Phase I study of vinorelbine, cisplatin, and concomitant thoracic radiation in the treatment of advanced chest malignancies.

PURPOSE: The cisplatin-vinorelbine regimen has superior activity in advanced non-small-cell lung cancer (NSCLC). We conducted a phase I trial to identify the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of this regimen with concomitant thoracic radiation (RT) in patients with advanced chest malignancies. PATIENTS AND METHODS: Patients with advanced chest malignancies that required RT were enrolled onto this phase I study of standard chest radiation (30 daily 2-Gy fractions for a total of 60 Gy) and concurrent chemotherapy with cisplatin starting at 100 mg/m2 every 3 weeks and vinorelbine starting at 20 mg/m2/wk. RESULTS: Thirty-seven patients were treated on this study. Two of three patients treated at the maximum-administered dose of cisplatin 100 mg/m2 per cycle and vinorelbine 25 mg/m2/wk experienced acute DLT (neutropenia), which required deescalation. The dose level of cisplatin 100 mg/m2 and vinorelbine 20 mg/m2/wk, although tolerated acutely, produced delayed esophagitis, which proved dose-limiting. The recommended phase II dose was cisplatin 80 mg/m2 every 3 weeks and vinorelbine 15 mg/m2 given 2 of every 3 weeks with concomitant chest RT. CONCLUSION: Concomitant chemoradiotherapy with cisplatin and vinorelbine is feasible. The recommended phase II dose is cisplatin 80 mg/m2 every 3 weeks with vinorelbine 15 mg/m2 given twice over 3 weeks on a day 1/day 8 schedule. Esophagitis is the DLT, with neutropenia occurring at higher dose levels. A Cancer and Leukemia Group B (CALGB) phase II trial is currently underway to evaluate further the efficacy and toxicities of this regimen in unresectable stage III NSCLC.

Diagnosis and Treatment of Early-Stage Non-Small Cell Lung Cancer.

Current recommendations for the diagnostic work-up and treatment of early-stage non-small cell lung cancer are presented, and the rationale behind these recommendations is reviewed. Early-stage disease is found in approximately 30% of patients at initial presentation. Surgeons continue to be uncertain with regard to how extensively they should look for metastatic disease, especially in asymptomatic patients with newly diagnosed lung cancer. While it is generally agreed that surgery is an important component of treatment for stage I and II non-small cell lung cancer, the role of adjuvant therapies in early-stage disease merits further study. Stage IIIa lung cancer is evolving as a disease for which multimodality therapy is likely to play a role, but the timing and sequence of treatment is an area of intense investigation. The recommendations made in this article are based upon the results of randomized clinical trials whenever possible.

Vinorelbine (Navelbine), cisplatin, and concomitant radiation therapy for advanced malignancies of the chest: a Phase I study.

Most patients with advanced solid tumors of the chest will have local and/or distant disease progression despite standard therapy. Vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Medicament, Paris, France) is a new semisynthetic vinca alkaloid with single-agent activity in lung cancer that recently also has been shown to act as a radiosensitizer in vitro. This study aims to define the maximum tolerated dose and dose-limiting toxicity when vinorelbine is given with cisplatin and concomitant radiation therapy. To date, 25 patients with advanced malignancies of the chest have been treated in a dose-escalation trial of vinorelbine administered once weekly with cisplatin (100 mg/m2 every 21 days) and concomitant thoracic radiation therapy (2 Gy/d x 30 fractions for 60 Gy). Vinorelbine was initially given at 20 and 25 mg/m2/wk. Acute dose-limiting toxicity was myelosuppression, which was seen at a vinorelbine dose of 25/mg/m2/wk, with grade 4 neutropenia in two of three patients and one treatment-related death from neutropenic sepsis. At vinorelbine 20/mg/m2/wk, no acute dose-limiting toxicity was seen, but grade 3 or 4 esophagitis developed in three of six patients near the end or after completion of radiation therapy. We subsequently decreased the administration of vinorelbine to weeks 1, 2, 4, and 5. Tolerance appears to be greater with this schedule; however, severe or life-threatening esophagitis at the completion of therapy continues to be observed. Given these preliminary results, it appears feasible to treat patients with advanced chest malignancies with concomitant cisplatin, vinorelbine, and radiation therapy. The significant dose reduction of vinorelbine that is necessary with concomitant radiation therapy provides the first in vivo evidence of a strong radiosensitizing effect of vinorelbine. The schedule is currently being modified to reduce the incidence of esophagitis.

