Jonathan C. Nesbitt

Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer

A retroviral vector containing the wild–type p53 gene under control of a β–actin promoter was produced to mediate transfer of wild–type p53 into human non–small cell lung cancers by direct injection. Nine patients whose conventional treatments failed were entered into the study. No clinically significant vector–related toxic effects were noted up to five months after treatment. In situ hybridization and DNA polymerase chain reaction showed vector–p53 sequences in posttreatment biopsies. Apoptosis (programmed cell death) was more frequent in posttreatment biopsies than in pretreatment biopsies. Tumor regression was noted in three patients, and tumor growth stabilized in three other patients.

Adenovirus-Mediated p53 Gene Transfer in Sequence With Cisplatin to Tumors of Patients With Non–Small-Cell Lung Cancer

PURPOSE To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay). RESULTS Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients. CONCLUSION Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Survival in early-stage non-small cell lung cancer

The duration of survival in early-stage lung cancer (stages I and II) varies between reports in the literature. Several reasons account for this: patient population heterogeneity, inconsistent staging, anatomic variability, dissimilar tumor morphology, and unpredictable tumor biology. This report addresses some of the issues in early-stage non-small cell lung cancer that relate to variability between estimates of survival in end stage reporting. We review several large series since the introduction of the International Staging System in 1986 and other selected, contemporary reports that address end results in patients with pathologic stage I or stage II lung cancer. Overall survival for patients with pathologic stage I disease is 64.6% (range, 55% to 72%) and 41.2% for patients with stage II disease (range, 29% to 51%). Reducing morphologic differences by placing patients in groups based on the TNM subset and refinement in categorization by matching TNM subsets based on histology and other factors can improve considerably homogeneity and enhance prognostic predictability. The development of more accurate measures for predicting prognosis may serve to clarify the roles of primary and adjuvant treatment, particularly in those patients with early-stage disease associated with poor prognostic factors in whom the potential for long-term survival is reduced.

Surgical Management of Renal Cell Carcinoma With Inferior Vena Cava Tumor Thrombus

BACKGROUND The optimal management of patients with renal cell carcinoma with inferior vena cava tumor thrombus remains unresolved. Traditional approaches have included resection with or without the use of cardiopulmonary bypass. Chemotherapy has played a minor role except for biotherapeutic agents used for metastatic disease. METHODS From January 1989 to January 1996, 37 patients with renal cell carcinoma and inferior vena cava tumor thrombus underwent surgical resection. The 27 men and 10 women had a median age of 57 years (range, 29 to 78 years). Thirty-six patients presented with symptoms; 21 had hematuria. Distant metastases were present in 12 patients. Tumor thrombi extended to the infrahepatic inferior vena cava (n = 16), the intrahepatic inferior vena cava (n = 16), the suprahepatic inferior vena cava (n = 3), and into the right atrium (n = 2). All tumors were resected by inferior vena cava isolation and, when necessary, extended hepatic mobilization and Pringle maneuver, with primary or patch closure of the vena cavotomy. Cardiopulmonary bypass was necessary in only 2 patients with intraatrial thrombus. RESULTS Complications occurred in 11 patients, and 1 patient died 2 days postoperatively of a myocardial infarction (mortality, 2.7%). Twenty patients are alive; overall 2- and 5-year survival rates were 61.7% and 33.6%, respectively. For patients without lymph node or distant metastases (stage IIIa), 2- and 5-year survival rates were 74% and 45%, respectively. The presence of distant metastatic disease (stage IV) at the time of operation did not have a significant adverse effect on survival, as reflected by 2- and 5-year survival rates of 62.5% and 31.3%, respectively. Lymph node metastases (stage IIIc) adversely affected survival as there were no long-term survivors. CONCLUSIONS Resection of an intracaval tumor thrombus arising from renal cell carcinoma can be performed safely and can result in prolonged survival even in the presence of metastatic disease. In our experience, extracorporeal circulatory support was required only when the tumor thrombus extended into the heart.

