Prospective study of combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin for unresectable or metastatic malignant pleural mesothelioma.

BACKGROUND: This study was designed to determine the efficacy and side effects of a combination of cyclophosphamide (C), doxorubicin (D), and cisplatin (P) in patients with inoperable, unresectable, or metastatic malignant pleural mesothelioma. METHODS: Twenty-three patients with unresectable or metastatic malignant pleural mesothelioma were entered onto the study. The median age was 62 years (range, 42-74 years); there were 20 males and 3 females; the median performance status was 1 (Zubrod's scale). The histologic types included epithelial (14 patients), sarcomatoid (4 patients), unclassified (4 patients), and mixed type (1 patient). Twenty patients were known to have been exposed to asbestos and 3 were not. All patients were treated with the following starting dose of chemotherapy: a cycle comprised of C, 500 mg/m2 intravenously, day 1; D, 50 mg/m2 intravenously, day 1; and P, 80 mg/m2 intravenously, day 1 every 3 weeks. The cisplatin dose was reduced to 50 mg/m2 for the subsequent courses. For the assessment of tumor response, all patients had computed tomography scans of the chest after each three cycles of chemotherapy. RESULTS: Overall, 7 of 23 patients (30%) had partial responses (durations of responses [weeks]: 158+, 91+, 70+, 41+, 40, 39, 25), three had minor responses, and 14 had stable or progressive disease. One partial responder later underwent surgical resection and no viable tumors cells were found in the pathologic specimen. All patients have stopped treatment, and eight are still alive. The most common side effect was granulocytopenia (grade 4, 52%; grade 3, 17%). Other hematologic side effects were modest. Nonhematologic side effects included mild to moderate nausea and vomiting, neutropenic fever (three patients), peripheral neuropathy (one patient), and congestive heart failure (one patient). The overall median duration of survival was 60 weeks. CONCLUSION: Combination chemotherapy with CDP was well tolerated and had significant activity against unresectable or metastatic malignant pleural mesothelioma. The median duration of responses was 60 weeks; however, the survival rate was far from satisfactory. Continued development of new approaches including the biologic understanding of tumor development and testing new agents is warranted.

Resection of sternal tumors: extent, reconstruction, and survival.

BACKGROUND: Resection of sternal tumors may be tailored to the patient and the location of the malignancy. METHODS: We reviewed our results of sternectomy (typically 5-cm margins) performed in 30 patients over a 10-year period. RESULTS: Thirteen patients had primary sternal sarcoma (six chondrosarcoma, five osteosarcoma, two other); 10 patients had local recurrence from breast cancer; 4 patients had metastases; 3 patients had other (two osteoradionecrosis, one malignant fibrous histiocytoma). Morbidity occurred in 8 patients (26.7%): wound dehiscence, 2; wound infection, 1; hemorrhage, 1; pneumonia, 1; prolonged air leak, 1; empyema, 1; and bronchopleural fistula, 1. One patient, with multiple metastases, died from adult respiratory distress syndrome on day 25 (overall mortality, 3.3%; 1 of 30). The area of reconstruction ranged from 35 to 264 cm2. The technique of reconstruction included muscle flap alone in 13 patients; muscle flap and mesh, 9; muscle flap and rigid prosthesis (Marlex methylmethacrylate), 7; or other, 1 patient. Nineteen patients (63%) were extubated within 24 hours after operation. Median intensive care unit stay was 2 days; median hospitalization, 6 days. Late local recurrence after resection occurred in 6 patients; 4 from breast cancer (3 patients had concurrent distant metastases). Five-year actuarial survival after primary tumor resection was 73% and 33% after resection of recurrent breast cancer (median, 21 months). CONCLUSIONS: Partial sternectomy may be performed for primary sternal tumors with short hospitalization and good local control. Wider local excision or total sternectomy may minimize local re-recurrence of breast carcinoma to the sternum.

Closure of massive chest wall defects after full-thickness chest wall resection.