Use of pleural catheter for the management of simple pneumothorax.

STUDY OBJECTIVE: We assessed the use of a pleural catheter (Thoracic Vent) to determine its effectiveness in treating simple pneumothorax (PTX) and in preventing recurrent PTX. DESIGN: A retrospective review was conducted of 84 patients treated with a pleural catheter for iatrogenic (52) and spontaneous (11 primary, 21 secondary) PTX between 1989 and 1994. PATIENTS: There were 45 men and 39 women with a mean age of 50.4 years (range, 18 to 85 years). RESULTS: Mean time to lung reexpansion was 0.5 +/- 0.1 days. Forty-five (57%) patients manifested an air leak after catheter placement for 2.0 +/- 0.2 days. The duration of time to catheter removal was 3.3 +/- 0.2 days. Seventy-one (85%) patients had resolution of PTX with this therapy alone. Thirteen patients (15%) failed to resolve their PTXs and required subsequent tube thoracostomy alone (6) or surgical therapy (7). Four of 11 patients who required tube thoracostomy also failed to respond to this therapy. Treatment failure was more common among patients with spontaneous PTX than with iatrogenic PTX (34% vs 4%; p < 0.005). During a mean follow-up of 3.0 +/- 0.2 years, 6 (7%) patients suffered recurrent PTX an average of 23 days after initial therapy. CONCLUSION: This pleural catheter is effective in the management of simple iatrogenic and spontaneous PTX.

Diffusing capacity predicts operative mortality but not long-term survival after resection for lung cancer.

OBJECTIVES: We sought to determine whether diffusing capacity influences operative mortality and long-term survival after resection for lung cancer. METHODS: We retrospectively reviewed the case histories of patients who underwent major resection for lung cancer. The association between operative mortality and predicted postoperative diffusing capacity was examined. Long-term survival among operative survivors was compared between the groups with high and low predicted postoperative diffusing capacity. RESULTS: The group comprised 410 patients with a mean age of 62.3 years. We performed 273 lobectomies, 35 bilobectomies, and 102 pneumonectomies. A total of 32 operative deaths (7.8%) were associated with low predicted postoperative diffusing capacity (P <.001). If we examine only operative survivors, there is no significant difference in survival data between patients with a predicted postoperative diffusing capacity of less than 50 and those with a predicted figure of 50 or more (stage I, 111 vs 90 months; stage II, 26 vs 32 months; stage IIIa 32 vs 26 months; log rank P >.5 for each). On the basis of the Cox proportional hazards model, predicted postoperative diffusing capacity did not have a statistically significant effect on long-term survival (estimated hazard ratio corresponding to a 20-point decrease in predicted postoperative diffusing capacity = 1. 13; 95% confidence interval: 0.92 to 1.37). CONCLUSION: A poor diffusing capacity is associated with high operative mortality but does not adversely affect long-term survival after major lung resection among operative survivors. Improving the perioperative management of patients undergoing major lung resection may enable inclusion of more patients with reduced diffusing capacity in the candidate pool for surgery, thus maximizing survival for early-stage lung cancer.

Clinical trials in general surgical journals: are methods better reported?

