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.

Intensive preoperative chemotherapy with colony-stimulating factor for resectable adenocarcinoma of the esophagus or gastroesophageal junction.

PURPOSE: The curative resection rate in patients with potentially resectable carcinoma of the esophagus is approximately 55% and their median survival time is 11 months. Preoperative chemotherapy with high doses of chemotherapeutic agents was used to evaluate clinical and pathologic responses, curative resection rate, toxicity, and survival. Colony-stimulating factor (CSF) was added to reduce the severity of myelosuppression. PATIENTS AND METHODS: Twenty-six consecutive assessable patients with potentially resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative courses of intensive chemotherapy (etoposide, doxorubicin, and cisplatin [EAP]) with granulocyte-macrophage CSF (GM-CSF). Additional three conventional-dose postoperative chemotherapy courses without GM-CSF were given to patients who responded to preoperative chemotherapy. RESULTS: A median of three courses (range, one to six), were administered. Of 27 patients, 26 were assessable for response to preoperative EAP; 13 (50%) achieved a major response. Among 23 patients who underwent surgery, 15 (65%) had a curative resection (58% of 26 assessable patients); none of the patients had a pathologic complete response, but two patients had only microscopic carcinoma in the resected specimen. Six patients had carcinoma present at the resection margins and received postoperative radiotherapy. Two patients were found to have liver metastases at exploration. At a median follow-up of 22 months, the median survival of 26 patients was 12.5 months (range, 2 to 32 +). Fourteen patients died of their carcinoma; two patients died of treatment-related causes; one died of an unrelated CNS arterial malformation; and the causes of death in two patients remain unknown. Seven patients are alive with no evidence of relapse. Major toxicities of this regimen included severe myelosuppression, nausea and vomiting, infections, and severe constitutional symptoms related to GM-CSF. However, subcutaneous injection of GM-CSF was well tolerated. CONCLUSION: High-dose EAP is active against locoregional adenocarcinoma of the esophagus and gastroesophageal junction but can be associated with significant toxicity. Although this strategy remains attractive and needs to be developed further, less toxic and more effective regimens need to be identified.

Prognostic significance of computed tomography in resected N2 lung cancer.

We reviewed 124 patients from 1982 to 1988 who had a resected primary non-small cell lung cancer metastatic to mediastinal (N2) lymph nodes and a preoperative assessment of the mediastinum with computed tomography of the chest. Sixty-three patients studied had computed tomographic evidence of mediastinal lymph node enlargement. In these patients the survival at 5 years was only 6.6%, compared with the 5-year survival of 13.5% in 61 patients in whom the mediastinum was normal. Plain chest roentgenography with evidence of mediastinal adenopathy did not predict a poorer outcome. In addition, patients with tumors located in the left upper lobe were found to have an improved survival. These patients had a 5-year survival of 20.8%. Tumor histology, central location of the tumor, extranodal extension, and type of resection did not result in a significant survival difference.

Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma.

Determinants of 5-year survival were evaluated after complete resection of pulmonary metastases from adult soft-tissue sarcomas. Fifty-eight patients had complete resection (median survival 25 months, P = 0.0002), with a 25.8% absolute 5-year survival (15 of 58 patients); six patients had unresectable disease (median survival 6 months) and were excluded from additional analysis. Eleven patients remain disease free, with a median follow-up of 76 months. Significant independent prognostic indicators associated with improved survival (P less than 0.05) included metastasis doubling time of 40 days or greater (median survival 37 months versus 15 months if less than 40 days); unilateral disease on preoperative radiography (33 months versus 15 months if bilateral disease); three or fewer nodules on preoperative computed tomography (40 months versus 14 months if 4 or more nodules); two nodules or fewer resected (40 months versus 17 months if 3 or more nodules resected), and tumor histology (33 months for malignant fibrous histiocytoma versus 17 months for all others). Multivariate analysis identified the number of nodules detected by computed tomography preoperatively as having significant prognostic value.

Prolonged chemotherapy for localised squamous carcinoma of the oesophagus.

