Joe B. Putnam

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.

Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer

Our previously reported randomized study of patients with untreated, potentially resectable clinical stage IIIA non-small-cell lung cancer found that patients treated with perioperative chemotherapy and surgery had a significant increase in median survival compared to patients treated with surgery alone. We have now re-analyzed the results of the study with a median time from random allocation to analysis for all patients of 82 months. The increase in survival conferred by perioperative chemotherapy was maintained during the period of extended observation.

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.

Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: Results of the American College of Surgery Oncology Group Z0030 Trial

OBJECTIVE To determine whether mediastinal lymph node dissection improves survival compared with mediastinal lymph node sampling in patients undergoing resection for N0 or nonhilar N1, T1, or T2 non-small cell lung cancer. METHODS Patients with non-small cell lung cancer underwent sampling of 2R, 4R, 7, and 10R for right-sided tumors and 5, 6, 7, and 10L for left-sided tumors. If all tumors were negative for malignancy, patients were randomized to no further lymph node sampling (mediastinal lymph node sampling) or complete mediastinal lymph node dissection. RESULTS Of 1111 patients randomized, 1023 (mediastinal lymph node sampling in 498, mediastinal lymph node dissection in 525) were eligible and evaluable. There were no significant differences between the 2 groups in terms of demographics, Eastern Cooperative Oncology Group status, histology, cancer location, type or extent of resection, and pathologic stage. Occult N2 disease was found in 21 patients in the mediastinal lymph node dissection group. At a median follow-up of 6.5 years, 435 patients (43%) have died: mediastinal lymph node sampling in 217 (44%) and mediastinal lymph node dissection in 218 (42%). The median survival is 8.1 years for mediastinal lymph node sampling and 8.5 years for mediastinal lymph node dissection (P = .25). The 5-year disease-free survival was 69% (95% confidence interval, 64-74) in the mediastinal lymph node sampling group and 68% (95% confidence interval, 64-73) years in the mediastinal lymph node dissection group (P = .92). There was no difference in local (P = .52), regional (P = .10), or distant (P = .76) recurrence between the 2 groups. CONCLUSIONS If systematic and thorough presection sampling of the mediastinal and hilar lymph nodes is negative, mediastinal lymph node dissection does not improve survival in patients with early stage non-small cell lung cancer, but these results are not generalizable to patients staged radiographically or those with higher stage tumors.

[18F]Fluorodeoxyglucose Uptake by Positron Emission Tomography Predicts Outcome of Non–Small-Cell Lung Cancer

PURPOSE To determine whether the standardized uptake value (SUV) of [(18)F]fluorodeoxyglucose uptake by positron emission tomography could be a prognostic factor for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS One hundred sixty-two patients with stage I to IIIb NSCLC were analyzed. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and local-regional control (LRC) were calculated by the Kaplan-Meier method and evaluated with the log-rank test. The prognostic significance was assessed by univariate and multivariate analyses. RESULTS There were 93 patients treated with surgery and 69 patients treated with radiotherapy. A cutoff of 5 for the SUV for the primary tumor showed the best discriminative value. The SUV for the primary tumor was a significant predictor of OS (P = .02) in both groups. Low SUVs (</= 5.0) showed significantly better DFS rates than those with high SUVs (> 5.0; surgery group, P = .02; radiotherapy group, P = .0005). Low SUVs (</= 5.0) indicated a significantly better DFS than those with high SUVs (> 5.0; stage I or II, P = .02; stage IIIa or IIIb, P = .004). However, using the same cutoff point of 5, the SUV for regional lymph nodes was not a significant indicator for DFS (P = .19), LRC (P = .97), or DMFS (P = .17). The multivariate analysis showed that the SUV for the primary tumor was a significant prognostic factor for OS (P = .03) and DFS (P = .001). CONCLUSION The SUV of the primary tumor was the strongest prognostic factor among the patients treated by curative surgery or radiotherapy.

Primary cardiac sarcomas

In marked contrast to benign cardiac tumors, primary cardiac sarcomas occur infrequently. Moreover, there is no uniform approach to treating such patients, and the benefits of postoperative chemotherapy are unclear. Between 1964 and 1989, 21 patients with primary cardiac sarcomas underwent surgical resection alone (n = 7), chemotherapy alone (n = 1), or combined operation and postoperative chemotherapy based on adriamycin (n = 13). Twenty-four operations were performed on 20 patients with relief of symptoms in all. Eleven patients had complete resection. Operative mortality was 8.3% (2/24). Histology and originating chamber(s) included angiosarcoma (n = 7; 6/7 in right atrium, 1 in left atrium), malignant fibrous histocytoma (7; all in left atrium), fibrosarcoma (2; 2/2 in left atrium), rhabdomyosarcoma (2; 1 in left atrium, 1 in right ventricle), leiomyosarcoma (2; 1 in left atrium, 1 in left ventricle); and one undifferentiated sarcoma (right atrium). Overall actuarial survival was 14% at 24 months after resection. Patients with complete resection had a median survival of 24 months compared with only 10 months in all other patients (p = 0.035). Postoperative chemotherapy did not enhance survival in patients with incomplete resection. At this time, aggressive and complete surgical resection seems to offer the best hope for palliation and survival in an otherwise fatal disease.