BACKGROUND: Reports of clinical trials often lack adequate descriptions of their design and analysis. Thus readers cannot properly assess the strength of the findings and are limited in their ability to draw their own conclusions. A review of 6 surgical journals in 1984 revealed that the frequency of reporting 11 basic elements of design and analysis in clinical trials was only 59%. This study attempted to identify areas that still need improvement. METHODS: Eligible studies published from July 1995 through June 1996 included all reports of comparative clinical trials on human subjects that were prospective and had at least 2 treatment arms. A total of 68 articles published in 6 general surgery journals were reviewed. The frequency that the previously identified 11 basic elements of design and analysis were reported was determined. RESULTS: Seventy-four percent of all items were reported accurately (a 15% increase from the previous study), 4% were reported ambiguously, and 23% were not reported; improvement was seen in every journal. The reporting of eligibility criteria and statistical power improved the most. For 3 items, reporting was still not adequate; 32% of reports provided information about statistical power, 40% about the method of randomization, and 49% about whether the person assessing outcomes was blind to the treatment assignment. CONCLUSIONS: Improvements have been made in reporting surgical clinical trials, but in general methodologic questions poorly answered in the 1980s continue to be answered poorly in the 1990s. Editors of surgical journals are urged to provide authors with guidelines on how to report clinical trial design and analysis.

Operative vs percutaneous drainage of intra-abdominal abscesses. Comparison of morbidity and mortality.

This retrospective case-controlled study compares the morbidity and mortality of 27 percutaneously drained (PD) abscesses with 27 that were surgically drained (SD). Patients were matched for age, sex, diagnosis, and abscess etiology and location. There was no difference in severity of illness (acute physiology score [APS] = 8.3 vs 10.2), comparable morbidity (29.6% vs 40.7%), or mortality (11.0% vs 7.4%) between PD and SD groups. Duration of drainage was significantly longer in the PD group; however, this is explained in part by the 48% vs 18.5% difference in associated fistulae. Failures of the SD group had a higher mean APS (15) than both failures of the PD group (APS = 9.3) and successes of the SD group (APS = 8.6). All three PD group deaths and half of the SD group deaths were related to ongoing sepsis. Surgical drainage of intra-abdominal abscess is as successful as PD. Percutaneous drainage is reasonable initial treatment for intra-abdominal abscess; however, early assessment of clinical status and frequent reassessment are mandatory to ensure that failures are dealth with early. We present a drainage algorithm.

Surgical decision analysis: esophagectomy/esophagogastrectomy with or without drainage?

Decision analysis was used to compare three management strategies for patients undergoing esophagogastrectomy for carcinoma of the esophagus or gastric cardia: drain all patients with either pyloromyotomy or pyloroplasty, drain no patient, or perform a test that stratifies patients into high-risk and low-risk groups for development of gastric outlet obstruction and drain the high-risk group. Results indicate that a "drain all" approach is appropriate in clinical settings where the risk of gastric outlet obstruction is greater than 10%, as long as the drainage procedure is 95% effective. If a test were developed to stratify patients, it would have to have a sensitivity of 80% when its specificity was 100%, and would require a higher sensitivity as the specificity fell below 100%.

Simple technique for sizing and positioning tracheal stents.

Accurate placement of tracheobronchial stents is essential, since little adjustment can be made once the stent is deployed. We describe the use of an inexpensive tool, a radio-opaque ruler, to aid in the proper positioning of tracheobronchial stents.

Pericardial cyst causing right ventricular outflow tract obstruction.

Pleuropericardial cysts are rare. Rarer still are cardiopulmonary complications caused by their presence. We report the case of a pericardial cyst producing high-grade right ventricular outflow tract obstruction and its subsequent management. The clinical importance of transesophageal echocardiography is highlighted.

Results of myotomy and partial fundoplication after pneumatic dilation for achalasia.

