Douglas J. Mathisen

POSTINTUBATION TRACHEAL STENOSIS. TREATMENT AND RESULTS

A total of 503 patients underwent 521 tracheal resections and reconstructions for postintubation stenosis from 1965 through 1992. Fifty-three had had prior attempts at surgical resection, 51 others had undergone various forms of tracheal or laryngeal repair, and 45 had had laser treatment. There were 251 cuff lesions, 178 stomal lesions, 38 at both levels, and 36 of indeterminate origin. Sixty-two patients with major laryngeal injuries required complete resection of anterior cricoid cartilage and anastomosis of trachea to thyroid cartilage, and 117 had tracheal anastomosis to the cricoid. A cervical approach was used in 350, cervicomediastinal in 145, and transthoracic in 8. Length of resection was 1.0 to 7.5 cm. Forty-nine had laryngeal release to reduce anastomotic tension. A total of 471 patients (93.7%) had good (87.5%) or satisfactory (6.2%) results. Eighteen of 37 whose operation failed underwent a second reconstruction. Eighteen required postoperative tracheostomy or T-tube insertion for extensive or multilevel disease. Twelve died (2.4%). The most common complication, suture line granulations (9.7%), has almost vanished with the use of absorbable sutures. Wound infection occurred in 15 (3%) and glottic dysfunction in 11 (2.2%). Five had postoperative innominate artery hemorrhage. Resection and reconstruction offer optimal treatment for postintubation tracheal stenosis.

Primary tracheal tumors: treatment and results.

One hundred ninety-eight patients with primary tracheal tumors were evaluated in 26 years. One hundred forty-seven tumors were excised (74%): 132 (66%) by resection and primary reconstruction, seven by laryngotracheal resection or cervicomediastinal exenteration, and eight by staged procedures. Eleven more were explored. Forty-four squamous cell carcinomas were resected, 60 adenoid cystic, and 43 assorted tumors, benign and malignant. Eighty-two patients underwent tracheal resection with primary reconstruction, and 50 had carinal resection and reconstruction. Surgical mortality for resection with primary reconstruction was 5%, with one death after tracheal and six after carinal repair. Six patients had stenosis after tracheal or carinal resection; all underwent reresection successfully. Nearly all patients with squamous or adenoid cystic carcinoma were irradiated postoperatively. Twenty of 41 survivors of resection of squamous cell carcinoma are living free of disease (some for more than 25 years), 39 of 52 with adenoid cystic carcinoma (up to nearly 19 years), and 35 of 42 with other lesions (5 lost to follow-up). Comparison of length of survival of patients with squamous cell carcinoma and adenoid cystic carcinoma who are alive without disease with those who died with carcinoma supports surgical treatment (usually followed by irradiation). Positive lymph nodes or invasive disease at resection margins appear to have an adverse effect on cure of squamous cell carcinoma; such an effect is not demonstrable with adenoid cystic carcinoma.

Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer.

PURPOSE The main objectives of this study were (a) to ascertain the feasibility and toxicity of preoperative twice-daily radiation therapy and concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA (N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor response, resection rate, pathologic tumor downstaging, and survival. METHODS Eligibility included biopsy-proven N2 lesion (stage IIIA) by mediastinoscopy, Karnofsky performance score > or = 70, and weight loss less than 5% in the 3 months before diagnosis. The treatment program consisted of two courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42 Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day; surgery on day 57; and one more course of postoperative chemotherapy and 12 to 18 Gy of concurrent twice-daily radiation. RESULTS Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15 women, age 38 to 77 years) were enrolled onto this prospective study. Forty of 42 patients tolerated the intended dose (42 Gy) of preoperative radiation and 37 of 39 resected patients received prescribed postoperative radiation. The intended dose of chemotherapy was given in 100%, 70%, and 60% of patients for the first, second, and third courses of chemotherapy. Marked dysphagia that required intravenous hydration was noted in 14% of patients (six of 42). Myelotoxicities included grade > or = 3 granulocytopenia in 23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile neutropenia that required hospital admission was noted in 9% of 113 chemotherapy courses. Surgical resection was performed in 93% of patients. Treatment-related mortality was noted in 7% of patients. The overall survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2,3, and 5 years, respectively, with a median follow-up time of 48 months. Pathologic examination of the surgical specimen showed a downward shift in tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (NO) in 24% (10 of 42), and to stage 0 (TONO) in 9.5%, for a total of 67%. The degree of tumor downstaging was also translated into a survival benefit: 5-year survival rates from the time of surgery were 79%, 42%, and 18% for postoperative tumor stages 0 and I, II, and III, respectively (P = .04). CONCLUSION Concurrent chemoradiotherapy using twice-daily radiation is an effective induction regimen that resulted in 67% tumor downstaging, and an encouraging 37% 5-year survival rate. The degree of tumor downstaging may be a useful intermediate end point for survival benefit in stage IIIA (N2) NSCLC.

