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Objective: We sought to study the clinical characteristics and outcomes of patients treated with a surgery-inclusive multimodality approach for Pancoast tumors., Methods: Clinical records of patients with Pancoast lung cancer who were enrolled for multimodality treatment between 1993 and 2003 at our institution were reviewed retrospectively., Results: Thirty-six patients completed neodjuvant chemoradiation followed by en bloc surgical resection, whereas one patient received high-dose radiation alone followed by surgical intervention. There were 22 men and 15 women. Thirty-four lobectomies and 3 pneumonectomies were performed. Pretreatment non-small cell lung cancer stages were IIB, IIIA, IIIB, and IV (presenting with solitary brain metastasis) in 18, 8, 6, and 5 cases, respectively. R0 resection was achieved in 36 (97.3%) patients. Operative mortality was 2.7% (n = 1). High-dose radiotherapy was successfully tolerated in all but 1 patient. Mean total radiation dose was 56.9 Gy. Pathologic complete response was found in 40.5% (n = 15) of patients. Recurrences were found in 50% (n = 18) of patients. Brain metastasis was the most common recurrence (n = 9), followed by other distant recurrences (n = 4) and local recurrences (n = 5). Median survival time for the group is 2.6 years, and median survival time (pathologic complete response) is 7.8 years. It is noteworthy that median survival time of patients with positive pretreatment lymph nodes (12 patients) was not reached., Conclusions: Surgical resection of Pancoast tumors after neoadjuvant high-dose radiation and chemotherapy can be safely performed. High-dose radiation in trimodality treatment is well tolerated and might be beneficial. Similar to other studies, late central nervous system relapse is problematic and indicates a need for assessing the role of prophylactic cranial irradiation in this disease.

Disease-directed treatment of lung cancer reduces the morbidity and extends life for patients. However, as providers we must recognize that treating the symptoms of the disease may be as important as the treatment of the disease itself. This is particularly true in advanced disease and after disease-directed therapies have been exhausted. Aggressive assessment of symptoms and use of palliative therapies can significantly reduce the symptomatology of advanced lung cancer. Though the impact of these symptoms (ie, pain, dyspnea, and cachexia) are well known, they tend to be under-treated. In addition, simple maneuvers such as opiate rotation for pain relief are underutilized. The diagnosis of lung cancer and its associated symptoms may result in severe psychosocial stress for the patient and further exacerbate the symptoms in a vicious cycle. Understanding of coping strategies may aid the medical provider in assisting the patient during his or her illness.

Purpose: To evaluate possible clinical and dosimetric predictors of acute esophagitis in patients with locally advanced non-small-cell lung carcinoma treated in a prospective Phase I-II trimodality protocol., Methods and Materials: The data from 36 patients with Stage III non-small-cell lung carcinoma treated in a Phase I-II high-dose concurrent chemoradiotherapy protocol were analyzed for possible predictors of acute esophagitis. The median age was 58 years (range, 38-77 years). Patients included in this study had either Stage IIIA (n = 24) or IIIB (n = 12) disease. All patients were treated with induction concurrent carboplatin (area under the plasma concentration-time curve 1), vinorelbine (5-15 mg/m(2)), and hyperfractionated radiotherapy (69.6 Gy) followed by consolidation chemotherapy (carboplatin area under the plasma concentration-time curve 6, vinorelbine 25 mg/m(2), docetaxel 75 mg/m(2)) or surgery (n = 19) plus consolidation chemotherapy. Acute toxicities were graded using the Radiation Therapy Oncology Group criteria. The following clinical and dosimetric parameters were analyzed: age, gender, race, T stage, N stage, pretreatment body mass index, percentage of weight lost during therapy, pretherapy serum albumin, tumor location, length of esophagus in treatment field, percentage of esophagus volume treated to >40, >45, >50, >55, >60, and >65 Gy. These parameters were coded and analyzed against Grade 2 and worse esophagitis using univariate and multivariate regression analyses., Results: Of the 36 patients, Grade 1, 2, and 3 acute esophagitis was observed in 16 (44%), 12 (33%), and 2 (5.5%) patients, respectively. Grade 4 or 5 toxicity was not observed in this patient cohort. Only the pretreatment body mass index (rho = -0.431, p = 0.004) and percentage of esophagus volume treated to >50 Gy (rho = 0.297, p = 0.040) demonstrated a statistically significant correlation with the incidence of Grade 2 or worse esophagitis on univariate analysis. These parameters retained their statistical significance on multivariate regression analysis (p = 0.029 and 0.049, respectively)., Conclusion: In patients undergoing concurrent high-dose chemotherapy and hyperfractionated radiotherapy, a low pretherapy body mass index and percentage of esophagus volume treated to >50 Gy were significantly associated with acute Grade 2 or worse esophagitis.