BACKGROUND: We questioned whether results of myotomy for achalasia are influenced by previous pneumatic dilation and whether surgical outcome is influenced by a dilation-related perforation necessitating urgent operation. METHODS: We performed a retrospective analysis of 60 patients who underwent transthoracic myotomy and fundoplication from 1977 to 1995. Dysphagia, heartburn, pain, and regurgitation were scored on a scale of 0 to 3 and results were classified according to combined symptom score. RESULTS: Dilation was performed before myotomy once in 15 patients, twice in 25, 3 times or more in 9, and never in 11 patients. Operation was urgent due to perforation in 6 patients (10%). There was no postoperative leak or mortality. Overall symptom score at last follow-up (57 +/- 8 months; 90% of patients) was improved compared with preoperative score (2.1 +/- 0.3 months versus 5.1 +/- 0.2 months; p < 0.0001). Outcome was unrelated to whether or not a perforation occurred (excellent/good outcomes in 100% and 88%, respectively) or to whether or not preoperative dilations had been performed (excellent/good outcomes in 90% and 89%, respectively). CONCLUSIONS: Myotomy and partial fundoplication is an effective technique for management of achalasia. Results are unaffected by the need for urgent operation for perforation and are unrelated to whether pneumatic dilation is performed preoperatively.

Assessment of pulmonary complications after lung resection.

BACKGROUND: We assessed the utility of maximum oxygen consumption during exercise (MVO2) and diffusing capacity for carbon monoxide (DL(CO)) in the prediction of postoperative pulmonary complications, and the effect of such complications on postoperative length of hospital stay and the cost of hospitalization. METHODS: Candidates for lung resection were prospectively studied by preoperative measurement of DL(CO) (expressed as a percentage of predicted [DL(CO)%]) and MVO2. Postoperative pulmonary complications, duration of postoperative hospitalization, and the cost of hospitalization were assessed. RESULTS: Forty patients had lung resection with no operative mortality. The postoperative length of hospitalization was longer for the 13 patients who developed pulmonary complications compared with the 27 patients who did not (7.7+/-0.8 vs 5.0+/-0.4 days, respectively; p = 0.007), and the cost of hospitalization in the former group was higher ($11,530+/-$1,959 vs $6,578+/-$406, respectively; p = 0.031). Diffusing capacity was higher in patients without than in patients with pulmonary complications (DL(CO)% 90.1+/-5.0 vs 65.3+/-5.9; p = 0.0034). The mean MVO2 did not differ between the groups (17.8+/-0.9 vs 16.3+/-1.2). DL(CO)% predicted pulmonary complications (p = 0.006). CONCLUSIONS: DL(CO)% predicts the likelihood of pulmonary complications after major lung resection, which are associated with increased length of hospital stay and cost.

Randomized trial of one-dose versus six-dose cefazolin prophylaxis in elective general thoracic surgery.

The objective of this study was to compare the efficacy of one to six doses of cefazolin as prophylaxis in general thoracic surgery using a randomized, double-blind design. Two-hundred eight consecutive patients admitted to a regional thoracic surgery unit for elective thoracotomy and lung resection were eligible for the trial. There were no wound infections in the one-dose group and two in the six-dose group (95% confidence intervals [CI]: -0.008, +0.048 [The positive number refers to the largest possible difference in favor of the one-dose group and the negative number, the largest possible difference in favor of the six-dose group]). Each group had eight postoperative chest infections (CI: -0.075, +0.077) and three empyemas (CI: -0.004, +0.050). Thirty-day mortality was 5% in the one-dose group and 4% in the six-dose group (CI: -0.053, +0.069). Postoperative duration of hospital stay, requirement for antibiotics, and the need for reoperation were comparable. These results suggest that six doses of cefazolin do not confer clinically important benefit beyond that obtained from a single dose for prophylaxis of wound infection in elective general thoracic surgery.

A randomized, controlled trial comparing thoracoscopy and limited thoracotomy for lung biopsy in interstitial lung disease.

