with carboplatin/paclitaxel is well-tolerated and provided superior overall and disease-specific survival compared with cisplatin/irinotecan chemoradiotherapy in the present study population. Further investigation is warranted.

Factors associated with severe acute esophagitis from hyperfractionated radiotherapy with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE: To describe incidence and identify factors associated with development of severe acute esophagitis during hyperfractionated radiotherapy with concurrent chemotherapy (BID-CRT) in patients with limited-stage small-cell lung cancer (SCLC). METHODS AND MATERIALS: Retrospective cohort analysis of patient-, tumor-, and treatment-related variables was performed to identify factors associated with Radiation Therapy Oncology Group (RTOG) Grade 3 acute esophagitis. Twice-daily chemoradiotherapy (BID-CRT) involved 45 Gy at 1.5 Gy per fraction, treated twice daily with concurrent platinum-based chemotherapy. Logistic regression analyses were used to identify factors associated with esophagitis. RESULTS: Between June 1999 and June 2007, 48 patients underwent curative intent BID-CRT for SCLC and were included in the analysis. Median radiotherapy dose was 45 Gy (range, 42-51 Gy) delivered with a median 4 cycles of chemotherapy (range, 2-6). RTOG Grade 3 acute esophagitis developed in 11 patients. No patient developed Grade 4 or 5 esophagitis. Simple logistic regression analyses demonstrated a highly significant association between Grade 3 acute esophagitis and mean esophageal dose (p = 0.002) as well as relative volume dosimetric area under curve (RV-AUC; p = 0.004). Using multiple regression analysis, RV-AUC was identified as the only factor associated with Grade 3 esophagitis (p = 0.004). The most strongly associated dosimetric volume was the V15 (Grade 3 esophagitis rates of 15% vs. 64% for V15 <60% versus >or=60%, respectively). CONCLUSIONS: RV-AUC is the factor most associated with development of Grade 3 acute esophagitis in limited stage SCLC patients receiving BID-CRT.

Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer.

BACKGROUND: A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule. METHODS: From February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days. RESULTS: The MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively. CONCLUSION: Vinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively. TRIAL REGISTRATION NUMBER: NCT00287963.

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial.

BACKGROUND: COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-kappaB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. METHODS: Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. RESULTS: No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. CONCLUSION: The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. TRIAL REGISTRATION NUMBER: NCT00290680.

Conformal high dose external radiation therapy, 80.5 Gy, alone for medically inoperable non-small cell lung cancer: a retrospective analysis.

BACKGROUND: Retrospective analysis of patients with medically inoperable non-small cell lung cancer treated with continuous high-dose external beam radiation therapy at the Medical University of South Carolina. METHODS: We identified 35 patients with non-small cell lung cancer treated 1998-2002. None were candidates for resection for reasons including: pulmonary function (n = 23), previous cancer (n = 9), other co-morbidities (n = 2), and refusal of surgery (n = 1). Median percent predicted forced expiratory volume in 1 second was 41.5%. Median age was 71 years. Five patients had more than one primary tumor: three were concurrently treated, two were sequentially treated. Lesion sizes were <3 cm (n = 24); 3-5 cm (n = 12), and >5 cm (n = 5). Nodal stage was as follows: N0 (n = 33) and N1 (n = 2). Radiation therapy was administered once daily: median dose was 80.5 Gy/35 fx/2.3 Gy/fx. The clinical target volume was tumor plus nodes > or =1.0 cm. V20 data were available for 12 patients, with a mean value of 15.7%. RESULTS: Thirty-four patients completed treatment. Median follow-up was 23.0 months. There were 26 deaths: 19 died from non-small cell lung (73%) and seven died from co-morbid illness (27%). Median survival was 24 months (95% CI, 18.0-31.9 months). Four patients were alive with disease, and five were alive disease-free at 10- and 68-month follow-ups. Of 41 lesions, local failure occurred in 15 lesions (37%) of which 3 local failure patients (9%) failed concomitantly in untreated regional lymph nodes. There were no isolated nodal recurrences. Distant progression: 10 patients (29%) of which 6 distant progression without local failure. Two patients who both had prior lobectomies experienced grade 5 toxicities. CONCLUSION: Continuous high-dose external beam radiation therapy 80.5 Gy administered in 35 fractions was tolerated. Treatment-related death was rare (6%) and isolated to patients with prior lobectomies in an extremely high-risk population. Most mortality was lung cancer-related. The dose of 80.5 Gy in 7 weeks is supported for patients with single lesions and no prior lobectomy. Local failure dominates and higher effective doses should be explored.