Background: Pulmonary resection after chemotherapy and concurrent full-dose radiotherapy (>59 Gy) has previously been associated with unacceptably high morbidity and mortality. Subsequently neoadjuvant therapy protocols have used reduced and potentially suboptimal radiotherapy doses of 45 Gy. We report a series of 40 patients with locally advanced non-small-cell lung cancer who successfully underwent pulmonary resection after receiving greater than 59 Gy radiation and concurrent chemotherapy. Operative results and midterm survival follow-up are presented., Methods: Data were reviewed from 40 consecutive patients who underwent lung resection after receiving high-dose radiotherapy and concurrent platinum-based chemotherapy between January 1994 and May 2000. The follow-up closing interval for this study was until August 2003 or time of death., Results: Preoperative stage was IIb (7 patients), IIIA (21 patients), IIIB (10 patients), and IV (2 patients with isolated brain metastasis). Thirteen patients exhibited Pancoast tumors. Median time from completion of induction therapy to surgery was 53 days. Twenty-nine lobectomies and 11 pneumonectomies (7 right, 4 left) were performed. There were no postoperative deaths. Intercostal muscle flaps were used prophylactically in all but one pneumonectomy patient. Seven patients required perioperative transfusions. Median intensive care unit (ICU) time averaged 2 days and the total length of stay was 6 days. One patient exhibited postpneumonectomy pulmonary edema and a bronchopleural fistula developed in another patient (not receiving an intercostal muscle flap). Thirty-four of 40 patients (85%; 95% CI: 70%-94%) were downstaged pathologically, 33 out of 40 patients (82.5%, 95% confidence interval [CI]: 67%-93%) indicated no residual lymphadenopathy, and 18 out of 40 patients (45%, 95% CI: 29%-61%) exhibited a complete pathologic response. Median follow-up was 2.8 years. The 1-, 2-, and 5-year overall survival rates were 92.4%, 66.7%, and 46.2%, respectively. Disease-free 1-, 2-, and 5-year survival rates were 73.0%, 67.2%, and 56.4%, respectively. Median disease-free survival has not been reached., Conclusions: Pulmonary resection may be performed safely after curative intent concurrent chemotherapy and radiotherapy to greater than 59 Gy. High pathologic complete response rates and sterilization of mediastinal lymph nodes were observed accompanied by highly favorable survival rates. This experience, though promising, will require confirmation in a prospective multiinstitutional clinical trial.

A phase II trial was designed to evaluate the efficacy and toxicity of gemcitabine in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-containing regimens and prospectively categorized for platinum response status. Treatment consisted of gemcitabine 1000 mg/m2 given intravenously on days 1 and 8 of a 21-day cycle. The status of p53 in pretreatment tumor tissue was assessed by immunohistochemistry (IHC). Sixty-one patients who progressed or recurred following platinum-based therapy were enrolled, 26 platinum-sensitive and 35 platinum-refractory. A median of 4 treatment courses (range, 2-7 courses) was delivered. Of the 55 patients assessable for response, there was 1 confirmed complete response and 3 with a confirmed partial response for an overall response proportion of 7%. Twenty-one patients had stable disease while 28 progressed and 2 patients had an unconfirmed partial response. Three of the responders (2 confirmed, 1 unconfirmed) were platinum-refractory. Median progression-free survival (PFS) and overall survival for all patients were 4.1 months and 8.6 months, respectively. Median PFS and overall survival for the platinum-sensitive and platinum-refractory cohorts were 5.4 months versus 3.1 months, and 11.9 months versus 7.1 months, respectively. Toxicity was principally hematologic with grade 3/4 neutropenia in 21% and grade 4 platelets in 8%. There were no treatment-related deaths. Twenty-four of 33 patients (73%) had p53-positive tumors. Although no significant association between platinum sensitivity and p53 status was seen, patients with platinum-sensitive disease and negative p53 by IHC had a trend toward longer survival compared to those with platinum-refractory disease and/or p53 positivity (P = 0.06). We concluded that salvage gemcitabine in this dose and schedule is safe and tolerable in previously platinum-treated patients with NSCLC.

Purpose: To determine the feasibility and a recommended phase II dose of tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC)., Experimental Design: Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m2) was given 1 h before cisplatin with planned dose escalation to 330 mg/m2 in the absence of dose-limiting toxicity, defined as > or =33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of tirapazamine (330 mg/m2), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation., Results: Thirty patients were enrolled at the 260 mg/m2 tirapazamine dose. All had performance status of 0-1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without tirapazamine, the present trial showed a higher rate of grade 3-4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months., Conclusions: Protocol-defined dose-limiting toxicity was observed at the initial tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of tirapazamine in LSCLC is warranted.