Is follow-up of lung cancer patients after resection medically indicated and cost-effective?

BACKGROUND There are no guidelines for the appropriate follow-up of patients after pulmonary resection for lung cancer. METHODS Three-hundred fifty-eight consecutive patients who had undergone complete resections of non-small cell lung cancer between 1987 and 1991 were evaluated for tumor recurrence and development of second primary tumors. Recurrences were categorized by site (local or distant), mode of presentation (symptomatic or asymptomatic), treatment given (curative intent or palliative), and duration of overall survival. RESULTS Recurrences developed in 135 patients (local only, 32; local and distant, 13; and distant only, 90). Of these, 102 were symptomatic and 33 were asymptomatic (most diagnosed by screening chest roentgenogram). Forty patients received treatment with curative intent (operation or radiation therapy > 50 Gy) and 95 were treated palliatively. The median survival duration from time of recurrence was 8.0 months for symptomatic patients and 16.6 months for asymptomatic patients (p = 0.008). Multivariate analysis shows that disease-free interval (greater than 12 months or less than or equal to 12 months) was the most important variable in predicting survival after recurrence and that mode of presentation, site of recurrence, initial stage, and histologic type did not significantly affect survival. New primary tumors developed in 35 patients. CONCLUSIONS Although detection of asymptomatic recurrences gives a lead time bias of 8 to 10 months, mode of treatment and overall survival duration are not greatly affected by this earlier detection. Disease-free interval appears to be the most important determinant of survival. Screening for asymptomatic recurrences in patients who have had lung cancer is unlikely to be cost-effective. Frequent follow-up and extensive radiologic evaluation of patients after operation for lung cancer are probably unnecessary.