We evaluated the feasibility of six courses of chemotherapy in 34 consecutive patients with localised squamous cell carcinoma of the oesophagus. All 32 evaluable patients first received at least two courses of chemotherapy. There were 18 patients with resectable carcinomas who underwent surgery and 14 patients with unresectable carcinomas who received definitive chemoradiotherapy. After two courses of 5-fluorouracil and cisplatin 21 (66%) of 32 patients had either a complete or major response. A median of five courses (range, 1-6 courses) was administered. 17 out of 18 (94%) patients with resectable carcinoma had a 'curative' resection (negative proximal, distal, and radial margins by histopathology in an en-block resection specimen) and 2 patients had a complete pathological response. The median survival duration of all patients was 28 months (range, 2-46+ months). The median survival duration of 14 patients with unresectable carcinoma was 23 months (range, 8-36+ months), and the median survival duration of 18 patients with resectable carcinoma has not been reached at a median follow-up of 24+ months (range, 10+ to 46+ months). No deaths occurred because of chemotherapy or chemoradiation therapy. Our data suggest that prolonged chemotherapy is feasible in patients with locoregional squamous carcinoma of the oesophagus. An ongoing controlled trial will determine the contribution of chemotherapy to patients' survival.

Efficacy of pulmonary metastasectomy for recurrent soft tissue sarcoma.

To evaluate surgical results of resection of second (recurrent) pulmonary metastases from adult soft tissue sarcoma, the survival of 39 patients was analyzed retrospectively. With the exclusion of two patients (one with interval metastases between staged resections and one without histologically proved metastases), three patients were found to have unresectable disease (median survival, 7 months). A significantly (P = 0.0001) longer median survival (28 months) was found for 34 patients whose recurrent metastases were completely resected. The only other factor predicting significantly longer post-thoracotomy survival was resection of a solitary metastatic nodule (median survival, 65 months). Patients who had two or more recurrent nodules resected had a median survival of 14 months only (P = 0.01). Although trends toward longer survival were noted for other prognostic factors, none reached statistical significance. We conclude that the complete resection of a solitary second (recurrent) pulmonary metastatic nodule from adult soft tissue sarcoma predicts long-term survival.

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.

Evaluation of pre- and postoperative chemotherapy for resectable adenocarcinoma of the esophagus or gastroesophageal junction.

Thirty-five consecutive patients with resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative and three or four postoperative chemotherapy courses consisting of etoposide, fluorouracil, and cisplatin (EFP) to evaluate the rate of curative resection, clinical and pathologic response, toxic effects, and survival. One hundred thirty-seven courses with a median number of five courses (range, one to six) were administered. Preoperative EFP resulted in 17 (49%) major responses, including six patients who did not have carcinoma cells in the repeat endoscopic biopsy specimens and cytologic brushings. Among 32 patients who had surgery, 25 (78%) had curative resection, one patient had a complete pathologic response, and one had microscopic carcinoma in the resected specimen. Six patients had microscopic carcinoma at the resection margins and received postoperative radiotherapy. At a median follow-up of 20 months, the projected survival of 35 patients is 23 months (range, 6 to 33+). Fifteen patients died of their carcinomas, and 15 patients were alive (median follow-up, 20+ months; range, 15+ to 33+ months) with no evidence of relapse. There were no deaths related to chemotherapy, surgery, or radiotherapy. EFP-induced toxic reactions were moderate. Our data suggest that multiple courses of EFP are feasible. Future strategies for this disease should consider prolonged chemotherapy with regimens that result frequently in pathologic complete responses.

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.

Comparison between clinical response and in vitro drug sensitivity of primary human tumors in the adhesive tumor cell culture system.

The newly described adhesive tumor cell culture system (ATCCS) offers a distinct advantage over other assays in that it has a high plating efficiency requiring low cell inoculum, it affords workable assays in approximately 70% of specimens from the heterogenous tumor types, and it has the ability to assay up to nine drugs at four different concentrations. Clinical correlations based on the ATCCS were obtained in 65 patients undergoing 71 clinical trials. Patients with melanoma, lung cancer, and sarcoma dominated the group. The most active in vitro drug was correlated per clinical trial. Thirteen of 17 (76%) sensitive in vitro predictions and 51 of 54 (94%) resistant in vitro predictions were accurate. The assay in this study had a sensitivity of 81% and specificity of 93%. These preliminary results are encouraging and warrant prospective trials to establish the true value of this assay to patients.