Purpose: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new drugs or new strategies to better use currently available agents. Sequential administration offers an opportunity to increase drug diversity while maintaining dose intensity. On the basis of the data indicating the activity of taxanes as second-line therapy and the lack of efficacy for more than three cycles of platinum-based therapy, this randomized Phase II study tested the concept of planned sequential chemotherapy in advanced NSCLC., Experimental Design: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0-1 and normal organ function were eligible., Therapy: arm 1, carboplatin (area under the curve = 5.5 mg/ml x min day 1) and gemcitabine (1000 mg/m(2) days 1 and 8 every 21 days x 3) followed by paclitaxel (225 mg/m(2) every 21 days x 3) or arm 2, cisplatin (100 mg/m(2) day 1), vinorelbine (25 mg/m(2) days 1 and 8 every 21 d x 3) followed by docetaxel (75-100 mg/m(2) every 21 days x 3)., Results: Two-hundred four patients were accrued, of whom, 178 were eligible and evaluable. Eighty percent of patients were stage IV on arm 1 and 85% on arm 2. Response rates were 21 and 28% on arms 1 and 2, respectively. Median, 1-year and 2-year survivals were 9 months, 34 and 13%, and 9 months, 36 and 8%, on arms 1 and 2, respectively., Conclusions: Sequential therapy, as used in this study, resulted in comparable efficacy to previous Southwest Oncology Group trials of two drug combinations in this population; however, it failed to meet criteria for further study.

Background: The need for better care for terminally ill patients led us to create an educational program to provide internal medicine residents and medical oncology fellows basic competency in palliative and end-of-life care., Methods: An interdisciplinary team identified educational strategies, course objectives, content, and evaluation instruments., Results and Conclusions: Our strategy is to use a required Web-based course to establish a knowledge base upon which specific training during clinical rotations build skills. Field testing of the Web course showed it was an effective tool for delivering clinically applicable content. Skill building experiences are now being integrated into selected clinical rotations.

Platinum-based chemotherapy is now established in the treatment of all stages of lung cancer. Despite the benefits of therapy, the majority of patients treated for lung cancer will ultimately progress. Some will retain good performance status and be candidates for additional, tumor-directed treatment. Docetaxel and pemetrexed have documented activity in phase III trials in patients progressing after first-line, platinum-based therapy. Gefitinib has recently been approved for treatment of disease in the third line. Numerous other agents with diverse mechanisms are currently undergoing evaluation in this setting. This review evaluates the population eligible for such treatments and discusses recent trials in second and subsequent lines of therapy.

Background: The regimens of carboplatin plus paclitaxel (CP) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) were compared in patients with advanced urothelial carcinoma., Methods: Patients with metastatic urothelial carcinoma were randomized to receive either CP (paclitaxel at a dose of 225 mg/m(2) and carboplatin [targeted area under the concentration-time curve (AUC) of 6] given every 21 days) or the standard M-VAC dosage., Results: Eighty-five patients were randomized to the respective treatment regimens (41 to CP and 44 to M-VAC). Response rates and overall survival were similar for both treatment arms. Patients treated with CP had an overall response rate of 28.2% (95% binomial confidence interval, 15.0-44.9%) compared with an overall response rate of 35.9% for the M-VAC arm (95% binomial confidence interval, 21.2-52.8%) (P = 0.63, Fisher exact test). The median progression-free survival among patients who were treated with M-VAC was 8.7 months and was 5.2 months for patients receiving CP (P = 0.24, log-rank test). At a median follow-up of 32.5 months, the median survival for patients treated with M-VAC was 15.4 months versus 13.8 months for patients treated with CP (P = 0.65, log-rank test). Patients treated with M-VAC were found to have more severe worst-degree toxicities compared with patients treated with CP (P = 0.0001). There were no significant differences with regard to quality of life as assessed by the Functional Assessment of Cancer Therapy-Bladder (FACT-BL) instrument (P = 0.33)., Conclusions: Interpretation of the results of this study must be made with caution because the study failed to reach its accrual goal. Patients treated with CP had a median survival of 13.8 months compared with 15.4 months for patients treated with M-VAC. Patients treated with CP appeared in general to better tolerate their treatment; however, there were no significant differences noted with regard to measured quality of life parameters., (Copyright 2004 American Cancer Society.)

