Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms.

PURPOSE: To define the maximum tolerated dose (MTD) and the nature of the toxicities associated with gemcitabine given as a short infusion to patients with non-small cell lung cancer (NSCLC). Secondary objectives were to monitor immunologic response, clinical response, and survival. PATIENTS AND METHODS: Thirty-two patients diagnosed with advanced inoperable NSCLC and performance status of 0 or 1 participated in this study. Patients consisted of 22 males and 10 females whose median age was 62 years (range 32-79). Gemcitabine was administered as a 30 min infusion once weekly for 3 weeks followed by 1 week of rest. Patients were enrolled at six gemcitabine dose levels ranging from 1000 to 3500 mg/m2. Patients completed a median of four cycles (range 1-17). Responses were evaluated after every two cycles. RESULTS: Toxicity was evaluated in all 32 patients. The MTD was not reached as gemcitabine was well tolerated at all dose levels. Grade 4 toxicity occurred in three (9%) patients: pulmonary and lymphocytopenia in one patient each, and both neurocortical and cardiac in one patient. Grade 3 toxicity was found in a total of 20 (63%) patients: pulmonary in 10 (31%) patients; pain in 6 (19%) patients; liver toxicity in 6 (19%) patients; leukopenia and lymphocytopenia in 5 (16%) patients each; anemia, nausea, and cardiac toxicity in 3 (9%) patients each; proteinuria and infection in 2 (6%) patients each; and hemorrhage in 1 (3%) patient. Of the 29 patients evaluable for response, seven objective responses were achieved: six at the 2200 mg/m2 dose level and one at the 2800 mg/m2 dose level. The distribution of responses differed significantly by dose (P = 0.0124 by the exact chi-square test for independence). The overall response rate was 24.1% (95% CI, 10.3-43.5%). At 6 h post-infusion, there was a significant increase in spontaneous tumor necrosis factor (TNF) release and stimulated interleukin (IL)-2 production, and significant decreases in total white blood cell and lymphocyte counts (CD3+, CD8+, and CD16+ lymphocytes) and resting and stimulated superoxide production by formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate, and opsonized zymosan (OPS-Z). At 24 h post-infusion, there were significant decreases in total lymphocyte count, lymphocyte subsets (CD3+, CD4-, CD8+, CD56+, CD19+), and in resting and stimulated superoxide production by fMLP and OPS-Z. There also appeared to be an association between the levels of spontaneous TNF release and the severity of both gastrointestinal (GI) and pulmonary toxicities. CONCLUSION: Gemcitabine given as a short infusion was well tolerated at the dose levels of 1000-3500 mg/m2. The MTD was not reached. Toxicities appeared to be cumulative with multiple cycles. Gemcitabine appears to have activity against NSCLC. Although there was a differential dose-response rate among dose levels, increasing the gemcitabine dose beyond 2200mg/m2 did not show increased clinical response. Gemcitabine appears to modulate the immune response, which may in turn mediate both response and toxicity, although no statistically significant correlation between immune and clinical response was detected.

Results of expandable metal stents for malignant esophageal obstruction in 100 patients: short-term and long-term follow-up.

BACKGROUND: Expandable metal stents palliate malignant dysphagia in most cases, but early complications and outcomes in long-term survivors have not been well described. This report summarizes our experience with expandable metal stents for malignant dysphagia. METHODS: Over a 48-month period, 127 stents were placed in 100 patients with dysphagia from esophageal cancer (93%) or lung cancer. Most had undergone prior treatment. Dysphagia scores, duration of palliation, complications, and reintervention were evaluated. RESULTS: Immediate improvement in dysphagia was observed in 85% of patients with no procedure-related deaths. Dysphagia score decreased from 3.3 before stent to 2.3 (p < 0.005). Average interval to reintervention was 80 days. In 40 patients surviving more than 120 days, 31 (78%) required reintervention. Major complications occurred in 3 patients receiving poststent chemoradiation (tracheoesophageal fistula, T1 vertebral body abscess, mediastinal abscess). Other complications included unsatisfactory deployment requiring immediate removal (3 patients), migration (11 patients), pain requiring removal (2 patients), food impaction (10 patients), and tumor ingrowth (37 patients). CONCLUSIONS: Expandable metal stents offer excellent short-term palliation of malignant dysphagia. In long-term survivors, recurrent dysphagia requiring reintervention is common. In a small subset of patients receiving chemoradiation after stent placement, major complications were observed.

