Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial.

PURPOSE: The 5-year survival rates with surgical resection for preoperatively identified stage IIIA N2 non-small-cell lung cancer (NSCLC) are less than 10%. A pilot study of mitomycin, vindesine, and cisplatin (MVP) induction chemotherapy was undertaken in an attempt to improve the curative potential of surgery in this group of patients. PATIENTS AND METHODS: Thirty-nine patients with mediastinoscopy stage IIIA N2 NSCLC received two cycles of MVP. Responding patients underwent thoracotomy for resection and two further courses of MVP. RESULTS: The overall response rate was 64% (25 of 39) with three complete and 22 partial responses. Twenty-two patients were resected, which included a radical mediastinal node dissection. Eighteen resections were complete and four were incomplete. Pathologically, three patients (7.7%) had no tumor remaining. Toxicity included two postoperative deaths secondary to a bronchopleural (BP) fistula, mitomycin pulmonary toxicity in two patients, and septic deaths in four patients. Twenty-eight patients have died; 20 have recurrent or progressive disease. Eight of the 18 patients completely resected have recurred, with a median time to recurrence of 20.6 months. Sites of recurrence include two locoregional, five distant (two in brain), and one in both. Median survival of all 39 patients is 18.6 months, with a 3-year survival of 26%. The median survival for those patients completely resected was 29.7 months with a 3-year survival of 40%. CONCLUSIONS: We conclude (1) that MVP is an effective but toxic chemotherapeutic regimen for limited NSCLC; (2) the median survival seems to be prolonged; and (3) the role of induction chemotherapy followed by surgery in stage IIIA N2 NSCLC requires a phase III randomized trial to compare it with other treatment modalities.

Staging of the mediastinum. Role of mediastinoscopy and computed tomography.

During the 1940s and 1950s, as many as 50% of thoracotomies identified nonresectable tumors. At present, better than 90% of patients undergoing thoracotomy for presumably resectable lung cancer are found to have operable tumors. This improvement is the result of major advances in the preoperative staging of this disease. Mediastinoscopy and computed tomography (CT) are the most valuable techniques for evaluating the mediastinum in patients with primary cancer of the lung. For each modality, the primary objective is to define the presence or absence of spread to mediastinal lymph nodes. In patients with non-small-cell lung cancer, surgical resection remains the treatment of choice so long as all recognizable tumor can be removed at operation. Both mediastinoscopy and CT provide critical information concerning the potential for a complete resection. Computed tomography remains the most effective noninvasive technique for the evaluation of mediastinal nodes.

Current status of surgical resection for lung cancer.

There have been no major breakthroughs in surgical management for primary lung cancer during the past 40 years. Improved 5-year survival relates primarily to improved preoperative staging and appropriate selection of patients for resection. Perioperative morbidity and mortality, however, has been significantly reduced. Certain principles pertain to current surgical management: resection remains the best treatment for patients with localized, non-small cell primary lung cancer. Accurate preoperative diagnosis and staging: whenever possible, it is desirable to establish the diagnosis and cell type before operation. Accurate evaluation of the N status warrants wide application of invasive staging with mediastinoscopy or a variant. Indications for resection: only patients in whom a complete resection is anticipated should be selected for surgery. Such cases included T1 to T4 stages, N0 and N1 tumors, and selected N2 cases. The indication for resection in patients with hematogenous metastases are anecdotal. Intraoperative staging: accurate and deliberate intraoperative staging with evaluation of nodes using the American Thoracic Society map is highly desirable. The nature of nodal metastases exerts a critical influence on prognosis and in the selection of patients for surgical resection. At present, there is no clear indication for adjuvant therapy in surgically resected cases other than for evaluation and clinical trials.

Lung cancer. The past twenty-five years.