Induction chemotherapy before surgery for early-stage lung cancer: A novel approach

OBJECTIVE This phase II trial assessed the feasibility, as measured by response rate, toxicity, resectability rate, and surgical morbidity and mortality rates, of perioperative paclitaxel and carboplatin chemotherapy in patients with early-stage non-small cell lung carcinoma. METHODS All patients required negative mediastinoscopy results and adequate medical parameters to undergo induction chemotherapy and an operation. Superior sulcus patients were excluded. Chemotherapy consisted of paclitaxel 225 mg/m(2) over 3 hours and carboplatin (area under the curve = 6) every 21 days for 2 cycles preoperatively. Three postoperative cycles of chemotherapy were planned for patients undergoing complete resection. RESULTS Between June 1996 and July 1998, 94 patients were entered into the study. Sixty-five (69%) were men, and the median age was 64 years (range, 34-79 years). After induction chemotherapy, 53 of 94 (56%; 95% confidence interval, 46%-67%) had a major objective response, 88 (94%) underwent surgical exploration, and 81 (86%; 95% confidence interval, 78%-92%) underwent complete resection. Reasons for not undergoing an operation included disease progression (n = 3), clinically unresectable status (n = 1), death (n = 1), and patient lost to follow-up (n = 1). Two postoperative deaths occurred. Six (6%; 95% confidence interval, 0%-13%) pathologic complete responses were observed. Ninety (96%) patients received the planned preoperative chemotherapy versus 45% receiving postoperative chemotherapy. No unexpected chemotherapy or surgical morbidity occurred. The 1-year survival is currently estimated at 85%, and the median survival has not yet been reached. CONCLUSIONS Induction chemotherapy with paclitaxel and carboplatin is feasible and produces a high response rate with acceptable morbidity and mortality rates in early-stage non-small cell lung carcinoma. A prospective randomized trial comparing 3 cycles of induction chemotherapy and surgery with surgery alone in early-stage non-small cell lung carcinoma is planned.Objective: This phase II trial assessed the feasibility, as measured by response rate, toxicity, resectability rate, and surgical morbidity and mortality rates, of perioperative paclitaxel and carboplatin chemotherapy in patients with early-stage non–small cell lung carcinoma. Methods: All patients required negative mediastinoscopy results and adequate medical parameters to undergo induction chemotherapy and an operation. Superior sulcus patients were excluded. Chemotherapy consisted of paclitaxel 225 mg/m2 over 3 hours and carboplatin (area under the curve = 6) every 21 days for 2 cycles preoperatively. Three postoperative cycles of chemotherapy were planned for patients undergoing complete resection. Results: Between June 1996 and July 1998, 94 patients were entered into the study. Sixty-five (69%) were men, and the median age was 64 years (range, 34-79 years). After induction chemotherapy, 53 of 94 (56%; 95% confidence interval, 46%-67%) had a major objective response, 88 (94%) underwent surgical exploration, and 81 (86%; 95% confidence interval, 78%-92%) underwent complete resection. Reasons for not undergoing an operation included disease progression (n = 3), clinically unresectable status (n = 1), death (n = 1), and patient lost to follow-up (n = 1). Two postoperative deaths occurred. Six (6%; 95% confidence interval, 0%-13%) pathologic complete responses were observed. Ninety (96%) patients received the planned preoperative chemotherapy versus 45% receiving postoperative chemotherapy. No unexpected chemotherapy or surgical morbidity occurred. The 1-year survival is currently estimated at 85%, and the median survival has not yet been reached. Conclusions: Induction chemotherapy with paclitaxel and carboplatin is feasible and produces a high response rate with acceptable morbidity and mortality rates in early-stage non–small cell lung carcinoma. A prospective randomized trial comparing 3 cycles of induction chemotherapy and surgery with surgery alone in early-stage non–small cell lung carcinoma is planned. (J Thorac Cardiovasc Surg 2000;119:429-39)

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.

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 < 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.