BACKGROUND: Lung biopsies are frequently needed to diagnose diffuse interstitial lung diseases. A prospective randomized, controlled trial comparing limited thoracotomy (open lung biopsy) and thoracoscopy for lung biopsy was done. METHODS: Ambulatory patients with a clinical diagnosis of diffuse interstitial lung disease were randomized to thoracoscopy or limited thoracotomy. Data on postoperative pain, narcotic requirements, operating room time, adequacy of biopsy, duration of chest tube drainage, length of hospital stay, spirometry, and complications were collected. RESULTS: A total of 42 randomized patients underwent lung biopsy (thoracoscopy 20, thoracotomy 22). The two study groups were comparable with respect to age, gender, corticosteroid use, and preoperative spirometry. Visual analog scale pain scores were nearly identical in the two groups (p = 0.397). Total morphine dose was 50.8 +/- 27.3 mg in the thoracoscopy group and 52.5 +/- 25.6 mg in the thoracotomy group (p = 0.86). Spirometry (FEV1) values in the two groups were not significantly different on postoperative days 1, 2, 14, and 28 (p = 0.665). Duration of operation was similar in both groups (thoracoscopy 40 +/- 30 minutes, thoracotomy 37 +/- 15 minutes; p = 0.67). The thoracoscopy and thoracotomy groups had equivalent duration of chest tube drainage (thoracoscopy 38 +/- 28 hours, thoracotomy 31 +/- 26 hours; p = 0.47) and length of hospital stay (thoracoscopy 77 +/- 82 hours, thoracotomy 69 +/- 55 hours; p = 0.72). Definitive pathologic diagnoses were made in all patients. CONCLUSIONS: There is no clinical or statistical difference in outcomes for thoracoscopic and thoracotomy approaches. Both thoracoscopy and thoracotomy are acceptable procedures for diagnostic lung biopsy in diffuse interstitial lung disease.

Sex-associated differences in survival of patients undergoing resection for lung cancer.

BACKGROUND: The increasing incidence of lung cancer among women prompted us to assess whether sex-associated differences exist in the presentation and survival of patients who undergo major lung resection for lung cancer. METHODS: We performed a retrospective review of patients who had major lung resection for lung cancer from January 1980 to June 1998. RESULTS: There were 265 men and 186 women. Women were younger (60.7+/-0.8 versus 63.6+/-0.6 years; p = 0.005). Adenocarcinoma was more common among women (48% versus 40%; p = 0.001). Pathologic stages for men were: I = 43%, II = 26%, IIIA = 25%, IIIB or IV = 6%, and for women: I = 52%, II = 20%, IIIA = 22%, IIIB or IV = 6% (p = 0.146). Median survival was better for women (41.8 versus 26.9 months; p = 0.006). This was due both to a difference in stage at presentation and to a better median survival rate for adenocarcinoma compared with squamous cell cancer. The data suggest an association between sex and survival, although this failed to reach statistical significance. Sex influenced survival with a relative risk for women of 0.67 (95% confidence interval 0.35 to 1.29; p = 0.231 adjusted for stage, cell type, age, and spirometry). CONCLUSIONS: There are sex-associated differences in the presentation and possibly in the survival of patients with lung cancer. This finding has possible implications regarding the selection of patients for therapy and for the design of randomized therapeutic trials.

Lung cancer staging and treatment in multidisciplinary trials: Cancer and Leukemia Group B cooperative group approach. Thoracic Surgeons of CALGB.

BACKGROUND: Aggressive routine surgical staging is necessary to evaluate patients to be treated on cooperative oncology protocols. Less than 1% of lung cancer patients in the United States are currently being treated in a clinical trial. Only with results from large, prospective trials can the questions of neoadjuvant and adjuvant therapy be answered. METHODS: An outline describing the schema of preoperative patient evaluation, surgical staging, and the definition of surgical staging and resection procedures appropriate for patients considered for cooperative group protocol is presented. Current Cancer and Leukemia Group B (CALGB) protocols are used in the discussion as examples of this systematic approach. CONCLUSIONS: Over the next few years, it will be important to enter the maximum number of patients into combined modality studies to identify the role of neoadjuvant treatment in lung cancer. Entry of patients into protocols will also make their pathological specimens and clinical information available for basic science research related to treatment results. Adherence to a logical sequence of patient evaluation as outlined above will optimize patient care, as well as accrual to cooperative group studies.