On the occasion of this Fourth World Conference on Lung Cancer, I am privileged to present the opening keynote address. This presentation has been sponsored by the Ontario Cancer Treatment and Research Foundation. In 1952, the Foundation established an annual lectureship in memory of one of their prominent physicians. Dr. Gordon Earle Richards was one of Canada's pioneer radiologists and radiotherapists who was appointed Director of the Institute of Radiotherapy at Toronto General Hospital at a time when radium and high-voltage x-rays were just coming into common use for the treatment of malignant disease. He established an international reputation for his contributions to clinical radiotherapy, and was subsequently appointed Professor of Radiology at the University of Toronto. He was Managing Director of the Ontario Cancer Treatment and Research Foundation between 1945 and 1949. I wish to thank the Foundation for the privilege of presenting the 33rd Gordon Richards Memorial Lecture.

Non-small cell lung cancer: role of surgery for stages I-III.

Survival following surgical resection of non-small cell lung cancer (NSCLC) has improved since the 1960s, although the 5-year survival rate remains low. This article provides an overview of the role of surgery for NSCLC stages I-III, with a focus on optimizing long-term survival in those patients with resectable disease. Topics explored include diagnosis and staging, indications for resection, types of resection, and indications for adjuvant therapy. A review of the literature indicates a clear survival advantage for complete resection, and is suggestive of an advantage for mediastinal lymph node dissection (vs lymph node sampling) and neoadjuvant therapy (vs adjuvant therapy).

Preoperative assessment of esophageal pathology.

Panmural esophagitis results in esophageal thickening and shortening and prevents adequate reduction of a hernia. Twenty patients with panmural esophagitis, treated by Belsey repair, have been followed up for more than 5 years; 9 of them remain asymptomatic and 11 have symptomatic reflux, 7 of whom have required further surgery. Belsey also has reported a 45 per cent recurrence rate in patients with this type of disease. Preoperative recognition of panmural esophagitis allows a planned surgical approach and the use of a surgical technique designed for the management of an irreducible hernia. The ability to predict these changes was studied in 124 patients, who were evaluated by history, radiology, endoscopy, and manometry prior to transthoracic hernia repair. The esophagus was inspected at operation to determine the presence of panmural changes. History was of no value in assessment. Radiologically, a large and irreducible hernia was associated with panmural changes, but these changes also occurred in the absence of ulceration. Manometric studies allowed accurate prediction of mural changes. Over 90 per cent of patients with panmural esophagitis have more than 40 per cent disordered motor activity (DMA) in the distal part of the esophagus, and 75 per cent of such patients have more than 60 per cent DMA. Combining these investigative data allowed the accurate prediction of panmural changes in 90 per cent of the 124 patients.

A bifurcated silicone rubber stent for relief of tracheobronchial obstruction.

Though the techniques for surgical treatment after postintubation tracheal stenoses are well defined, the management of major airway obstruction by tracheal tumor, external compression, or diffuse intrinsic tracheal disease below the thoracic inlet still presents a difficult problem. Existing methods do not provide safe and effective relief at the level of the distal trachea, carina, and main bronchi. This report describes a bifurcated silicone rubber stent initially designed to preserve patency of the airways in a patient after severe and diffuse scalding injury to the trachea and main bronchi. This stent has since been used to provide relief from airway obstruction by tracheal or mediastinal tumors below the thoracic inlet. The method for insertion by tracheostomy with guide bougies passed under direct bronchoscopic vision past the obstructing lesion is described in detail and illustrated by reference to two patients with tracheobronchial obstruction. Once the tube is in place, the patient breathes normally through the mouth and nose and can speak, cough, or clear his own airway by suction if necessary. This method has proved a safe and effective means to restore patency of the major airways and provide relief from asphyxia while further treatment is planned or healing ensues. Our initial experience indicates that the tube may be allowed to remain in position for several months without adverse effects.

Massive hiatus hernia: evaluation and surgical management.