Therapeutic video-assisted thoracoscopic surgical resection of colorectal pulmonary metastases.

OBJECTIVE: Careful patient selection is vital when video-assisted thoracoscopic surgical (VATS) therapeutic pulmonary metastasectomy of colorectal carcinoma is considered. Complete resection of all metastatic disease remains a vital concept. We reviewed our VATS experience for therapeutic metastasectomy of peripheral colorectal pulmonary metastases. METHODS: Over 90 months, therapeutic VATS metastasectomy was accomplished upon 80 patients with colorectal metastases. Thin cut computed tomography (CT) was central in identifying lesions. The mean interval from primary carcinoma to VATS resection was 41 months (1-156 months; median, 33). A solitary lesion was resected in 60 patients and multiple (2-7) lesions resected in 20 patients. Statistics were obtained using the Student's t-test. RESULTS: No operative mortality or major postoperative complications occurred. The hospital stay was 4.5+/-2. 2 days (range, 1-13). All lesions were resected by VATS, with four conversions to thoracotomy to improve the margins. The mean survival of patients with one lesion was 34.8 months compared with 26.5 months for patients with multiple lesions (P=0.37). The mean survival was 20.5 months when metastases occurred <3 years vs. 28.1 months for >3 years from primary carcinoma resection (P=0.20). Twenty-five (31%) patients are disease free; with a mean interval of 38.7 (3-84; median, 35) months. Sixty-nine percent (55/80) of patients developed a recurrence: 6/80 (8%) local; 19/80 (24%) regional (same hemithorax away from resection); and 30/80 (38%) distant. The overall survival at 1 year was 81.2%, 48.4% at 3 years and 30.8% at 5 years. CONCLUSIONS: Therapeutic VATS resection of colorectal metastases appears efficacious. Preoperative CT can identify peripheral colorectal metastases amenable to VATS. Conversion to thoracotomy is indicated when none of the lesions identified by CT are found or when clear surgical margins are jeopardized.

Total videothoracoscopic lobectomy versus open thoracotomy for early-stage non small-cell lung cancer.

Lobectomy remains the standard procedure for early-stage non small-cell lung cancer (NSCLC). Advances in minimally invasive surgery allow lobectomy to be performed by videothoracoscopy (VATSLOBE). The objective of this study was to compare open thoracotomy (OPENLOBE) to VATSLOBE in the treatment of early-stage NSCLC. A retrospective review over a 6-year period at a single tertiary care center identified 31 patients treated by VATSLOBE. A comparison was made with 31 patients undergoing OPENLOBE during the same time period. The cases were matched for age, pulmonary function testing, tumor size, and comorbidities. The VATSLOBE technique was carried out using four 1 cm thoracoports, one of which was enlarged to a 4-6 cm access incision for lobe retrieval. OPENLOBE was performed by standard posterolateral thoracotomy. The VATSLOBE group had a longer operative time (214.03 min) compared to OPENLOBE (140.67 min). There was no difference in the extent of lymph node dissection or in morbidity between the two groups. VATSLOBE patients had their chest tubes removed earlier (4.77 vs. 8.16 days) and stayed in the hospital for a shorter time (7.07 vs. 11.94 days) compared to OPENLOBE patients. In this retrospective review, lobectomy performed by the videothoracoscopic approach was comparable to OPENLOBE in terms of lymph node dissection, morbidity, and long-term survival. VATSLOBE had the advantages of a shorter hospital stay and fewer days with a chest tube. Minimally invasive surgery for early-stage lung cancer should be further investigated in multi-institutional controlled trials.

Diagnostic and therapeutic video-assisted thoracic surgery resection of pulmonary metastases.