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

BACKGROUND Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and β-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non–Small-Cell Lung Carcinoma

PURPOSE We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study.

PURPOSE This phase II trial was designed to evaluate the feasibility, toxicity, response rates, and survival for neoadjuvant chemotherapy and radiotherapy (RT) followed by surgical resection in newly diagnosed patients with surgically staged IIIA non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS Previously untreated patients with NSCLC underwent bronchoscopy, chest and abdominal computed tomography (CT), bone scan, and surgical staging of the mediastinum. Neoadjuvant treatment consisted of concurrent chemotherapy and RT. Patients then underwent surgical resection, which was followed in turn by additional chemotherapy and RT. Chemotherapy included cisplatin 100 mg/m2 on days 1 and 29, vinblastine 3 mg/m2 on days 1 and 3 and 29 and 31, and fluorouracil (5-FU) 30 mg/kg/d by infusion on days 1 to 3 and 29 to 31 (FVP). RT began on day 1 and included 3,000 cGy in 15 fractions. Surgery took place on day 55, and one more cycle of chemotherapy and an additional 3,000 cGy of RT began on day 85. RESULTS Forty-one eligible patients (median follow-up, 53 months) were studied. N2 disease was present in 80%, whereas 20% had T3N0 or T3N1 lesions. Response to neoadjuvant chemotherapy and RT included no complete responses (CR), 21 (51%) partial responses (PR) or regressions, 19 (46%) stable disease (SD), and one (2%) progressive disease (PD). Thirty-one patients underwent surgery, and 25 were resected. In four of the 25 resection specimens, no viable tumor was present, whereas in three of the six unresectable patients, extensive biopsy results demonstrated only necrotic tumor. The maximum response achieved using all protocol treatment was 27 (66%) CRs, seven (17%) PRs or regression, six (15%) SDs, and one (2%) PD. Toxicity was substantial and primarily hematologic. There were six (15%) treatment-related deaths, which included three perioperative deaths and three chemotherapy-related toxicity deaths. The Kaplan-Meier curve indicated a 1-year survival of 58% and a median survival of 15.5 months. Nine patients (22%) remain disease-free. CONCLUSIONS There was a reasonably high rate of PR associated with concurrent neoadjuvant chemotherapy and RT, and a high percentage of patients who ultimately were rendered completely disease-free. However, treatment-related morbidity and mortality was common. Median survival seemed to be only modestly improved beyond that achieved with less intensive means of treatment. However, a group has emerged of patients who enjoy prolonged disease-free survival and possible cure.

FDG–PET in staging and restaging non-small cell lung cancer after neoadjuvant chemoradiotherapy: correlation with histopathology

This study was performed to investigate the utility of FDG-PET for: (1) initial staging, and (2) restaging of the primary and mediastinal nodal lesions 2 weeks after the completion of preoperative chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC). Twenty-six patients with histologically confirmed stage III NSCLC were accrued to this study from April 1993 to July 1998. They included 21 with stage IIIA (N2) NSCLC who were enrolled into an institutional phase II study, and 5 patients with a highly selected subset of stage IIIB disease characterized by the presence of microscopic metastatic disease in contralateral mediastinal lymph nodes who were also treated with preoperative chemoradiotherapy; N3 lesions (n=3) and minimal T4 lesions. Demographic characteristics included median age 62 years (a range from 47 to 73) and gender ratio of male 15 to female 11. Histologic types of tumor consisted of squamous cell carcinoma 6, adenocarcinoma 11, large cell carcinoma 5, and non-small cell carcinoma 4. All patients had FDG-PET imaging of the chest before the initiation and 2 weeks after completion of preoperative therapy. The FDG-PET images were evaluated qualitatively for uptake at the primary tumor sites and mediastinal lymph nodes. Standard uptake values (SUVs) were also calculated for the primary tumors and all PET findings were correlated with surgical histopathologic data. Preoperative chemoradiotherapy resulted in complete pathologic response in 8 of 26 primary lesions. By qualitative analysis, 96% of these tumors showed level 3 or 4 uptake before preoperative chemoradiotherapy. After chemoradiotherapy, 57% (15/26) of patients showed at least a one level decrease in uptake, and the sensitivity and specificity of FDG-PET for differentiating residual tumor from pathologic complete response were 67% (12/18) and 63% (5/8). Mean SUV was 14.87+/-7.11 at baseline and decreased to 5.72+/-3.35 after chemoradiotherapy (n=21, P<0.00001). When a value of 3.0 was used as the SUV cut-off, sensitivity and specificity were 88 and 67%, respectively. The mean values of visual intensity were 3.87+/-0.35 and 3.8+/-0.51 for patients who achieved pathologic complete response (n=8) and for those who showed residual cancer after the preoperative therapy (n=18), respectively. The mean SUVs were 16.97+/-8.52 and 14.03+/-6.61 for patients who achieved pathologic complete response (n=6) and for those who showed residual cancer (n=15) after the preoperative therapy, respectively. Therefore, the degree of FDG uptake before preoperative chemoradiotherapy did not provide predictive value for subsequent tumor response. For mediastinal initial staging, the sensitivity and specificity of FDG-PET were 75 and 90.5%. The sensitivity and specificity of FDG-PET for mediastinal restaging were 58.0 and 93.0%. These results indicate that FDG-PET is useful for monitoring the therapeutic effect of neoadjuvant chemoradiotherapy in patients with stage III NSCLC. For the primary lesions, SUV based analysis has high sensitivity but limited specificity for detecting residual tumor. In contrast, for restaging of mediastinal lymph nodes, FDG-PET is highly specific, but has limited sensitivity.