Purpose: Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC., Patients and Methods: Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n=5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC)=6 on day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n=4), carboplatin dose was reduced to AUC=5. In cohort 3 (n=7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated., Results: Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed., Conclusion: The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.

Paraneoplastic syndromes are common complications of lung cancer. Although most frequently associated with advanced disease, paraneoplastic syndromes may also occur at early stages. Occasionally, the paraneoplastic syndrome may be the presenting symptom of lung cancer. For most paraneoplastic syndromes, the best treatment is to treat the underlying malignancy. However, in many cases, treatment of moderate efficacy or urgent therapy is required. Specific recommendations for the management of the most common paraneoplastic syndromes, including cachexia, hypercalcemia, and hyponatremia, are provided.

Purpose: Limited small-cell lung cancer (LSCLC) is characterized by a high initial response rate to chemoradiotherapy, but local or systemic relapse occurs in the majority of patients. Previous Southwest Oncology Group trials in LSCLC have utilized cisplatin and etoposide (PE) delivered concurrently with thoracic radiotherapy followed by two consolidation cycles. Newer chemotherapy regimens such as paclitaxel and carboplatin are active in small-cell lung cancer and hold the promise of improving both local and systemic control. S9713 evaluated the substitution of paclitaxel and carboplatin for PE consolidation in LSCLC., Patients and Methods: Between July 1998 and August 1999, 96 patients were accrued from 43 institutions. Eighty-nine patients were eligible; 87 were assessable for survival and response. Treatment consisted of cisplatin 50 mg/m(2) on days 1, 8, 29, and 36, and etoposide 50 mg/m(2) on days 1 to 5 and days 29 to 33, with concurrent radiotherapy of 61 Gy beginning on day 1. Consolidation therapy was carboplatin (area under the curve = 6) and paclitaxel 200 mg/m(2), both drugs administered on day 1 of a 21 day cycle for three cycles., Results: The response rate was 86% (complete response, 33%; partial response, 53%). Median overall survival was 17 months (95% CI, 12.7 to 19.0). One- and 2-year overall survivals were 61% and 33%, respectively. Median progression-free survival (PFS) was 9 months, 1-year PFS was 40%, and 2-year PFS was 21%., Conclusion: Consolidation therapy with paclitaxel and carboplatin in LSCLC resulted in an outcome similar to that seen in prior Southwest Oncology Group trials. This study and others which have tested paclitaxel in small-cell lung cancer dampens enthusiasm for this agent in the primary management of LSCLC.

Background: Platinum-based regimens have improved response rates and survival in patients with advanced transitional cell carcinoma (TCC) of the urothelial tract. However, the toxicities of platinum-based chemotherapy are considerable. Regimens with reduced toxicity that are applicable to a broader group of TCC patients without sacrificing activity therefore are of interest., Methods: Because gemcitabine, paclitaxel, and methotrexate have each been reported to possess single-agent activity in this disease, the authors evaluated the tolerability and efficacy of fixed doses of paclitaxel (100 mg/m(2) over 3 hours) and methotrexate (30 mg/m(2)) with escalating doses of gemcitabine (800-1000 mg/m(2)), all given on Days 1 and 8 every 21 days, in patients with previously untreated unresectable or metastatic TCC., Results: Twenty-five patients were enrolled. Two patients were ineligible and were excluded from analysis. Because no dose-limiting toxicity occurred in the first 4 patients who were given gemcitabine at a dose of 800 mg/m(2), the gemcitabine dose was escalated to 1000 mg/m(2) in the next 21 patients. Of the 21 patients assessable for response, 6 had achieved a complete response (CR) and 6 had achieved a partial response, for an overall response rate of 57%. An additional patient was converted to a CR surgically. The median overall and progression-free survival times were 18 months and 9.2 months, respectively. Toxicity was predominantly neutropenia: Grade 3 in 9 patients (39%) and Grade 4 in 4 patients (17%) (according to the Southwest Oncology Group Toxicity Criteria, version 12/1994). One patient died of septic shock associated with febrile neutropenia after three cycles., Conclusions: The regimen of gemcitabine, paclitaxel, and methotrexate at this dose and schedule was found to possess activity in patients with locally advanced or metastatic TCC. Further studies of this regimen are warranted., (Copyright 2003 American Cancer Society.)