BACKGROUND: Appropriateness of video-assisted thoracic surgery (VATS) pulmonary metastasectomy for curative intent has been a controversial topic. We reviewed our experience with VATS wedge resection for peripheral lung metastases to determine the efficacy and potential adverse consequences of this approach for pulmonary metastasectomy. METHODS: One hundred seventy-seven patients underwent VATS resection of pulmonary metastases. Diagnostic resection (VATS-dx) was performed for 78 patients when percutaneous biopsy was unsuccessful or not feasible. Potentially curative resections (VATS-rx) were performed for 99 patients. The histologic findings in this group included colorectal (68), renal (7), sarcoma (6), breast (4), melanoma (3), head/neck (3), lymphoma (2), uterine (1), and "other" (5). The average number of lesions resected was 1.4 (range, 1-7). RESULTS: VATS resection was successfully performed for all VATS-dx and VATS-rx patients. There were no perioperative deaths. Longitudinal follow-up demonstrated a mean survival of 18 months in the VATS-dx group and 28 months in the VATS-rx group. In the VATS-rx group, 37 (37%) of 99 were free of disease, at a mean follow-up interval of 37 months. Of the 57 recurrences, 5% were local, 26% were regional, and 69% were distant. CONCLUSIONS: Results with VATS resection of peripheral pulmonary metastases for diagnostic and potentially curative intentions appear comparable with historical results by "open" thoracotomy. Careful patient selection based on high-resolution helical CT scanning is important to avoid compromise of therapeutic intent. Conversion to thoracotomy is indicated when lesions identified preoperatively are not found or when technical problems encountered may compromise surgical margins when resecting lung metastases for potential cure.

Computed tomography-guided wire localization of pulmonary lesions before thoracoscopic resection: results in 101 cases.

The authors determine the success rate, safety, and potential complications of computed tomography-guided preoperative hookwire localization of small peripheral pulmonary nodules. One hundred one consecutive wire localizations with addition of methylene blue injection were performed in 94 patients immediately before thoracoscopic resection of small lung lesions. Sixty-two patients had a known primary malignancy, whereas 32 had an asymptomatic nodule. Eighty-eight patients underwent single lesion localization, five underwent double localization, and one underwent triple wire placement. Five patients had previously undergone percutaneous biopsy that was nondiagnostic. The nodule was within the first wedge biopsy of lung tissue in 95 of 97 specimens (98%). A second wedge and an open lobectomy were required in one patient each. Three additional biopsies were intraoperatively deferred after the histologic diagnosis was established after removal of another nodule. The procedure was terminated before wire placement in one patient who was unable to successfully hold his breath. The wire dislodged with the tip in the pleural space rather than in the lung parenchyma in 22 cases; however, methylene blue tattoo allowed localization in 13 of these (59%). In the other nine cases, extra portals, digital palpation, or expanded wedge resection was required. Complications included pneumothorax in 48 cases, moderate pleuritic pain in five cases, seven small intercostal hematomas, and a 7-mm wire fragment retained in one patient's lung along the suture line. No patient required a preoperative drain for treatment of pneumothorax. Wire dislodgement occurred in 6 of 52 (12%) cases without an initial pneumothorax and in 16 of 48 (33%) cases if a pneumothorax occurred. Wires dislodged less frequently if placed either directly into or through the nodule in 11 of 64 (17%) cases than if placed adjacent to the nodule in 11 of 36 (31%) cases. Average wire tip depth from the visceral pleura was significantly less when the wire dislodged (11 mm) than when the wire remained in place (25 mm). Wire localization of small peripheral pulmonary nodules is a safe and effective procedure to assist thoracoscopic sublobectomy resection.

Ablation of persistent air leaks after thoracic procedures with fibrin sealant.

Prolonged air leak after thoracic procedures was successfully treated in 11 of 12 patients under local anesthesia using video thoracoscopic instillation of fibrin sealant over the site of the leak. No related complications occurred. This method should be considered an effective option for the treatment of persistent pulmonary air leaks.

Photodynamic therapy for treatment of malignant dysphagia.

Photodynamic therapy (PDT) was recently approved by the Food and Drug Administration for palliating obstructing esophageal cancer. This report reviews our initial experience using PDT to treat malignant dysphagia. Patients with inoperable, obstructing esophageal cancer were considered for PDT. Photofrin was injected 48 hours before endoscopic laser activation. Dysphagia score was assessed. Thirty patients underwent 53 PDT courses. Improvement in dysphagia occurred in 83%. Mean dysphagia score decreased from 2.8 to 1.8 (p < 0.05). Complications included esophageal stricture (9.4%), candida esophagitis (5.7%), symptomatic pleural effusion (5.7%), contained esophageal perforation (1.9%), aspiration pneumonia (1.9%), and sunburn (13.2%). Seventeen patients (57%) required more than one PDT treatment, and in 10 an expandable metal stent was used as an adjunct. The 30-day mortality rate was 7%. PDT is effective in palliating patients with malignant dysphagia. The ideal patient for PDT has an obstructing, primarily endoluminal esophageal tumor with minimal extrinsic compression.