Outcome after failed initial therapy for rupture of the esophagus or intrathoracic stomach.

Survival after rupture of the esophagus or intrathoracic stomach is improving, but continued leakage after initial therapy remains a problem. We retrospectively reviewed patients with rupture of the esophagus or intrathoracic stomach to determine the prevalence of continued leakage after initial therapy and how this complication affects outcome. Our review included 58 patients, 38 (66%) of whom had preexisting esophageal disease. The etiology of perforation was spontaneous rupture in 17, penetrating trauma in four, and iatrogenic injury in 35; two patients had perforation from other causes. Initial therapy consisted of drainage in eight, primary repair in 24, resection in 18, bypass in two, and observation in six. The overall mortality rate was 12% (7 of 58 patients) and continuing leaks were identified in 21% (12 of 58 patients). These leaks were unrelated to patient age, existence of prior disease, or delay in therapy but were more common after initial treatment by primary repair with or without pleural flap coverage compared to other management strategies (6 of 9 vs. 6 of 49; P < 0.001). Salvage therapy with survival was possible in 10 (83%) of 12 patients by means of esophagectomy in four, exclusion in one, drainage in two, or observation in three. Continuing leaks can be avoided by providing soft tissue coverage other than pleura over a primary repair and by not leaving an intrathoracic esophageal stump. Aggressive management of continuing leaks results in survival in more than 80% of patients.

Surgical strategies for metastatic lung cancer.

The role of surgery in the management of synchronous and metachronous metastatic lung cancer is examined. The approach to lung cancer metastatic to the brain is summarized and the literature on the surgical management of solitary adrenal metastasis from lung cancer is reviewed.

Frequent exposure to invasive medical care in early childhood and operative dental treatment associated with dental apprehension of children at 9 years of age.

AIM: This was to study prospectively a cohort of children as to whether behaviour at a 3-year examination, exposure to medical care and operative dental treatment are associated with each other, and with the level of dental apprehension at 9 years of age. METHODS: Data were collected at three subsequent dental examinations of 126 children (67 boys, 59 girls). Cooperation, general health condition and operative dental treatment during the preceding 3 years were obtained at dental examinations with 3-year intervals, i.e. at 3, 6 and 9 years of age. Children's dental apprehension was assessed at the age of 9 years. The data were analysed using an ordinal logistic regression model. RESULTS: Dental apprehension at 9 years of age was associated with frequent exposure to invasive medical care (p<0.001) and past experience of operative dental care (p<0.002), but not with cooperation at 3 years of age (p=0.124). CONCLUSION: Frequent invasive medical care in early childhood and operative dental treatment, tooth extractions in particular, are associated with dental apprehension at 9 years of age.

Caries prevention with xylitol lozenges in children related to maternal anxiety. A demonstration project.

AIM: This was to compare the effect of a prevention program between children of anxious and non-anxious mothers. METHODS: Mothers (n=120) with high and low dental anxiety scores (DAS>15 and DAS <8, respectively), and with high levels of mutans streptococci (>10(5)cfu/mL) were recruited at a maternity clinic of Tartu, Estonia. Two groups: 30 highly anxious, and 30 non-anxious mothers used xylitol (6 g/day) for 33 months and a non-treatment group of 60 mothers, both highly and low anxious (30 in each sub-group), acted as controls. All mothers were interviewed for oral health habits and education, and their dental health was examined. Due to discontinued participation 75% of the children (n=90) were examined at 2 and at 3 years of age. RESULTS: Anxious mothers brushed less frequently (p=0.014), had a longer time since their last dental visit (p<0.0001), and a lower level of education (p<0.0001) than their non-anxious counterparts. However, maternal anxiety had no effect on children's dental health, contrary to the caries prevention program which was effective both at 2 and at 3 years of age (p<0.01; OR 6.6, 1.8-25.0 and OR 3.9, CI 1.5-10.0, respectively). CONCLUSION: Children benefited from the caries prevention program, irrespective of maternal anxiety.