Brain metastases are a common complication for patients with non-small-cell lung cancer and a significant cause of morbidity and mortality. In the past, treatment of brain metastases and lung cancer focused on symptom palliation with whole-brain radiotherapy (WBRT) and steroids because of the grim outlook for patients. However, recent advances in technology and surgical techniques have created more options for the management of brain metastases, which include surgery, irradiation, stereotactic radiosurgery, and chemotherapy. These aggressive approaches have resulted in an improvement of neurologic outcomes and survival rates of patients with non-small-cell lung cancer. Central nervous system (CNS) metastases can be divided into three groups: solitary CNS metastases with controlled or controllable primary disease, oligometastatic disease (fewer than 3 metastases), and multiple metastases. For patients with solitary CNS metastases, long-term survival is possible. A radical treatment approach involving surgical resection or radiosurgery, followed by WBRT, is recommended. For patients with oligometastatic disease, surgical resection or radiosurgery is considered in selected cases and WBRT is indicated. For patients with multiple metastases, WBRT is recommended. For patients with oligometastatic disease and those with multiple metastases, recent evidence indicates that systemically effective chemotherapy may produce responses and can be instituted safely before radiotherapy. The treatment timing of chemotherapy and radiotherapy should be individualized.

Of the patients with non-small cell lung cancer, 60% present with localised or locally advanced disease. Although they may be considered potentially curable, the vast majority will die, usually from systemic disease. So far, adjuvant (postoperative) therapy has failed to demonstrate benefit. In contrast, chemotherapy has demonstrated clear advantages when administered prior to, or concurrently with radiotherapy in Stage III disease or prior to surgery in Stage III disease. Chemotherapy administered prior to surgery, termed neoadjuvant therapy, in Stage I and II disease has been demonstrated to be feasible. Several trials employing currently available agents have yielded promising results. Whether these regimens will result in an unequivocal benefit is the subject of several ongoing studies in the US and Europe. Current research is focusing on the role of newer drugs including novel antitubulin agents, growth factor receptor antagonists, eicosanoid modulators and various other agents.

Purpose: Butyrate is a small polar compound able to produce terminal differentiation and apoptosis in a variety of in vitro models at levels above 50-100 microM. Previously our group demonstrated that daily oral administration of the prodrug, tributyrin, is able to briefly achieve levels >100 microM. Given in vitro data that differentiating activity requires continuous butyrate exposure, the short t1/2 of the drug and a desire to mimic the effects of an intravenous infusion, we evaluated a three times daily schedule., Patients and Methods: Enrolled in this study were 20 patients with advanced solid tumors for whom no other therapy was available, had life expectancy greater than 12 weeks, and normal organ function. They were treated with tributyrin at doses from 150 to 200 mg/kg three times daily. Blood was sampled for pharmacokinetic analysis prior to dosing and at 15 and 30 min and 1, 1.5, 2, 2.5, 3, 3.5 and 4 h thereafter., Results: The patients entered comprised 15 men and 5 women with a median age of 61 years (range 30-74 years). Prior therapy regimens included: chemotherapy (median two prior regimens, range none to five), radiation therapy (one), no prior therapy (one). There was no dose-limiting toxicity. Escalation was halted at the 200 mg/kg three times daily level due to the number of capsules required. A median butyrate concentration of 52 microM was obtained but there was considerable interpatient variability. No objective responses were seen. There were four patients with prolonged disease stabilization ranging from 3 to 23 months; median progression-free survival was 55 days. Two patients with chemotherapy-refractory non-small-cell lung cancer had survived for >1 year at the time of this report without evidence of progression., Conclusion: Tributyrin is well tolerated and levels associated with in vitro activity are achieved with three times daily dosing.

Purpose: We evaluated the combination of UCN-01 plus cisplatin and sought to determine how the cell cycle effects of each agent affected the combined response. Cisplatin-induced DNA damage results in cell cycle arrest, primarily at the S and G(2) checkpoints, providing the opportunity for DNA damage repair prior to mitosis. Thus, strategies to enhance cisplatin cytotoxicity include attenuation of DNA damage-induced checkpoints. The cyclin-dependent kinase inhibitor 7-hydroxystaurosporine (UCN-01) can potentiate cisplatin activity, likely via abrogation of the S and G(2) checkpoints. UCN-01 has additional effects on cell cycling, including induction of an RB-associated G(1) arrest., Methods: NSCLC cell lines A549 (wt p53, wt RB), Calu1 ( p53-null, wt RB) and H596 (mt p53, RB-null) were treated with UCN-01 and/or cisplatin with two-drug treatments delivered in alternate sequences. Effects of drug treatment on cell growth, cell cycling, apoptosis and levels and phosphorylation of cell cycle-associated proteins were evaluated. The interaction between the two drugs was assessed using median effect analysis., Results: When UCN-01 preceded cisplatin, growth inhibition was additive or less than additive, as assessed by median effect analysis. In contrast, when NSCLC cells were treated with cisplatin followed by UCN-01, the combination was synergistic. In this treatment sequence, a decrease in the proportion of cells at the G(2) checkpoint was confirmed by reduced expression of cyclins A and B and activation of Cdk1. Abrogation of the G(2) DNA damage checkpoint and apoptosis were prevalent only in cell populations treated with cisplatin followed by UCN-01 and was markedly enhanced in the cell lines with disrupted p53., Conclusions: These studies indicate that timing of drug administration strongly influences response to cisplatin plus UCN-01 in NSCLC cells, and this is related to the cell cycle-modulatory effects of these agents. Furthermore, this sequence combination was more effective in cell lines with dysfunctional p53. These findings support the hypothesis that checkpoint abrogation is the major mechanism of UCN-01-mediated potentiation of cisplatin cytotoxicity.