OBJECTIVE: Paraesophageal hernias represent advanced degrees of sliding hiatus hernia with intrathoracic displacement of the intraesophageal junction. Gastroesophageal reflux disease occurs in most cases, resulting in acquired short esophagus, which should influence the type of repair selected. METHODS: Between 1960 and 1996, 94 patients with massive, incarcerated paraesophageal hiatus hernia were operated on at the Toronto General Hospital. The mean age was 64 years (39 to 85 years), with a female to male ratio of 1.8:1. Organoaxial volvulus was present in 50% of cases. Clinical presentation in these patients included postprandial pain in 56%, dysphagia in 48%, chronic iron deficiency anemia in 38%, and aspiration in 29%. Symptomatic reflux, either present or remote, was recorded in 83% of cases. All patients underwent endoscopy by the operating surgeon. In 91 of 94 patients, the esophagogastric junction was found to be above the diaphragmatic hiatus, denoting a sliding type of hiatus hernia. Gross, endoscopic peptic esophagitis was observed in 36% of patients: ulcerative esophagitis in 22% and peptic esophagitis with stricture in 14%. A complete preoperative esophageal motility study was obtained for 41 patients. The lower sphincter was hypotensive in 21 patients (51%), and the amplitude of peristalsis in the distal esophagus was diminished in 24 patients (59%). These abnormalities are both features of significant gastroesophageal reflux disease. In 13 recent, consecutive patients with paraesophageal hernia, the distance between the upper and lower esophageal sphincters was measured during manometry. The average distance was 15.4 +/- 2.33 cm (11 to 20 cm), which is consistent with acquired short esophagus. The normal distance is 20.4 cm +/- 1.9 (p < 0.0001). RESULTS: All 94 patients were treated surgically: 97% had a transthoracic repair with fundoplication. A gastroplasty was added in 75 cases (80%) because of clearly defined or presumed short esophagus. There were two operative deaths, and two patients were never followed up. Among the 90 available patients, the mean follow-up was 94 months; median follow-up was 72 months. Seventy-two patients (80%) are free of symptoms (excellent result); 13 (13%) have inconsequential symptoms requiring no therapy (good result); and three patients (4%) are improved but have symptoms requiring medical therapy or interval dilatation (fair result). Two patients had poor results because of recurrent hernia and severe reflux. Both were successfully treated by reoperation with the addition of gastroplasty because of acquired shortening, which was not recognized at the first operation. CONCLUSIONS: Most of these 94 patients had symptoms or endoscopic, manometric, and operative findings that were consistent with a sliding hiatus hernia. There was a high incidence of endoscopic reflux esophagitis and of acquired short esophagus. True paraesophageal hernia, with the esophagogastric junction in a normal abdominal location, appears rare. Our observations were supported by measurements obtained at preoperative endoscopy and manometry, and by findings at the time of surgical repair. These observations support the choice of a transthoracic approach for repair in most patients.

Subglottic stenosis complicating Wegener's granulomatosis: surgical repair as a viable treatment option.

Wegener's granulomatosis frequently involves the subglottis and trachea, often leading to compromise of the upper airway. Moreover, the stenotic segments may persist or progress despite control of the disease elsewhere in the body. In this report, we describe the cases of five patients with Wegener's granulomatosis who, in addition to nasal, sinus, pulmonary and renal involvement, had symptomatic subglottic or tracheal stenosis. Biopsy specimens from involved sites in the subglottis and trachea were often not diagnostic, and the diagnosis was later confirmed by a positive antineutrophil cytoplasm antibody titer. All patients had clinical remission on standard therapeutic regimens with prednisone and cyclophosphamide but continued to have symptoms of extrathoracic airway obstruction. Three of the five patients underwent primary thyrotracheal anastomosis while their disease was in clinical remission, without postoperative compromise of anastomotic integrity or wound healing despite concurrent use of prednisone and cyclophosphamide. There has been no evidence of local disease recurrence during follow-up periods ranging from 3 months to 14 years. We conclude that surgical intervention is a viable treatment option for patients who have symptomatic stenotic segments of the subglottis and trachea as a result of Wegener's granulomatosis in clinical remission.

Prospective, randomized, double-blind study using prophylactic cephalothin for major, elective, general thoracic operations.