A Multidisciplinary Approach to Therapy for Unresectable Malignant Thymoma

Malignant thymoma is a rare mediastinal tumor [1]. The important prognostic factors in this condition are disease stage and completeness of surgical resection [2-4]. In the early stages, the tumor can be completely resected. However, complete resection of advanced-stage tumors has been difficult [4], and surgery in such cases has not substantially changed the biology of the tumor because gross residual disease or microinvasion of surrounding structures, including the pleura and the pericardium, has led to a high incidence of eventual recurrence. Ki-67 has been used as an important indicator of the biological behavior of tumor cells [5, 6]. In cases of invasive thymoma, expression of Ki-67 has correlated with proliferating activity of tumor cells and clinical stage. There is also a general correlation between the labeling index of Ki-67 and both invasiveness and histologic subtype [6]. We investigated whether such correlations were valid in tissue samples obtained from our patients. Radiation therapy has been important in the management of patients with advanced thymoma. Postoperative irradiation of tumors graded stage II or beyond has been shown to reduce the risk for recurrence in patients with invasive thymoma who have had complete resection [7, 8]. However, in cases of incomplete resection, postoperative irradiation has not substantially changed overall survival rates; disease tends to recur both locally and distantly [9, 10]. Chemotherapy has shown significant antitumor activity against unresectable, recurrent, or metastatic thymomas [11, 12]. Our experience and that of others has indicated that overall major response rates with combination chemotherapy based on cisplatin and doxorubicin were between 50% and 90% in chemotherapy-naive patients [11-14]. To improve tumor resectability and to determine the disease-free and overall survival times of patients with locally advanced unresectable thymoma, we designed a prospective study of a multimodal treatment regimen. Methods Patients Patients with Masaoka stage III or IVA tumors [2] were eligible for this study. The resectability of disease was determined by the thoracic surgeons before patients entered the protocol. Patients had a performance status of less than 2 on the Zubrod scale, bidimensional measurable disease, adequate bone marrow (absolute granulocyte counts > 1500 cells/mm3 and platelet counts > 100 000 cells/mm3), adequate hepatic function (serum total bilirubin level < 1.5 mg/dL [25.65 mol/L]), and adequate renal function (serum creatinine level < 1.5 mg/dL [132.6 mol/L]). Left ventricular ejection fraction in all participants was examined by using two-dimensional echocardiography before treatment. Signed informed consent was obtained, and the protocol was approved by the institutional review board at the M.D. Anderson Cancer Center. Protocol We designed this prospective study for patients with pathologically confirmed malignant thymoma. The study schema consisted of three courses of induction chemotherapy, surgical resection, radiation therapy, and three courses of consolidation chemotherapy (Figure 1). Figure 1. Treatment schema and outcome for patients with locally advanced unresectable thymoma (stage III or IVA). Induction chemotherapy consisted of cyclophosphamide, 500 mg/m2, on day 1; continuous infusion of doxorubicin, 20 mg/m2 per day, on days 1 to 3 (total, 60 mg/m2); cisplatin, 30 mg/m2 per day, on days 1 to 3 (total, 90 mg/m2); and prednisone (100 mg/d for 5 days). This cycle was repeated three times at 3- to 4-week intervals. Prophylactic granulocyte colony-stimulating factor was not used. After induction chemotherapy, we assessed clinical response by measuring tumor size on computed tomography [13]. Within 3 to 4 weeks after the last chemotherapy cycle, we used computed tomography to assess tumor resectability. Resection was done during this exploration, and the pathologic specimen was assessed for the degree of tumor necrosis. Within 3 to 6 weeks of surgery, patients who had had complete resection and whose tumors were at least 80% necrotic began radiation therapy with a total dose of 50 Gy. Patients were irradiated with a total dose of 60 Gy if resection was incomplete or if less than 80% of the tumor was necrotic. Consolidation chemotherapy with 80% doses of cyclophosphamide, doxorubicin, and cisplatin and a 100% dose of prednisone was repeated every 3 to 4 weeks for three courses. Ki-67 Expression After induction chemotherapy, 11 patients had surgical resection (1 patient did not have surgery) and 16 tissue samples were obtained. All samples underwent immunohistochemical analysis so that we could determine whether Ki-67 expression correlated with tumor necrosis after chemotherapy. Anti-Ki-67 antibody (clone MIB1) was obtained from Zymed Laboratory, Inc. (San Francisco, California), and immunohistochemistry was done by using the standard procedure [6]. Statistical Analysis Overall survival was measured from the date of registration for induction chemotherapy to the date of last follow-up or death. Disease-free survival was measured from the date of last treatment to the date of last follow-up or recurrence. We estimated survival curves by using the method of Kaplan and Meier [15]. We calculated the Pearson correlation coefficient between Ki-67 expression and percentage of tumor necrosis, using the average if a participant had multiple observations. All calculations were done by using SAS software (SAS Institute, Inc., Cary, North Carolina). Results From February 1990 to December 1996, a total of 13 patients were consecutively enrolled in the study. One of these patients was later deemed ineligible because a final pathologic diagnosis of thymic carcinoma was made. Patient characteristics are shown in Table 1. Table 1. Patient Characteristics Induction chemotherapy produced three complete responses, eight partial responses, and one minor response, for an overall major response rate of 92%. Eleven patients had surgical exploration; 1 patient refused surgical resection. Tumors were completely resected in all 3 patients whose disease responded completely and in 6 of the 8 patients whose disease responded partially; thus, 9 of 11 patients (82%) were responders. Resection was incomplete in 2 patients (18%), including 1 of the patients with partial response and the 1 patient with a minor response. All pathologic specimens obtained during surgery were evaluated for extent of tumor necrosis. Two of the three complete responders had 100% tumor necrosis, and one complete responder and one partial responder had tumor necrosis greater than 80%. Seven other patients had tumor necrosis less than 80%. All 12 patients received radiation therapy. The 4 patients (36%) whose tumors had more than 80% necrosis on complete resection received 50 Gy; the 7 patients who had less than 80% necrosis or had incomplete resection received 60 Gy. The patient who refused surgery received only 54 Gy of the planned 60 Gy because of insufficient compliance. All 11 patients who underwent surgery had consolidation chemotherapy (Figure 1). Overall, after completion of the planned therapy, 10 patients remain disease free at a median follow-up period of 43 months (disease-free survival rate at 7 years, 73%). Two patients who had incomplete tumor resection had locoregional recurrent disease but are still alive (overall survival rate at 7 years, 100%). The major side effect during induction and consolidation chemotherapy was myelosuppression. One patient required a prophylactic platelet transfusion but had no bleeding. Other hematologic side effects were modest. The most common nonhematologic side effects were fatigue, nausea and vomiting, and decreased appetite. Two patients developed neutropenic fever during induction chemotherapy but recovered fully with intravenous antibiotics. One patient developed radiation-induced mild pneumonitis and esophagitis. No patients developed cardiac toxicity. No surgical morbidity or mortality occurred. We correlated the degree of tumor necrosis with Ki-67 expression in the samples after induction chemotherapy. The samples with tumor necrosis greater than 80% expressed a minimal degree of Ki-67 (mean labeling index, 0.02 [range, 0.01 to 0.03]). The overall correlation between tumor necrosis and Ki-67 expression was high (Pearson r = 0.88). Discussion Complete surgical resection is an important prognostic factor for locally advanced malignant thymoma [16]. It is critical to convert locally advanced unresectable tumors (stage III and IVA) to resectable tumors. Complete resection of these advanced tumors is often unfeasible because the tumors invade adjacent mediastinal structures, including major blood vessels and the pericardium. Preoperative (neoadjuvant or induction) chemotherapy may enhance tumor resectability. With this goal in mind, we administered induction chemotherapy to all patients and achieved a major response rate of 92%. Our results and those of others [17-19] suggest that malignant thymoma is highly responsive to chemotherapy. More important, disease in all of our patients became resectable with this preoperative chemotherapy. Another striking finding was the degree of tumor necrosis in tissue specimens. Almost half of the patients whose tumors were completely resected had tumor necrosis greater than 80% in resected specimens. All patients received postoperative radiation therapy. Komaki and Cox [7] summarized data from the literature showing that recurrence (local or distant) was found in 25% of patients who received postoperative radiation therapy and 57% of patients who did not receive this therapy. These data clearly show that postoperative radiation therapy for tumors graded stage II or higher further reduces risk for recurrence in patients who have had even complete resection. The total dose of radiation therapy in the postoperative setting has not been well established in thymoma; we used doses similar to those that palli