Background: Cryptophycin 52 is a novel antitubulin drug with in vitro and in vivo activity in non-small cell lung cancer. Based upon promising Phase 1 data, a multicenter trial was performed to evaluate the drug in previously treated non-small cell lung cancer (NSCLC)., Methods: Patients with Stage IIIb (pleural effusion) or Stage IV NSCLC and performance status 0-1 with adequate organ function who had received at least one and no more than two prior chemotherapy regimens (one of which must have contained a platinum agent) were eligible. Cryptophycin 52 was administered at a dose of 1.5 mg/m(2) day 1 and 8 every 3 weeks. Patients were reassessed every two cycles., Results: Twenty-six patients were enrolled of whom 25 are evaluable for toxicity and response. There were no responders, toxicity was predominantly neurologic in the form of peripheral neuropathy and constipation. After the first 12 patients were enrolled, the dose was lowered to 1.125 mg/m(2) day 1 and 8. Toxicity was substantially reduced with this maneuver. Median survival was 4.1 months. The median number of cycles was two, however ten patients received four or more courses of therapy., Conclusion: Cryptophycin 52 failed to produce measurable responses utilizing this schedule. In 40% of patients there was evidence of disease stabilization. Toxicity at 1.5 mg/m(2) was unacceptable. Since activity and toxicity may be dose and schedule dependent, other schedules of cryptophycin 52 should be considered., (Copyright 2002 Elsevier Science Ireland Ltd.)

Multimodality management of locally advanced non-small cell lung cancer is commonplace. Locally advanced disease is defined as patients with stage IIIA, IIIB (without pleural effusions), and Pancoast tumors. Improvements in the median and landmark survival rates of patients have been accomplished by integration of chemotherapy, radiotherapy, and surgery. Although the optimal sequencing and number of modalities remains to be established, the safe treatment of patients requires cooperation of the specialties (joint clinics and tumor boards). The toxicities of chemoradiotherapy are esophagitis, pneumonitis, and myelosuppression. These complications are a function of the dose and fractionation scheme of radiotherapy and the dose, schedule, and specific chemotherapy agents used. The use of modern techniques, including three-dimensional conformal radiotherapy, limitation of field size, and aggressive treatment of symptoms reduces toxicity and the number of treatment breaks, and allows delivery of planned therapy in many patients. In appropriate patients, surgery may be successful after induction chemotherapy or chemoradiotherapy. In addition to exclusion of medically inappropriate patients, patients with persistent mediastinal adenopathy after induction therapy are not likely to benefit from resection. Therefore, mediastinal sampling must be repeated after chemoradiotherapy and before surgery.

Brain metastases are a common complication for patients with non-small cell lung cancer and a significant cause of morbidity and mortality. In the past, treatment of brain metastases and lung cancer focused on symptom palliation with whole brain radiotherapy (WBRT) and steroids because of the grim outlook for patients. However, recent advances in technology and surgical techniques have created more options for the management of brain metastases, which include surgery, irradiation, stereotactic radiosurgery, and chemotherapy. These aggressive approaches have resulted in an improvement of neurologic outcomes and survival rates of patients with non-small cell lung cancer. Central nervous system (CNS) metastases can be divided into three groups: solitary CNS metastases with controlled or controllable primary disease, oligometastatic disease (fewer than three metastases), and multiple metastases. For patients with solitary CNS metastases, long-term survival is possible. A radical treatment approach involving surgical resection or radiosurgery, followed by WBRT, is recommended. For patients with oligometastatic disease, surgical resection or radiosurgery is considered in selected cases and WBRT is indicated. For patients with multiple metastases, WBRT is recommended. For patients with oligometastatic disease and patients with multiple metastases, recent evidence indicates that systemically effective chemotherapy may produce responses and can be instituted safely before radiotherapy. The treatment timing of chemotherapy and radiotherapy should be individualized.