A total of 211 patients were entered into a randomized, double-blind study of postoperative infection in which an antibiotic (cephalothin) and a placebo were used. The antibiotic was effective in reducing sleep wound infections (p less than 0.05) and superficial wound infections (p less than 0.01). The incidence of pulmonary infections was decreased, but the change was not statistically significant, and the incidence of empyema was unaffected.

Gastroplasty and fundoplication in the management of complex reflux problems.

Between 1963 and 1976, 220 patients with complex reflux problems were managed by combining a modified Collis gastroplasty with a Belsey type of partial fundoplication. All patients had one or more of the following complicating conditions considered indications for the combined operation: peptic stricture (104), esophagitis and shortening without stricture (25), one or more prior hiatal repairs (65), massive herniation (33), and motor disorders associated with reflux (26). Ninety-six percent of the patients were evaluated by personal interview from 1 to 15 years after repair. The operative mortality rate was 0.5 percent. The incidence of significant symptomatic reflux requiring medical therapy was 3 percent and the incidence of troublesome dysphagia was 11 percent. No patient has required further operation for the relief of recurrent symptomatic reflux. Two patients required additional operation for severe residual dysphagia. Twenty patients managed by this repair were evaluated by preoperative, intraoperative, and sequential postoperative esophageal pressure studies. The mean postoperative pressure of 21.4 mm. Hg was more than double the preoperative value. Two publications from other centers reported on similar groups of patients managed by gastroplasty and partial fundoplication, evaluated by preoperative and postoperative esophageal pressures. In these latter publications, the percentage increase in postoperative lower esophageal pressure was significantly less than in our study, and a much higher incidence of symptomatic reflux was recorded. We suggest that the differences in postoperative pressures observed in account for the pronounced differences in the quality of results obtained.

Use of the silicone tracheal T-tube for the management of complex tracheal injuries.

This paper reports on the use of the silicone Montgomery T-tube for the management of 18 patients with complex tracheal injuries. Our use of the tube was as follows: prior to definitive resection, as a better alternative to tracheostomy tube, while we were awaiting the most appropriate time for resection; at the time of resection, as an adjunct to segmental subglottic resection, used to stent residual abnormal laryngeal mucosa: following tracheal resection for uncertain or unsatisfactory healing: as sole treatment, when resection was deemed unsuitable or inappropriate. When stenting the high region, the upper limb of the T-tube can be brought through the vocal cords with preservation of a functional voice and without injury to the vocal cords even with prolonged use. In contrast to a tracheostomy tube, the T-tube provides respiration through the the nasopharynx, so that humidification and phonation are maintained. It is generally trouble free, requires little if any maintenance, and can remain in place for a year or more when necessary.

Experience with primary neoplasms of the trachea and carina.

From 1963 to 1983, 44 patients presented with a primary tracheal neoplasm that was amenable to surgical treatment. Forty-two of the 44 tumors were malignant. Thirty-three patients were managed by resection and primary anastomosis. The following resections were done: trachea only, 12; trachea plus carina, 13; trachea plus cricoid cartilage, four; and trachea plus larynx, four. There were two operative deaths in these 33 patients. Prosthetic reconstruction with heavy-duty Marlex mesh was done in six patients. Three of the six died of erosion of the innominate artery during the postoperative period. In three patients with nonresectable tumors, a silicone-coated Montgomery T-tube provided transient but worthwhile palliation. In two patients with nonobstructive adenoid cystic carcinoma involving the subglottis, irradiation was chosen as the initial treatment, since resection would necessitate laryngectomy. Resection, including laryngectomy, may be required in the future. The following points are emphasized: (1) A majority of operable neoplasms can be resected through a cervical collar incision and median sternotomy. Median sternotomy is the optimal operative exposure in most neoplasms necessitating resection of the carina. (2) Partial resection of the cricoid with sparing of the recurrent laryngeal nerves and larynx is possible in some patients with primary malignant tumors involving the proximal trachea and subglottic region. (3) In patients with adenoid cystic carcinoma, resection may afford excellent, long-term palliation even when the resection is incomplete. Pulmonary metastases are common in patients with adenoid cystic tumors. However, they usually progress slowly, may remain asymptomatic for many years, and are not necessarily a contraindication to resection of the primary tumor even when they are synchronous. Our experience suggests that adjunctive radiotherapy is beneficial in patients with adenoid cystic carcinoma.