Hodgkin's disease presenting with a bronchoesophageal fistula.

Bronchoesophageal fistula is a rare complication of Hodgkin's disease. We report a case of Hodgkin's disease presenting with a bronchoesophageal fistula that was successfully treated with bipolar esophageal exclusion and substernal gastric bypass. Direct invasion from mediastinal lymph nodes was the probable cause. Although bronchoesophageal fistula can result as a complication during the course of treatment for Hodgkin's disease, it rarely occurs as the presenting feature. Early recognition and surgical treatment are key aspects of management.

Differentiation and programmed cell death-related intermediate biomarkers for the development of non-small cell lung cancer: a pilot study.

Fifty samples of lung tissue from patients with non-small cell lung cancer were analyzed for the expression and localization of biomarkers related to squamous differentiation and programmed cell death. These markers include tissue transglutaminase (tTG), keratinocyte transglutaminase (kTG), involucrin, loricrin, and Bcl-2. We found that all of these markers are overexpressed in tumors as compared with histologically normal lung epithelium, where expression is minimal. Expression of the oncoprotein, Bcl-2, increased starting in squamous metaplasia and remained elevated in all lesions, including frank carcinoma. In contrast, expression of the other markers was elevated in the histologically abnormal noninvasive lesions but was decreased somewhat in invasive malignancy. In addition, we found that tTG, kTG, and Bcl-2, when expressed, were detected in mutually exclusive areas. These findings suggest that (1) these markers may prove useful, with more extensive testing and clinical correlation, in predicting risk for the development of lung cancer; and (2) pulmonary carcinogenesis may result from the failure of differentiation and programmed cell death mechanisms in the presence of oncogene overexpression rather than through oncogene/tumor suppressor gene abnormalities alone.

Preliminary results of thoracoscopic Belsey Mark IV antireflux procedure.

Laparoscopic Nissen fundoplication has replaced open approaches for refractory gastroesophageal reflux disease (GERD) in many major medical centers. Here we report our preliminary results of the Belsey Mark IV antireflux procedure performed by video-assisted thoracoscopy (VATS-Belsey). Fifteen patients underwent VATS-Belsey. The indications for surgery included GERD refractory to medical therapy (n=10), achalasia (n=2), diffuse esophageal spasms (n=1), epiphrenic esophageal diverticulum (n=1), and paraesophageal hernia (n=1). The median operative time was 235 min. There were three conversions to open minithoracotomy (8-10 cm) necessitated by severe adhesions (n=2) and repair of a gastric perforation (n=1). The median hospital stay was 4 days. Postoperative complications included persistent air leaks, requiring discharge with a Heimlich valve in one patient. There were no perioperative deaths. At a median follow-up of 19 months, ten patients (66%) were asymptomatic and were not taking any antacids. One patient who had taken proton pump inhibitors preoperatively required postoperative H2 blockers for mild heartburn. In three patients, recurrent GERD symptoms (mean follow-up 6 months) led to laparoscopic takedown of the Belsey and Nissen fundoplication. One patient with achalasia, who had recurrent dysphagia after 1 year of relief following VATS myotomy and Belsey, underwent esophagectomy. The Belsey Mark IV antireflux procedure is technically feasible by VATS with minimal morbidity. However, our preliminary results suggest that open thoracotomy for Belsey Mark IV should remain the standard operation for GERD with poor esophageal motility when a thoracic approach is desired. We have modified our approach to laparoscopic partial fundoplications (Toupet or Dor) for severe GERD and poor esophageal motility when an abdominal approach is possible.

Thoracoscopic techniques for the management of intrathoracic metastases. Results.