A multidisciplinary surgical approach to superior sulcus tumors with vertebral invasion

BACKGROUND Vertebral body invasion by superior sulcus tumor has traditionally been considered a contraindication to surgical resection. Attempts at definitive radiation or chemoradiation have not been successful. Recent advances in spinal instrumentation have allowed more complete resection of vertebral body tumors. We, therefore, reviewed our recent experience with vertebral resection of superior sulcus tumors. METHODS All patients (n = 17) undergoing resection of superior sulcus tumors with T4 involvement of the vertebrae from October 18, 1990 to September 21, 1998 at the University of Texas M.D. Anderson Cancer Center (MDACC) were evaluated. Their clinical and pathologic data were reviewed and analyzed for short- and long-term outcomes. RESULTS Total vertebrectomy was performed in 7 patients (42%), partial vertebrectomy in 7 (42%), and 3 (18%) underwent neural foramina or transverse process resection. The median hospital stay was 11 days. Postoperative complications occurred in 7 patients (42%) and included pneumonia (6, 36%), arrhythmia (2, 12%), cerebrospinal fluid leak (2, 12%), wound breakdown (1, 6%), and reoperation for bleeding (1, 6%). Sixteen out of 17 patients received preoperative or postoperative radiation therapy. No perioperative mortality occurred. All patients remained ambulatory after spinal reconstruction. Overall actuarial survival at 2 years was 54%, with 11 patients still alive 2 to 50 months after resection. Locoregional tumor recurrence was noted in all 6 patients who had positive surgical margins, as opposed to 1 out of 11 patients (9%) with negative margins (p < 0.006). Additionally, the 2-year actuarial survival of patients with negative microscopic margins was 80% versus 0% for positive margins (p < 0.0006). CONCLUSIONS An aggressive multidisciplinary approach to superior sulcus tumors with vertebral invasion can lead to long-term survival with acceptable morbidity if negative margins can be obtained. Vertebral body invasion should no longer be considered a contraindication for resection of superior sulcus tumors.