In the past decade unequivocal evidence regarding the benefit of platinum-based chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) has emerged. Several regimens consisting of either cisplatin or carboplatin combined with agents such as paclitaxel, docetaxel, gemcitabine, vinorelbine, or irinotecan have demonstrated superiority over older combinations or single-agent platinums. These regimens have roughly equivalent activity in terms of response and survival. The major differences have been in terms of toxicities and expense. Gemcitabine/carboplatin is a combination with clear activity in advanced disease and excellent tolerability. Unlike taxane-based therapy, there is minimal neuropathy and little alopecia. For registration purposes, gemcitabine was initially combined with cisplatin. Regimens combining gemcitabine with carboplatin reported a similar rate of myelotoxicity (primarily thrombocytopenia) as gemcitabine/cisplatin. The observation that a 21-day schedule in which carboplatin is administered on day 1 and gemcitabine on days 1 and 8 could substantially reduce this toxicity provided a preferred schedule for administration. The major factor limiting acceptance of this regimen was the absence of phase III data. This year a number of phase III trials were presented, which coupled with the results of large, multicenter phase II studies (including one from a US cooperative group), has now established gemcitabine/carboplatin as a standard regimen for the treatment of advanced NSCLC. Its excellent toxicity profile has also led several groups to utilize the regimen as a platform for combination with newer drugs.

Purpose: Gemcitabine and paclitaxel are chemotherapeutic agents with clinical antitumor activity in a broad range of malignant solid tumors. Because of preclinical synergy, unique mechanisms of action and resistance, and nonoverlapping toxicities, gemcitabine and paclitaxel combinations are attractive for testing in clinical trials. Prior weekly gemcitabine and paclitaxel regimens administered on a 28-day cycle have been limited by cumulative hematological toxicity on day 15, thus reducing the planned gemcitabine dose intensity. We therefore conducted a phase I trial of a 21-day schedule of weekly gemcitabine and paclitaxel to determine the tolerability, maximum tolerated dose (MTD), and preliminary estimates of efficacy of this regimen., Patients and Methods: Forty-one patients with advanced malignant solid tumors were accrued. Gemcitabine was given at a fixed dose of 1000 mg/m2 while paclitaxel was administered at an initial dose of 60 mg/m2, then escalated by 15 mg/m2 increments over seven dose levels to a prospectively planned maximum dose of 150 mg/m2. Both agents were infused intravenously on days one and eight every 21 days. At least three patients were enrolled per dose level. No intrapatient dose escalation was allowed., Results: All patients were assessable for toxicity and 31 were assessable for response. The regimen was generally well-tolerated. Dose-limiting thrombocytopenia was observed in one patient at a paclitaxel dose of 135 mg/m2/week (dose level 6). After expansion of this dose level by 14 additional patients, no further dose-limiting toxicities were observed although one patient at dose level seven died of neutropenic sepsis after completing three cycles. There were eight partial responders for an overall response proportion of 26% (95% CI: 11, 41). Twelve patients (39%) had stable disease., Conclusion: This 21-day schedule of gemcitabine and paclitaxel is safe, well-tolerated, and active. The recommended phase II dose is gemcitabine 1000 mg/m2 and paclitaxel 150 mg/m2 on days one and eight every 21 days. The antitumor activity observed with this regimen warrants further investigation.

Background: Tamoxifen has been reported to enhance the antitumor activity of cisplatin in preclinical models by modulation of protein kinase C signal transduction and apoptosis-related pathways., Methods: We conducted a phase I study of high-dose oral tamoxifen in combination with intravenous cisplatin, with two objectives: 1) to determine tolerability, and 2) to determine the daily tamoxifen dose required to achieve serum levels equivalent to in vitro concentrations reported to enhance cisplatin cytotoxicity in preclinical models. Tamoxifen was administered days one through seven at escalating daily doses of 160 mg/m2 (n = 5), 200 mg/m2 (n = 6), and 250 mg/m2 (n = 4) by patient cohort, followed by cisplatin at 100 mg/m2 on day eight. Serum concentrations of tamoxifen and its hydroxylated metabolite N-desmethyltamoxifen were determined by high-performance liquid chromatography (HPLC) on day eight of the first treatment cycle in seven patients., Results: Fifteen patients with advanced malignancies received treatment with tamoxifen at 160 mg/m2, 200 mg/m2, and 250 mg/m2 per cycle, respectively. Serum concentrations of tamoxifen and N-desmethyltamoxifen on day eight of the first cycle ranged from 1.75-8.22 microM (mean 4.72 microM) and 3.62-10.85 microM (mean 3.87 microM), respectively. Toxicity analysis demonstrated that grade 3/4 nonhematological toxicity occurred in 0/5 at a tamoxifen dose of 160 mg/m2, 1/6 at a tamoxifen dose of 200 mg/m2, and in 1/4 patients at the 250 mg/m2 dose level. No grade 4 hematological toxicity occurred. Classic dose-limiting toxicity was not observed; the trial was closed to further accrual after documentation that targeted tamoxifen levels (around 5 microM) were achieved with daily tamoxifen doses > or = 160 mg/m2 in combination with cisplatin., Conclusions: This regimen of high-dose tamoxifen in combination with cisplatin can be safely administered. Serum tamoxifen levels comparable to concentrations required for enhancement of cisplatin sensitivity in vitro are clinically achievable with acceptable toxicity. The level of antitumor activity in nonsmall cell lung cancer NSCLC is encouraging (partial response in 4/10 patients). Based on these data, a Phase II study of high-dose tamoxifen in combination with cisplatin in patients with metastatic NSCLC is being conducted through the Southwest Oncology Group.