A phase II trial of 6-hydroxymethylacylfulvene (MGI-114, irofulven) in patients with relapsed or refractory non-small cell lung cancer.

PURPOSE: To assess the efficacy and toxicity of 6-hydroxymethylacylfulvene (HMAF; MGI-114, irofulven) as therapy for relapsed or refractory non-small cell lung cancer. METHODS: A two-stage phase II design was employed separately for refractory and relapsed patients to differentiate between ineffective treatment (response rate < or =10%) and active treatment (response rate > or =30%). Eligible patients received HMAF 11 mg/m2 per day intravenously over 5 min on days 1-5, with cycles repeated every 28 days. RESULTS: Thirty-six patients (15 relapsed; 21 refractory) were treated, and no responses were seen. TOXICITY: Grade 3 neutropenia and grade 3 thrombocytopenia each occurred in 11% of the patients. Grade 3 nausea occurred in 47%; grade 3-4 vomiting in 42%. Twenty-two percent developed grade 3 fatigue. Eleven percent developed grade 3 hallucinations. CONCLUSIONS: HMAF, administered at this dose and schedule, is not active as salvage therapy for relapsed or refractory non-small cell lung cancer.

A phase I study of sequential administration of escalating doses of intravenous paclitaxel, oral topotecan, and fixed-dose oral etoposide in patients with solid tumors.

BACKGROUND: Based on preclinical findings and on the clinical antitumor efficacy of sequential paclitaxel/topotecan and topotecan/etoposide, the authors sought to define the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) associated with a sequential combination of paclitaxel, topotecan, and etoposide in patients with solid tumors. METHODS: The MTDs were determined through standard dose escalation in cohorts of three patients. Patients with refractory solid tumors and performance status < or = 2 were treated with intravenous paclitaxel 50-110 mg/m(2) (Day 1), oral topotecan 0.5-2.0 mg/m(2) (Days 2-4), and oral etoposide 160 mg/m(2) (Days 5-7) during every 21-day cycle. For dose-limiting neutropenia, granulocyte-colony-stimulating factor (G-CSF) was administered on Day 8 in subsequent cohorts. Blood samples were obtained before treatment during Cycle 1 (Days 1, 2, and 5) for topoisomerase I assessment. RESULTS: Twenty-eight patients received a combined total of 129 cycles. The MTDs were paclitaxel 80 mg/m(2), topotecan 1.5 mg/m(2), and etoposide 160 mg/m(2) without G-CSF. In minimally pretreated patients, G-CSF allowed paclitaxel dose escalation to 110 mg/m(2). Three patients (11%) had radiologic partial responses, and 4 patients (14%) had stable disease. Day 2 topoisomerase I levels increased by 2-15 times relative to baseline levels in 7 of 14 patients analyzed (50%). CONCLUSIONS: The novel sequential combination that was evaluated generally was well tolerated and active in patients with refractory solid tumors. Based on hematologic DLTs, the authors recommend further evaluation of paclitaxel 110 mg/m(2), topotecan 1.5 mg/m(2), and etoposide 160 mg/m(2) with G-CSF support in minimally pretreated patients.

Lunx is a superior molecular marker for detection of non-small cell lung cancer in peripheral blood [corrected].

The clinical management of non-small cell lung cancer (NSCLC) would benefit greatly by a test that was able to detect small amounts of NSCLC in the peripheral blood. In this report, we used a novel strategy to enrich tumor cells from the peripheral blood of 24 stage I to IV NSCLC patients and determined expression levels for six cancer-associated genes (lunx, muc1, KS1/4, CEA, CK19, and PSE). Using thresholds established at three standard deviations above the mean observed in 15 normal controls, we observed that lunx (10 of 24, 42%), muc1 (5 of 24, 21%), and CK19 (5 of 24, 21%) were overexpressed in 14 of 24 (58%) peripheral blood samples obtained from NSCLC patients. Patients who overexpressed either KS1/4 (n = 2) or PSE (n = 1) also overexpressed either lunx or muc1. Of patients with presumed curable and resectable stage I to II disease (n = 7), at least one marker was overexpressed in three (43%) patients. In advanced stage III to IV patients (n = 17), at least one marker was overexpressed in 11 patients (65%). These results provide evidence that circulating tumor cells can be detected in NSCLC patients by a high throughput molecular technique. Further studies are needed to determine the clinical relevance of gene overexpression.