We report an unusual repair of a massive chest wall defect resulting from resection of a chronic ulcer after radiation therapy for stage IV breast carcinoma. The defect was 690 cm2 and included the body of the sternum, 10 ribs, and the anterior portion of the diaphragm. Chest wall reconstruction was accomplished with multiple flaps: a pectoralis major advancement flap, a reversed abdominoplasty, an omental flap, and a latissimus dorsiscapular-parascapular musculofasciocutaneous (hemiback) flap. Skeletal reconstruction with prosthetic material or bone grafts was not performed in this patient. The problems associated with complex chest wall reconstructions are discussed.

Resection of lung cancer is justified in high-risk patients selected by exercise oxygen consumption.

The medical criteria for inoperability have been difficult to define in patients with lung cancer. Sixty-six patients with non-small cell lung cancer and radiographically resectable lesions were evaluated prospectively in a clinical trial. The patients were considered by cardiac or pulmonary criteria to be high risk for pulmonary resection. If exercise testing revealed a peak oxygen uptake of 15 mL.kg-1.min-1 or greater, the patient was offered surgical treatment. Of the 20 procedures performed, nine were lobectomies, two were bilobectomies, and nine were wedge or segmental resections. All patients were extubated within 24 hours and discharged within 22 days after operation (median time to discharge, 8 days). There were no deaths, and complications occurred in 8 (40%) of the 20 patients. Five patients whose peak oxygen uptake was lower than 15 mL.kg-1.min-1 also underwent surgical intervention; there was one death. Thirty-four patients whose peak oxygen uptake was less than 15 mL.kg-1.min-1 and 7 who declined operation underwent radiation therapy alone (35 patients) or radiation therapy and chemotherapy (6 patients). There were no treatment-related deaths, and the morbidity rate was 12% (5/41). The median duration of survival was 48 +/- 4.3 months for the patients treated surgically and 17 +/- 2.7 months for those treated medically (p = 0.0014). We conclude that a subgroup of patients who would be considered to have inoperable disease by traditional medical criteria can be selected for operation on the basis of oxygen consumption exercise testing. There is a striking survival benefit to an aggressive surgical approach in these patients.

Comparison of three techniques of esophagectomy within a residency training program.

Residency training programs commonly emphasize a single technique of esophagectomy, as the safety and the efficacy of teaching or performing more than one type of esophagectomy are unclear. Between 1986 and 1992, 248 patients were explored for possible esophageal resection. Thoracic surgical residents or fellows performed major components of all resections. Two hundred twenty-one patients (adenocarcinoma, 146; squamous cell carcinoma, 72; and other, 3) underwent transthoracic esophagectomy (n = 134), transhiatal esophagectomy (n = 42), or total thoracic esophagectomy (n = 45), a resectability rate of 89.1% (221/248). Complications occurred in 75% of patients with transthoracic esophagectomy, in 69% with transhiatal esophagectomy, and in 80% with total thoracic esophagectomy. The overall operative mortality rate was 6.8% (15/221). Patients with a cervical anastomosis had a higher leak rate (13%) than those with an intrathoracic anastomosis (6%). Median survival was 22 months (19% 5-year survival) and did not differ by operation type or stage. No patient with unresectable disease (n = 27) survived longer than 10 months. Survival for patients with adenocarcinoma stages 3 and 2a suggested a trend toward improved survival after transthoracic esophagectomy despite similar rates of local and distant recurrence. Transthoracic esophagectomy, transhiatal esophagectomy, and total thoracic esophagectomy performed within a residency training program have similar morbidity, mortality, and recurrence rates as those in other modern series. A specific technique of esophagectomy can be selected for individual patients. Survival and sites of recurrence primarily reflect disease stage, not the technique of esophagectomy used.

Primary osteosarcoma of the lung. Report of two cases and review of the literature.

Two cases of primary osteosarcoma of the lung are presented. In one case, the radiologic, clinical, and cytologic findings led to a preoperative diagnosis of undifferentiated carcinoma of the lung. In the second case, a lung nodule was discovered during postchemotherapy follow-up in a patient with lymphoma. Fine needle aspiration in the second case showed lymphoma, and further chemotherapy was instituted; however, persistent growth of the nodule prompted a resection. Microscopic examination of the resected tumors in both cases revealed histologic features of high-grade osteosarcoma. Flow cytometric analyses of the primary tumors showed abnormal hyperdiploid deoxyribonucleic acid populations in accordance with those seen in high-grade malignant neoplasms. Immunohistochemical studies supported a mesenchymal origin for these tumors. These tumors shared clinical features with other reported cases of primary osteosarcoma of the lung such as large size at diagnosis, occurrence in older individuals, and aggressive behavior.