BACKGROUND: The authors reviewed a series of 74 patients with cancer metastatic to the chest cavity undergoing thoracoscopic procedures. Indications, feasibility, and outcome of thoracoscopy were analyzed. METHODS: Perioperative and survival data on patients undergoing 89 operative thoracoscopic procedures between January 1991 and August 1993 were retrieved from a prospective database. These procedures included pulmonary wedge resection (n = 61), lobectomy (n = 2), pleurodesis (n = 11), pleural biopsy (n = 7), decortication (n = 1), and mediastinal mass resection (n = 2). In 13 cases, combined procedures were performed. Five thoracoscopies were converted to open thoracotomies to facilitate resection. RESULTS: Thoracoscopic pulmonary resections were performed for either diagnostic (n = 45) or curative (n = 18) intent. Diagnostic thoracoscopies were done for lesions in which less invasive biopsy attempts had failed to provide tissue, or that were considered too small for successful percutaneous biopsy. Thoracoscopic diagnostic accuracy was 100%. For the 18 patients undergoing potentially curative resection, mean follow-up is 15.4 months. Sixteen of these patients are currently alive, and eight are free of disease. Five complications related to the procedure included persistent air leak (n = 2), atrial fibrillation (n = 2), and urinary retention (n = 1). Overall hospital stay for thoracoscopic lung resection was 4.6 +/- 2.2 days, for converted open thoracotomy 6.8 +/- 1.9 days, and for patients undergoing pleurodesis 8.9 +/- 5.3 days. Mean chest tube duration after thoracoscopic resection was 2.6 +/- 1.6 days. CONCLUSIONS: Thoracoscopic procedures are safe, well tolerated, and useful for diagnosis and treatment of selected patients with suitable intrathoracic metastatic disease.

The role of video-assisted thoracic surgery in pulmonary metastases.

The role of VATS in the management of patients with isolated pulmonary metastases is clear when performed for diagnostic purposes. In those patients with metastases that are too small for needle biopsy, when needle biopsy has been unsuccessful, or when more tissue is necessary for analysis, a VATS wedge resection can be performed with a high degree of success and minimal morbidity or inconvenience. The value of VATS for therapeutic resection of pulmonary metastases has not been demonstrated. Ideally, multicenter trials could address this issue along with the many unanswered questions concerning the fundamental concept of resection of pulmonary metastases.

The role of thoracoscopy in lung cancer management.

Video-assisted thoracic surgery (VATS) has enabled more complex procedures previously requiring thoracotomy to be accomplished in lung cancer management. VATS today can be employed in the evaluation of idiopathic (and known) malignant pleural effusions, mediastinal adenopathy, indeterminate pulmonary nodules, and compromise resection and lobectomy of peripheral stage I non-small cell lung cancer. Thus, VATS is becoming an accepted approach to a variety of intrathoracic problems, although its absolute indications for patients with lung cancer have yet to be firmly defined. This article reviews the authors' current experience with VATS procedures in the treatment of patients with lung cancer.

Future directions in esophageal cancer.

The incidence of esophageal cancer in the United States has been increasing in recent years. Since multimodality therapy for esophageal cancer has produced discouraging results, recent approaches have focused on molecular biological techniques, positron emission tomography, and minimally invasive surgery to improve pretreatment staging which will facilitate a more accurate assessment of new treatment. This article summarizes the results of studies investigating these approaches and outlines the strategy currently used at the University of Pittsburgh Medical Center.

Minimally invasive approach to esophagectomy.

BACKGROUND: Recent advances in laparoscopic and thoracoscopic surgery have made it possible to perform esophagectomy using minimally invasive techniques. The aim of this report was to present our preliminary experience with minimally invasive esophagectomy. METHODS: We reviewed our experience on eight patients who underwent minimally invasive esophagectomy using either laparoscopic and/or thoracoscopic techniques from June 1996 to May 1997. Indications for esophagectomy included stage I carcinoma (5), palliative resection (1), Barrett's with high grade dysplasia (1) and end stage achalasia (1). RESULTS: The average age was 68 years (54-82). The surgical approach to esophagectomy included laparoscopic transhiatal esophagectomy with cervical anastomosis (n = 4), thoracoscopic and laparoscopic esophagectomy with cervical anastomosis (n = 1), and laparoscopic mobilization with right mini-thoracotomy and intra-thoracic anastomosis (n = 3). Conversion to mini-laparotomy was required in two patients (25%) to complete esophageal dissection and facilitate gastric pull-up. The mean operative time was 460 minutes. The mean intensive care stay was 1.9 days (range of 0-7 days) with a mean hospital stay of 13.8 days. Minor complications included atrial fibrillation (n = 1), pleural effusion (n = 2) and persistent air leak (n = 1). Major complications included cervical anastomotic leak (n = 1), and delayed gastric emptying requiring pyloroplasty (n = 1). There was no perioperative mortality. CONCLUSIONS: This preliminary experience suggests that minimally invasive esophagectomy is safe and feasible in centers with experience in advanced minimally invasive surgical procedures. Further studies are necessary to determine advantages over open esophagectomy.