The role of radiotherapy and chemotherapy for curative management of medically inoperable and stage III nonsmall cell lung cancer, and radiotherapy for palliation of symptomatic disease.

Radiotherapy has an expanding role in all phases of treatment of nonsmall cell lung cancer. Evolutions in technique, such as three-dimensional conformal radiotherapy, hold the promise for more effective treatment of patients with early stage disease who are not candidates for surgical intervention. Multimodality therapy for patients with locally advanced disease is evolving rapidly, with evidence accruing as to the optimal schedules and doses of radiotherapy and combination chemotherapy. Palliative dose schedules are being refined that maximize patient comfort while providing substantial symptom relief.

Influence of celiac axis lymph nodes in the definitive treatment of esophageal cancer.

The management of patients with cancer of the distal thoracic esophagus is often made difficult by the presence of disease in the celiac axis lymph nodes. We investigated the outcome of such patients treated for cure in an attempt to better define the best treatment. The charts of all patients with esophageal cancer treated at the Department of Radiation Oncology at the Medical University of South Carolina between 1990 and 1998 were reviewed. Three groups of patients were analyzed: NoMo, N1Mo, and patients with positive celiac axis lymph nodes (M1a). Among 217 patients, 56 patients received radiotherapy with intent to cure, along with surgery, chemotherapy, or some combination of these modalities. Of these, 14 had disease of the distal esophagus with the celiac axis as their only site of distant disease. Comparison of survival curves in the three analyzed groups revealed no statistically significant differences in terms of overall survival (p = 0.3458 by the log-rank test) or disease-free survival (p = 0.5509 by the log-rank test). Patients with positive celiac axis lymph nodes as their only site of "M1" disease experienced a 2-year survival rate similar to "Mo" patients when treated with curative intent.

Weekly, high-dose paclitaxel in advanced lung carcinoma: a phase II study with pharmacokinetics by the Cancer and Leukemia Group B.

BACKGROUND: The Cancer and Leukemia Group B conducted a Phase II trial to evaluate the efficacy, toxicity, and pharmacokinetics of paclitaxel administered at a maximum dose density for patients with chemotherapy-naïve, advanced-stage non-small cell lung carcinoma (NSCLC). METHODS: Patients with Stage IIIB/IV or recurrent NSCLC, a performance status (PS) score of 0-1, and no history of chemotherapy exposure were eligible. Paclitaxel, 150 mg/m(2), was administered over 3 hours during Weeks 1-6 of an 8-week cycle. Doses were modified for ANC < 1500/microL or for >or= Grade 2 neuropathy on the day of therapy. Treatment continued until toxicity or disease progression. Pharmacokinetics were assessed at Weeks 1, 3, and 5 of Cycle 1. RESULTS: Thirty-eight patients (median age, 64 years; range, 31-81 years) were treated. There were 21 males (PS = 0 for 17). Eleven patients had received previous radiation, 2 had brain metastases, 25 had adenocarcinoma, 23 had Stage IV disease, 6 had StageIIIB disease, and 9 had recurrent disease. Grade 3-4 granulocytopenia occurred in 39% of patients. There were no deaths due to toxicity. Grade 2 or 3 neuropathy occurred in 29% and 24% of patients, respectively. Ten (27%) patients had Grade 3 hyperglycemia (glucose concentration > 250 mg/dL). There were 16 partial responses (42%; 95% confidence interval [CI], 26-59%). The median survival period was 12.3 months (95% CI, 7.9-19.6%), and the 1-year and 2-year survival rates were 52% (95% CI, 39-71%) and 26% (95% CI, 15-45%), respectively. Paclitaxel pharmacokinetics were consistent with published values and clearance was not induced. Older age and hyperglycemia were associated with greater neurotoxicity. CONCLUSIONS: Paclitaxel at 150 mg/m(2) per week x 6 every 8 weeks can be administered safely in the cooperative group setting. These Phase II data are comparable to those associated with combination therapy. The weekly dose-dense schedule may be more active than conventional schedules.