Several chemotherapeutic regimens have emerged in the past 5 years with the capability to improve survival and quality of life of patients with advanced non-small cell lung cancer (NSCLC). Among these treatments, the regimen of gemcitabine (Gemzar) and carboplatin (Paraplatin) has gained increasing acceptance. The combination of these two drugs was initially hampered by unacceptable platelet toxicity. However, the use of a 21-day schedule with the administration of gemcitabine on days 1 and 15 or the use of a 28-day schedule with the omission of day-15 gemcitabine has clearly been well tolerated and active. Unlike taxane based regimens, there is no need for steroid premedication, and neurotoxicity and alopecia are absent. This regimen is well tolerated and easily administered on an outpatient basis. It therefore represents an excellent "platform regimen" for the addition of new agents, particularly those associated with minimal myelotoxicity. Three-drug regimens consisting of gemcitabine/carboplatin and a taxane have been evaluated both with concurrent and sequential administration of the drugs. Trials are under way or planned for the addition of novel agents such as C225, UCN-01, PKC-alpha antisense, bexarotene, COX-2 inhibitors and other agents., (Copyright 2002 Elsevier Science Ireland Ltd.)

In view of favorable reports with the 3-drug combination of PGV (cisplatin/gemcitabine/vinorelbine), this multicenter phase II study evaluated the therapeutic index of PGV in patients with advanced non-small-cell lung cancer (NSCLC). Thirty-two patients with stage IV NSCLC and 1 with stage IIIB were studied. There were 23 men and 10 women, with a median age of 63 years (range, 38-80 years). Twelve patients had a performance status (PS) of 0, and 21 patients had a PS of 1. Treatment consisted of cisplatin 50 mg/m2, gemcitabine 1000 mg/m2, and vinorelbine 25 mg/m2 all given intravenously on days 1 and 8, in 21-day cycles. Fifteen patients (45%; 95% confidence interval (CI), 28%-64%) achieved a partial response. Median response duration was 3 months (range, 1-9 months). The median and 1-year survival rates were 9.4 months and 39% (95% CI, 23%-58%), respectively. The median number of cycles was 4. Only 3 patients (9%) completed treatment without regimen modifications. Median dose intensity (% planned) was cisplatin 24 mg/m2/week (72%), gemcitabine 483 mg/m2/week (72%), and vinorelbine 12 mg/m2/week (72%). Toxicities were predominantly hematologic, with grade 3/4 neutropenia (67%), febrile neutropenia (21%), and thrombocytopenia (67%). There were 3 (9%) treatment-related deaths due to neutropenic complications. This study confirms the substantial antineoplastic activity of PGV. We observed a high rate of severe hematologic toxicity, especially febrile neutropenia, despite a lower delivered dose intensity of PGV. Given these results, PGV appears to offer no therapeutic advantage to current doublet regimens.

Non-small-cell lung cancer (NSCLC) is responsible for more deaths each year in the United States than is any other malignancy. Early stage disease can be cured with surgical resection. Postoperative surveillance for recurrent disease and the development of second malignancies are important parts of the overall treatment plan. Follow-up strategies have been analyzed and guidelines (most notably those of the National Comprehensive Cancer Network ) have been published. However, common practice often does not comply with these rationally developed guidelines. Understanding the general principles of effective surveillance may improve compliance with the guidelines and may lead to more cost-effective management. New methods of surveillance, postoperative risk stratification, and emerging therapies may alter these recommendations for postoperative surveillance of patients with early stage NSCLC in the future.