Predicted pulmonary function and survival after pneumonectomy for primary lung carcinoma.

Between 1982 and 1987, 139 patients with primary carcinoma of the lung were treated with pneumonectomy. Thirty-nine patients (28%) were in clinical stage I, 10 (7%) were in clinical stage II, and 90 (65%) were in clinical stage III. Overall actuarial 3-year survival was 33%. Actuarial 3-year survival for patients in clinical stage I was 44%; for those in clinical stage II, 48%; and for those in clinical stage III, 28%. Risk factors for operative mortality examined included preoperative forced vital capacity (FVC) of 2.13 L or less and forced expiratory volume in 1 second (FEV1) of 1.65 L or less, percent predicted FVC of 64% or less and FEV1 of 65% or less, predicted postoperative FVC of 1.31 L or less and FEV1 of 0.89 L or less, and predicted postoperative percent predicted FVC of 41% or less and FEV1 of 34% or less. Operative deaths occurred only in clinical stage III patients (7/90 or 8%). Patients with compromised pulmonary function based on one or more of the examined risk factors were at increased risk for death (2/10) compared with patients with better pulmonary function (5/80 or 6.25%). Actuarial 3-year survival for high-risk clinical stage III patients ranged from 0% to 16% compared with 28% for other clinical stage III patients. Thirty-day mortality for pathological stage III patients was 6.3% (5/79), and 3-year actuarial survival was 24%. No patient in pathological stage III who was at high risk survived beyond 3.1 years. Select individuals with adequate pulmonary function and stage III disease can achieve substantial long-term survival after pneumonectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of adjuvant surgery in the combined modality therapy of small-cell bronchogenic carcinoma after a chemotherapy-induced partial remission.

Twenty-six patients with a limited-disease presentation of small-cell bronchogenic carcinoma (SCBC) had surgery after achieving a partial remission with three cycles of chemotherapy. Persistent SCBC was found in 15 patients (58%), non-small-cell bronchogenic carcinoma (NSCBC) in six patients (23%), and no malignancy in five patients (19%). Twelve patients have died since surgery. Tumor-node-metastasis (TNM) staging prior to or after chemotherapy was not predictive of outcome, but an N0 status found at pathological examination of the surgical specimen was predictive of long-term survival. Median survival for this group of patients was 25 months. Adjuvant surgery is feasible and may be beneficial.

Primary mucinous adenocarcinoma of the lung with signet-ring cells: a histochemical comparison with signet-ring cell carcinomas of other sites.

Five cases of primary mucinous adenocarcinomas of the lung with signet-ring cells were studied with regard to clinical, pathologic, and prognostic implications and compared with the signet-ring cell adenocarcinomas of extrapulmonary sites. The patients ranged in age from 55 to 74 years, with a mean age of 67.8 years. There were three men and two women. Histologically, three cases were usual adenocarcinomas and two were bronchioloalveolar carcinomas. The percentage of signet-ring cells ranged from 10% to 50%, with a mean of 22% and a median of 20%. Therapy included lobectomy, radiation, and chemotherapy. Three of five patients died of their disease within 9 months and two patients showed no evidence of disease 5 months after presentation. Routine histology showed no significant differences between the signet-ring cells of any of the tumors; however, by special histochemistry, tumors originating from lung, stomach, and colon showed a more intense reaction with alcian blue stain than tumors from nose, breast, or bladder. Contrary to a previous report, we found no increase in sulfated acid mucins in these five cases of lung tumor. We also were unable to demonstrate a qualitative or quantitative difference between mucopolysaccharides produced by lung, stomach, or colon tumors. Although rare, mucinous adenocarcinoma of the lung with signet-ring cells can exist as a primary tumor.

Current management of chest-wall tumors.