Primary tracheal anastomosis after resection of the cricoid cartilage with preservation of recurrent laryngeal nerves.

Resections at the cricoid level pose the problems of damage to the recurrent laryngeal nerve and loss of circumferential cartilaginous support. Strictures within the cricoid ring have usually been managed with keels or stents, whereas neoplasms have been managed by laryngectomy. This paper reports on 6 patients with lesions involving the cricoid who were successfully treated by segmental tracheal resection and removal of all but a thin shell of posterior cricoid plate. The distal trachea was anastomosed at the subglottic level within 1 cm. or less of the vocal cords. Two patients had traumatic transection at the cricotracheal level with disruption of cricoid cartilage and avulsion of both recurrent nerves. Of the other 4 patients with tracheal lesions involving the cricoid, 2 had postintubation strictures, another had chemical burns, and the fourth had adenoid cystic carcinoma. Primary healing and good clinical results were obtained in all 6 patients. In the 4 patients with intact recurrent nerves, nerve function was preserved. This technique provides a method for resection and reconstruction in one stage for selected lesions at the cricoid level.

Surgery in pulmonary aspergillosis.

Pulmonary aspergillosis is a rare disease, most commonly presenting as secondary invasion of pre-existing cavitary disease. In Toronto General Hospital 24 patients have been recognized as having this disorder in the 10 years from 1965 to 1975. The most common presenting symptoms were cough, sputum production, and hemoptysis, with the hemoptysis occasionally being massive. Tuberculosis and bronchiectasis were the commonest pre-existing diseases. Thirteen of these patients were treated by surgical resection because of major complications or progression of the aspergillosis. Five of these patients died following surgery, all of these having had major complications prior to surgical intervention. Of the eight surviving patients seven are progressing well, but one had developed further extension of his disease.

Prospective evaluation of mediastinoscopy for assessment of carcinoma of the lung.

Between 1979 and 1984, mediastinoscopy was performed on 1,000 of the 1,500 patients admitted to the Thoracic Surgical Service of the Toronto General Hospital with the diagnosis of carcinoma of the lung. In 144 cases, concomitant anterior mediastinoscopy was also performed. Abnormal mediastinal nodes were found in 296 (29.6%). The overall complication rate was 2.3%, with no deaths. Mediastinoscopy revealed diseased nodes in 24% of patients with squamous cell carcinoma, 29% with adenocarcinoma, 54% with small cell undifferentiated carcinoma, 31% with large cell undifferentiated carcinoma, and 12% with bronchoalveolar carcinoma. Abnormal mediastinal nodes were found with equal frequency in right- and left-sided tumors and occurred in 31% of tumors in the main bronchus, 25% of upper lobe tumors, and 17% of lower lobe tumors. Of the 704 patients having negative results of mediastinoscopy, 590 were subjected to thoracotomy. Ninety-three percent underwent resection (85% curative, 7% palliative) and 7% had unresectable tumors. Of the resections, 20% were pneumonectomies. At thoracotomy, 52 of the 590 patients with negative mediastinoscopic results were found to have abnormal mediastinal nodes. Sixty-two of the 296 patients with positive results of mediastinoscopy were selected for thoracotomy. Eighty-six percent had resectable lesions (67% curative, 18% palliative) and 14% unresectable. The pneumonectomy rate in this group was 35%. These current data support our previous opinion that routine mediastinoscopy can be done with negligible morbidity and provides essential information for the classification and management of cancer of the lung.

Subglottic tracheal resection and synchronous laryngeal reconstruction.