Incidence of major pulmonary morbidity after pneumonectomy: association with timing of smoking cessation

BACKGROUND The prevention of major pulmonary events (MPEs) after pneumonectomy may minimize postoperative mortality rates. The purpose of this study was to identify preoperative and perioperative factors associated with the development of MPEs after pneumonectomy to help predict which patients are at increased risk for MPEs. METHODS We retrospectively reviewed the medical records of all patients (n = 261) who underwent pneumonectomies between January 1990 and May 1999. We analyzed preoperative and perioperative risk factors, the primary end point of an MPE and the secondary end points of mortality (in-hospital or 30 days postprocedure), length of stay, and hospital charges. A postoperative MPE included only pneumonia or acute respiratory distress syndrome as defined by the Centers for Disease Control and the American and European Consensus Conferences established criteria. Simple atelectasis that did not progress to pneumonia or a documented aspiration was not included. RESULTS Four patients died within 12 hours of operation; the records of the remaining 257 patients were analyzed. An MPE occurred in 33 (12.8%) of 257 patients; 16 (6.2%) of 257 patients died. A multivariate analysis performed on relevant variables showed that only the timing of smoking cessation (1 month or sooner before operation) was a significant predictor of an MPE. Age, side of pneumonectomy, and the use of preoperative chemotherapy or combined chemotherapy and radiation therapy were not significant predictors of an MPE. An MPE significantly increased the mortality rate 2.1% versus 39.3%, p < 0.001). CONCLUSIONS Mortality after pneumonectomy increased significantly with the development of an MPE. Patients who continue to smoke within 1 month of operation are at an increased risk for developing an MPE. Interventions to minimize MPEs may minimize the mortality rate after pneumonectomy.

Anterior Approaches to the Thoracic Spine in Patients With Cancer: Indications and Results

BACKGROUND Multidisciplinary surgical teams enable an aggressive approach to tumors involving the thoracic spine. METHODS From February 1994 to July 1996, 61 patients underwent anterior resections of thoracic spine tumors. Their median age was 56 years. The indications for operation were curative in intent in 7 of 61 and palliative in 54 of 61 (to relieve intractable metastatic bone pain with neurologic compromise [n = 38] and pain alone [n = 16]). Sixteen patients came to our institution unable to ambulate with impending paraplegia. RESULTS Anterior approaches included combined left side of the neck and median sternotomy for lesions involving vertebrae T-1 through T-3 (n = 9), posterolateral thoracotomy for T-3 through T-10 (n = 39), and thoracoabdominal approach at T-11 and T-12 (n = 13). Median hospital stay was 9.0 days (range, 4 to 57 days). Complications occurred in 18 of 61 (29.5%). In 55 of 61 (90%), pain was significantly improved after the operation. Twelve of the 16 patients who initially presented in wheelchairs regained ambulatory function. There were five perioperative deaths (8.2%). The 1-year cumulative survival for the entire group was 60%. CONCLUSIONS An aggressive surgical approach in cancer patients with locally advanced or metastatic disease in the thoracic spine was associated with acceptable morbidity and mortality. There was significant improvement in their quality of life by control of intractable pain in 90% and recovery of ambulatory function in 75% of patients who presented with critical spinal cord compromise.

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.