Chest-wall resection can be performed with low morbidity and mortality rates and remains the primary treatment for most chest-wall tumors. However, some lesions are best treated with a multimodality approach including preoperative chemotherapy. Therefore, pretreatment tissue diagnosis is essential in planning. The biopsy should be done at the medical center where the definitive treatment will be undertaken, and frequently, a needle biopsy will be sufficient. Osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma, and other small-cell sarcomas are sensitive to chemotherapy, which should be given preoperatively, continued postoperatively, and modified according to the tumor response. Chondrosarcomas and most adult soft-tissue sarcomas are well controlled by primary excision and selective use of adjuvant irradiation. Better systemic and local therapy is needed for the recurrent soft-tissue sarcomas and the aggressive unclassified sarcomas. Chest-wall resection continues to play a primary role in the management of locally and regionally recurrent breast cancer but is best combined with systemic chemotherapy. Chest-wall resection can provide a long disease-free survival in patients with isolated metastases from sarcomas or carcinomas. In addition, significant palliation can be afforded patients with symptomatic chest-wall metastases and a shortened life expectancy.

Determinants of perioperative morbidity and mortality after pneumonectomy.

A total of 197 consecutive patients undergoing pneumonectomy at the M.D. Anderson Cancer Center from 1982 to 1987 were reviewed. Sixty-five variables were analyzed for the predictive value for perioperative risk. The operative mortality rate was 7% (14/197). Patients having a right pneumonectomy (n = 95) had a higher operative mortality rate (12%) than patients having a left pneumonectomy (1%, p less than 0.05). The extent of resection correlated with the operative mortality rate (chest wall resection or extrapleural pneumonectomy, n = 39, 15%; versus simple or intrapericardial pneumonectomy, n = 158, 5%; p less than 0.05). Patients whose predicted postoperative pulmonary function, by spirometry and xenon 133 regional pulmonary function studies, was a forced expiratory volume in 1 second greater than 1.65 L, forced expiratory volume in 1 second greater than 58% of the preoperative value, forced vital capacity greater than 2.5 L, or forced vital capacity greater than 60% of the preoperative value had a lower operative mortality rate (p less than 0.05). Atrial arrhythmia was the most common postoperative complication (23%). Xenon 133 regional pulmonary function studies are useful in predicting the risks of pneumonectomy.

Current techniques for chest wall reconstruction: expanded possibilities for treatment.

Myocutaneous flaps and prosthetic materials have greatly facilitated reconstruction after massive chest wall resection. This series includes 112 such procedures. Latissimus dorsi, rectus abdominis, omental, pectoralis major, and contralateral breast flaps were used in 80 patients. Early in the series, 3 flaps were lost because of technical problems. Minor areas of incomplete healing that resolved completely with local wound care occurred in 16 of 80 flaps. Skeletal reconstruction was performed in 82 patients without complication. Marlex mesh was used for flat surfaces, and Marlex mesh with methyl methacrylate was used for the sternum and the curved surface of the lateral chest wall. These results have allowed an expansion of the indications for chest wall resection to include the curative treatment of primary chest wall tumors and palliative treatment for breast cancer patients with osteoradionecrosis, local recurrence (in select patients), chest wall infection, and tumors metastatic to the chest wall.

Resection of pulmonary metastases from squamous carcinoma of the head and neck.

The purpose of this study was to determine the survival results and identify favorable selection factors for a group of patients who were found to have metastatic disease from the upper aerodigestive tract to the lung and subsequently underwent pulmonary resection. The medical records of 44 patients treated at our institution were reviewed. The cumulative 5-year survival rate after pulmonary resection was 43 percent. The optimal interval between diagnosis of the primary tumor and the development of pulmonary metastases was 13 to 24 months (p less than 0.005). The most favorable primary site was the larynx. No significant prognostic effect was noted for single versus multiple metastases or T-stage of the primary tumor. The presence of intervening locoregional recurrence prior to pulmonary diagnosis likewise had no significant effect on the survival rate. The initial presence of nodal metastases and primary tumor in the oral cavity had a poor outcome. The worst prognostic indicator was the presence of mediastinal disease (p less than 0.001). We have concluded that aggressive surgical treatment for isolated pulmonary metastases from the upper aerodigestive tract in the absence of mediastinal involvement is therapeutically beneficial. Selection criteria for resection should include site and stage of primary disease, locoregional control, interval from primary to pulmonary diagnosis, extent of pulmonary disease and mediastinal involvement, and the general medical condition of the patient.