Postintubation injury of the upper airway commonly results in stenotic lesions of the larynx, subglottis, and adjacent trachea. The traditional approach to surgical correction is laryngofissure for the laryngeal component and staged plastic reconstruction of the subglottic stenosis. Reported results are variable and unpredictable, and permanent extubation is impossible in a significant number of patients. We report experience with 15 patients with combined laryngeal, subglottic, and tracheal stenosis who were managed by a one-stage operation: circumferential resection of the subglottis and trachea with primary thyrotracheal anastomosis, combined with laryngofissure and laryngeal reconstruction. These procedures required the collaboration of the Departments of Otolaryngology and Thoracic Surgery of the Toronto General Hospital. Between 1972 and 1991, our thoracic surgical division did 53 circumferential subglottic tracheal resections with primary thyrotracheal anastomosis for benign disease. There were no operative deaths and 51 of 53 patients were successfully extubated. In 15 of these patients, a concomitant laryngofissure for laryngeal reconstruction was required. Laryngeal repair included excision or incision of interarytenoid scar (n = 13), interarytenoid mucosal graft (n = 6), or mobilization of cricoarytenoid joint (n = 3). A temporary laryngotracheal stent (usually a Montgomery T tube) was maintained after the operation in all cases (duration 3 to 42 months). Thirteen of these 15 patients are now permanently extubated and none has functionally significant restenosis. Vocal function is satisfactory to good in these patients. The approach described for these combined laryngotracheal lesions provides better results than those reported with traditional staged and plastic techniques of reconstruction. The collaboration of the departments of otolaryngology and thoracic surgery was essential to achieve these results.

Intraoperative and postoperative esophageal manometric findings with Collis gastroplasty and Belsey hiatal hernia repair for gastroesophageal reflux.

The combination of a Collis gastroplasty with a Belsey Mark IV fundoplication has proved clinically effective in the management of certain patients with complications of gastroesophageal reflux. The present study measured the effect of gastroplasty and Belsey repair on intraluminal pressure changes in the gastroplasty and lower esophagus. Manometric studies were performed preoperatively, intraoperatively, and postoperatively. In each case the gastroplasty segment of the esophagus was found to function as a high pressure zone (HPZ). The pressure in this zone further increased following the fundoplication. It could be diminished with intravenous administration of Buscopan and augmented with intravenously given pentagastrin. The original lower esophageal sphincter in most instances was included in the upper segment of the gastroplasty tube, but the entire length of the gastroplasty tube functioned as an HPZ, and pressures in the tube were considerably higher than those originally present in the lower esophageal sphincter. These studies provide a physiological rationale for the effectiveness of gastroplasty and fundoplication.

Carinal resection. A report of two cases and a description of the anesthetic technique.

Two cases of carinal tumor managed by resection and primary anastomosis are presented. Their course is discussed and a description of an anesthetic technique which obviates the need for cardiopulmonary bypass is presented. The principles of carinal surgery are discussed, emphasizing expert anesthesia and resection line control by frozen-tissue examination.

One-stage reconstruction for pharyngolaryngectomy. Esophagectomy and pharyngogastrostomy without thoracotomy.

From 1969 to 1981, a total of 22 patients underwent laryngopharyngectomy and nonthoracotomy esophagectomy, with immediate pharyngogastrostomy, for hypopharyngeal or postcricoid carcinoma. Thirteen initially had been treated by high-dose radiotherapy, but the tumor had either persisted or recurred. Four patients underwent planned preoperative irradiation on the morning of the operation. Two patients had had previous high-dose local irradiation to the neck for other disease, and three patients had no irradiation. There was one operative death. Anastomotic leaks developed in four patients, but only one of the leaks was considered a serious problem. Three patients had transient dysphagia, but only one required dilatation. Transient delayed gastric emptying was a problem in three other patients. The average postoperative stay was 31 days, with 38% of patients being discharged by 21 days. All patients were discharged eating a normal diet. Fifty percent survived longer than 12 months, with an actuarial survival rate of 30% at 5 years. The patient surviving longest is disease free at 12 years. Palliation was considered excellent in all 21 operative survivors. Immediate pharyngogastrostomy via nonthoracotomy esophagectomy is a safe and excellent means of palliation in this group of patients, for whom palliation is often the only option.