Thoracoscopic lung biopsy or open lung biopsy for interstitial lung disease.

Both traditional open lung biopsy through a limited thoracotomy and VATS lung biopsy are effective methods for obtaining parenchymal samples in patients who have respiratory insufficiency and radiographic pulmonary infiltrates. For patients with slowly progressive disease processes, who require an elective biopsy, VATS biopsy is the procedure of choice because of the ability to visualize and sample multiple areas of the lung, and because of the decreased postoperative pain. On the other hand, when patients are critically ill and already on high-level ventilatory support, the VATS method offers no advantages over the standard minimal thoracotomy.

Effect of minimally invasive thoracic surgical approaches on acute and chronic postoperative pain.

Acute postthoracotomy pain and chronic postthoracotomy pain are significant problems leading to increased length of hospital stay and medical costs, reduction in patient quality of life and patient productivity, and potential immunologic derangement that may compromise oncologic surgical results. Minimally invasive surgical approaches can potentially benefit the patient by reducing postoperative pain-related morbidity. Objective data supporting our inclination that these VATS approaches are superior to open thoracic surgical techniques is accumulating. Further study of the relative costs, risks, and benefits of standard postoperative analgesic management (e.g., epidural analgesia) combined with limited thoracotomy compared to VATS techniques is warranted as we try to define the most effective perioperative management of the patient requiring pulmonary resection.

Minimally invasive surgical staging is superior to endoscopic ultrasound in detecting lymph node metastases in esophageal cancer.

OBJECTIVE: Endoscopic ultrasonography is frequently used to locally stage esophageal cancer, but few studies exist to validate its accuracy for lymph node metastases. Our objective was to compare endoscopic ultrasonography with video-assisted thoracoscopic and laparoscopic staging in evaluating lymph node metastases in esophageal cancer. METHODS: Twenty-six patients with potentially resectable esophageal cancer were identified by conventional imaging. Endoscopic ultrasonography was performed followed by laparoscopic and thoracoscopic staging, and locoregional staging was compared. RESULTS: In eight patients endoscopic ultrasonography indicated N0 disease, but laparoscopy and thoracoscopy documented N1 disease in six. In five of 26 (19%) obstruction prevented endoscopic ultrasonography; three had N1 by laparoscopy and thoracoscopy. Thirteen patients had N1 disease according to endoscopic ultrasonography, and 12 of 13 (92%) had N1 disease by laparoscopy and thoracoscopy. The sensitivity and specificity of endoscopic ultrasonography for nodal evaluation were 65% and 66%, respectively. Sensitivity decreased to 44% for lymph node metastases less than 1 cm. No instances of T4 disease were found by surgical staging when endoscopic ultrasonography indicated T3 disease. Endoscopic ultrasonography revealed no distant metastases in any patient, but in four of 26 (15%) laparoscopy identified liver metastases. CONCLUSIONS: The accuracy of endoscopic ultrasonography in the diagnosis of lymph node metastases in esophageal cancer was 65% and only 44% for lymph node metastases less than 1 cm diameter. Laparoscopy and thoracoscopy improved the accuracy of staging lymph node metastases in esophageal cancer and had the advantage of evaluating the thoracic and abdominal cavities for metastases.

Minimally invasive surgical biopsy confirms PET findings in esophageal cancer.

This report describes our initial experience using positron emission tomography (PET) scanning in esophageal cancer patients. In two patients PET identified distant metastatic disease missed by conventional staging. Laparoscopic biopsy provided histological confirmation of metastases. In the third patient, locoregional lymph nodes were identified by PET and confirmed by surgical staging. In this preliminary report, PET appears to be a promising new noninvasive modality for staging patients with esophageal cancer.