Long-term effects of intravenous hyperalimentation administered during intensive chemotherapy for small cell bronchogenic carcinoma.

Sixty-five patients with small cell bronchogenic carcinoma received their first two of three courses of intensive induction chemotherapy with (30 patients) or without (35 patients) intravenous hyperalimentation (IVH). Patients predominantly had extensive disease (55%), Zubrod's performance status 0 to 2 (63%) and less than or equal to 6% pretreatment weight loss (68%). Both treatment arms were comparable by prognostic factors. The chemotherapy included six remission induction courses of ECHO chemotherapy (E: epipodophyllotoxin VP-16-213; C: cyclophosphamide; H: hydroxydaunorubicin; O: oncovin [vincristine]) followed by six courses of maintenance with PRIME (PR: procarbazine; I: ifosfamide; ME: methotrexate). Prophylactic brain irradiation was given to all patients. Patients with limited disease received chest irradiation at the completion of ECHO. Fifty of 52 (96%) evaluable patients responded with a complete (56%) or partial (40%) remission. The complete remission (CR) rate was higher in the control arm (66% versus 43%; P = 0.11). Response duration and survival of patients was similar for both treatment arms. Combined median survival duration for all patients with limited and extensive disease was 15.75 and 11.50 months, respectively. Combined median survival duration for CR patients with limited and extensive disease was 25 and 13 months, respectively. Administration of IVH did not ameliorate the hematologic, gastrointestinal and infectious morbidity of ECHO chemotherapy. The IVH was effective in preserving body weight and improving delayed hypersensitivity reaction to a battery of skin test antigens. Administration of intensive ECHO chemotherapy to patients with small cell bronchogenic carcinoma resulted in high response rates, acceptable toxicities and improved survival. Administration of IVH did not improve the short- and long-term results of chemotherapy, and did not ameliorate its morbidity. Nutritional support, however, was helpful in preventing patient's weight loss.

Diagnosis for interstitial lung disease in patients with acquired immunodeficiency syndrome (AIDS): a prospective comparison of bronchial washing, alveolar lavage, transbronchial lung biopsy, and open-lung biopsy.

This study was undertaken to compare prospectively the diagnostic yield of the various bronchoscopic techniques with that of open-lung biopsy for interstitial lung disease in patients with acquired immunodeficiency syndrome (AIDS). Under general anesthesia, 15 patients sequentially underwent bronchial washing, transbronchial lung biopsy, alveolar lavage, and open-lung biopsy in the same segment of lung. Of nine patients with Pneumocystis carinii, seven were diagnosed by means of the transbronchial lung biopsy, eight by the open-lung biopsy, and all nine by alveolar lavage. Of the six patients with cytomegalovirus, five were diagnosed by the open-lung biopsy, five by the transbronchial lung biopsy, and three by alveolar lavage. The sensitivities of the procedures for identifying infection were washings (15%), transbronchial lung biopsy (50%), alveolar lavage (73%), and open-lung biopsy (88%). Combined, transbronchial lung biopsy and alveolar lavage showed a diagnostic yield (85%) for infections comparable to that of open-lung biopsy (88%), thereby obviating the need for open-lung biopsy for such diagnoses. However, open-lung biopsy was the only procedure that diagnosed Kaposi's sarcoma in lung.

A surgical approach to the treatment of pericardial effusion in cancer patients.

Pericardial effusion in patients with malignant disease often presents a difficult management problem. Effective therapy for the condition can prolong and improve the quality of life and permit further treatment of malignancies in previously compromised patients. Nonsurgical treatment of pericardial effusion, including repeated pericardiocenteses and radiation therapy, is associated with a significant failure rate and occasional complications. In our experience, surgical drainage of the pericardium is successful in controlling the effusion in over 90% of those treated. It is a safe procedure, even in patients with advanced disease. Survival duration after pericardial window formation is dependent on the underlying disease status and rarely is adversely affected by the surgical procedure.

Roentgenographic evaluation of mediastinal nodes for preoperative assessment in lung cancer.