Surgical Management and Radiological Characteristics of Bronchogenic Cysts

Forty-two patients with bronchogenic cysts were treated over a 30-year period (1962 to 1991). The location was mediastinal in 37 and intrapulmonary in 5. Cysts were symptomatic in 21 patients (50%) and complications occurred in 11 (26%). The complications included infection in 5 patients, hemorrhage into the cyst in 2 patients, dysphagia due to esophageal compression in 2, adenocarcinoma arising from a bronchogenic cyst in an 8 1/2-year-old girl, and an esophagobronchopleurocutaneous fistula as a result of previous incomplete resection in 1 patient. Magnetic resonance imaging has been found to provide specific diagnostic information about bronchogenic cysts. All but 2 patients were treated with complete excision. One patient was managed by observation and another had drainage of the cyst by mediastinoscopy. Complications of treatment occurred in only 2 patients. One had a minor wound infection and the other had Clostridium difficile enterocolitis. Only 4 patients were lost to follow-up. No late complication or recurrence developed in those patients having complete excision. We recommend complete excision in most instances to confirm the diagnosis, relieve symptoms, and prevent complications.

Postpneumonectomy bronchopleural fistula after sutured bronchial closure: Incidence, risk factors, and management

OBJECTIVE Postpneumonectomy bronchopleural fistula remains a morbid complication after pneumonectomy. The incidence, risk factors, and management of postpneumonectomy bronchopleural fistula were evaluated in 256 consecutive patients who underwent pneumonectomy with a standardized suture closure of the bronchus. METHODS Pneumonectomy was performed for lung cancer in 198 cases, for other malignancy in 20 cases, and for benign causes in 38 cases. The bronchial stump was closed with interrupted simple sutures to emphasize a long, membranous wall flap. All stumps were covered by autologous tissue. RESULTS The incidence of postpneumonectomy bronchopleural fistula was 3.1%. Risk factors for bronchopleural fistula were the need for postoperative ventilation (p = 0.0001) and right pneumonectomy (p = 0.04). Five patients had bronchopleural fistulas as a result of pulmonary complications necessitating ventilation; the cause in the remaining three cases appeared to be technical. Reclosure was successful in five cases (mean postoperative day 12); in one case a pinhole fistula was healed by drainage alone. Two (25%) of the eight patients who had bronchopleural fistulas died. CONCLUSIONS Careful, sutured closure of the main bronchus with a tissue buttress after pneumonectomy yields excellent results. The most significant risk factor for bronchopleural fistula is a pulmonary complication necessitating ventilation. Contrary to previous reports, reclosure is usually successful even if performed late.

Transthoracic Esophagectomy: A Safe Approach to Carcinoma of the Esophagus

Transthoracic esophagogastrectomy is a safe operation. Mechanical staplers and a cervical anastomosis have been emphasized to avoid catastrophic consequences of anastomotic leaks in the chest. Transhiatal esophagectomy has been proposed to bring the anastomosis into the neck. It is meant to be a palliative procedure and consequently denies the patient the best chance for surgical cure. The emphasis should be on anastomotic technique and sound principles of surgical oncology. Since 1980, we have performed 104 esophagectomies for carcinoma of the esophagus. We used a left thoracoabdominal incision for distal tumors (64) and the Ivor Lewis technique (40) for more proximal tumors. A two-layer inverting interrupted silk suture technique was used for all anastomoses. More than 90% of the procedures were performed by resident staff. The operative mortality was 2.9% (3 patients). There were no anastomotic leaks. Five patients required between one dilation and three dilations postoperatively. A positive smoking history was present in 83 patients and substantial alcohol use, in 33. Median estimated blood loss was 500 ml, and 60% of patients required no transfusions. Major complications included pneumonia (12 patients) and reexploration for bleeding (2). Minor complications included atelectasis (71 patients), atrial fibrillation (9), ventricular arrhythmias (9), urinary tract infection (3), and wound infection (2). Squamous cancer was present in 31 patients and adenocarcinoma, in 73. Positive lymph node metastases were present in 75%. Anastomotic recurrence was documented in 6 patients. Standard techniques of esophagogastrectomy and a two-layer anastomosis will give excellent results with low mortality and acceptable morbidity.