Evaluation of mediastinal nodal metastases is a critical step in the assessment of potential surgical candidates with lung cancer. Mediastinal tomography (TOMO) and chest computerized tomography (CT) visualize the mediastinal nodes more clearly than a chest roentgenogram (CXR). A prospective study was undertaken to determine the clinical value of these three tests for mediastinal staging in 102 surgical patients with lung cancer. All patients underwent thoracotomy and mediastinal nodal dissection. The roentgenographic findings were compared with the histologic evaluation of paratracheal, tracheobronchial angle, aortic window, subcarinal, and inferior pulmonary ligament nodes. TOMO, and especially CT, correctly predicted the size and location of mediastinal nodes; however, the overall accuracies were CXR (74 percent), TOMO (74 percent), CT (61 percent). These results demonstrated that the improvement in mediastinal imaging is counteracted by the fact that enlarged nodes need not contain metastases and normal-appearing small nodes may harbor microscopic disease. Computed tomography and TOMO had little clinical impact on the assessment of mediastinal nodes in potential surgical candidates with lung cancer.

Complications of colonic interposition.

The roentgenographic and surgical experience with 44 patients treated with colon interpositions was examined. Forty-two of these patients had carcinoma of the esophagus. Staged therapy consisted of mediastinal irradiation, colonic interposition, and total esophagectomy. The more common complications related to luminal patency and conduit integrity. A total of 29.5% developed anastomotic narrowing due to postoperative edema. Anastomotic leaks arose only at the proximal anastomosis and had an incidence rate of 31.8%. Thirty-four percent had fistulous tracts originating in the reconstructed upper gastrointestinal tract. In eighty percent of the patients with leaks or fistulae, their defects healed spontaneously or with simple drainage. Strictures were encountered in 59.1%, and there were 5 instances of colonic graft ischemia. The mortality directly related to surgery was 6.8%. Ischemia, particularly at the cervical anastomosis, is probably the most common cause of complications. Radiographic evaluation is recommended using a single contrast barium examination unless gross extravasation is expected.

Critical evaluation of the gallium-67 scan for surgical patients with lung cancer.

Seventy-five patients with lung cancer underwent a gallium scan and thoracotomy with total mediastinal nodal dissection. Evaluation of mediastinal lymph nodes by means of the gallium scan showed a sensitivity of 23 percent (3/13), a specificity of 82 percent (31/38), an accuracy of 67 percent (34/51), a positive predictive valve of 30 percent (3/10), and a negative predictive value of 76 percent (31/41) in those patients whose primary tumors demonstrated uptake of radioactive gallium. The low sensitivity was due to an inability to detect microscopic disease in mediastinal lymph nodes. The specificity was decreased by gallium-67 uptake in enlarged inflamed nodes that contained no metastases. These results do not support the use of the gallium scan in the selection of patients with lung cancer for thoracotomy.

Immune function during intravenous administration of a soybean oil emulsion.

The effect of a continuous infusion of a soybean oil emulsion on immune function was evaluated in 40 malnourished patients who were randomized to receive preoperatively either a 25% glucose-5% amino acid solution (group G) or a 15% glucose-3.3% Intralipid-5% amino acid solution (group G-F). Average length of total parenteral nutrition (TPN) was 10.3 +/- 0.9 days for group G and 9.0 +/- 0.8 days for group G-F. Initial nutritional status and response to TPN were similar for both groups. Immune function was assessed before TPN and after nutritional repletion prior to surgery for each patient. The levels of immunoglobulins, C3, C4, circulating B lymphocytes and T lymphocytes, suppressor T lymphocytes, natural killer cell activity, and monocytes were normal before TPN and after nutritional therapy. However, the total number of T cells and helper T cells were low before TPN and remained so after TPN. In addition, lymphocyte function measured by the lymphocyte blastogenic response to phytohemagglutinin and pokeweed mitogen was depressed prior to TPN and was not improved by either regimen. Neutrophil chemotaxis and bactericidal activity were not affected by either nutritional regimen while neutrophil phagocytosis was enhanced before TPN and remained elevated throughout TPN with either regimen. There were no differences in infection rates during TPN. The addition of Intralipid to the TPN regimen did not alter immune function in these patients who showed depressed cell-mediated immunity before TPN compared with the standard glucose TPN regimen.