Katherine M. Pisters

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.

Preoperative chemotherapy for stage IIIa (N2) lung cancer: The Sloan-Kettering experience with 136 patients

From 1984 to 1991, 136 patients with histologically confirmed non-small cell lung cancer and stage IIIa (N2) disease received two to three cycles of MVP (mitomycin + vindesine or vinblastine + high-dose cisplatin) chemotherapy. All patients had clinical N2 disease, defined as bulky mediastinal lymph node metastases or multiple levels of lymph node involvement in the ipsilateral mediastinum or subcarinal space on chest roentgenograms, computed tomographic scans, or mediastinoscopy. The overall major response rate to chemotherapy was 77% (105/136). Thirteen patients had a complete response and 92 patients had a partial but major response (> 50%). The overall complete resection rate was 65% (89/136) with a complete resection rate of 78% (82/105) in patients with a major response to chemotherapy. There was no histologic evidence of tumor in the resected specimens of 19 patients. The overall survival was 28% at 3 years and 17% at 5 years (median, 19 months). For patients who had complete resection, the median survival was 27 months and the 3-year and 5-year survivals were 41% and 26%, respectively. There were seven treatment-related deaths, five of which were postoperative deaths. To date, 33 patients, all of whom had complete resection, have had no recurrence after treatment. These results demonstrate that (1) preoperative chemotherapy with MVP produces high response rates in stage IIIa (N2) disease, (2) high complete resection rates occur after response to chemotherapy, and (3) survival is longest in patients who have a complete resection after major response to chemotherapy.

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.

Multicenter Phase II Trial of Neoadjuvant Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Radiation for Malignant Pleural Mesothelioma

PURPOSE Neoadjuvant pemetrexed plus cisplatin was administered, followed by extrapleural pneumonectomy (EPP) and hemithoracic radiation (RT), to assess the feasibility and efficacy of trimodality therapy in stage I to III malignant pleural mesothelioma. PATIENTS AND METHODS Requirements included stage T1-3 N0-2 disease, no prior surgical resection, adequate organ function (including predicted postoperative forced expiratory volume in 1 second > or = 35%), and performance status 0 to 1. Patients received pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) for four cycles. Patients without disease progression underwent EPP followed by RT (54 Gy). The primary end point was pathologic complete response (pCR) rate. RESULTS Seventy-seven patients received chemotherapy. All four cycles were administered to 83% of patients. The radiologic response rate was 32.5% (95% CI, 22.2 to 44.1). Fifty-seven patients proceeded to EPP, which was completed in 54 patients. Three pCRs were observed (5% of EPP). Forty of 44 patients completed irradiation. Median survival in the overall population was 16.8 months (95% CI, 13.6 to 23.2 months; censorship, 33.8%). Patients completing all therapy had a median survival of 29.1 months and a 2-year survival rate of 61.2%. Radiologic response of complete or partial response was associated with a median survival of 26.0 months compared with 13.9 months for patients with stable disease or progressive disease (P = .05). CONCLUSION This multicenter trial showed that trimodality therapy with neoadjuvant pemetrexed plus cisplatin is feasible with a reasonable long-term survival rate, particularly for patients who completed all therapy. Radiologic response to chemotherapy, but not sex, histology, disease stage, or nodal status, was associated with improved survival.

Cancer Care Ontario and American Society of Clinical Oncology Adjuvant Chemotherapy and Adjuvant Radiation Therapy for Stages I-IIIA Resectable Non–Small-Cell Lung Cancer Guideline

PURPOSE To determine the role of adjuvant chemotherapy and radiation therapy in patients with completely resected stage IA-IIIA non-small-cell lung cancer (NSCLC). METHODS The Cancer Care Ontario Program in Evidence-Based Care and the American Society of Clinical Oncology convened a Joint Expert Panel in August 2006 to review the evidence and draft recommendations for these therapies. RESULTS Available data support the use of adjuvant cisplatin-based chemotherapy in completely resected NSCLC; however, the strength of the data and consequent recommendations vary by disease stage. Adjuvant radiation therapy appears detrimental to survival in stages IB and II, with a possible modest benefit in stage IIIA. CONCLUSION Adjuvant cisplatin-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA disease. Although there has been a statistically significant overall survival benefit seen in several randomized clinical trials (RCTs) enrolling a range of people with completely resected NSCLC, results of subset analyses for patient populations with stage IB disease were not significant, and adjuvant chemotherapy in stage IB disease is not currently recommended for routine use. To date, very few patients with stage IA NSCLC have been enrolled onto RCTs of adjuvant therapy; adjuvant chemotherapy is not recommended in these cases. Evidence from RCTs demonstrates a survival detriment for adjuvant radiotherapy with limited evidence for a reduction in local recurrence. Adjuvant radiation therapy appears detrimental to survival in stage IB and II, and may possibly confer a modest benefit in stage IIIA.

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)

Phase I Trial of Oral Green Tea Extract in Adult Patients With Solid Tumors

PURPOSE This trial was designed to determine the maximum-tolerated dose, toxicity, and pharmacology of oral green tea extract (GTE) once daily or three times daily. PATIENTS AND METHODS Cohorts of three or more adult cancer patients were administered oral GTE with water after meals one or three times daily for 4 weeks, to a maximum of 6 months, depending on disease response and patient tolerance. Pharmacokinetic analyses were encouraged but optional. RESULTS Dose levels of 0.5 to 5.05 g/m(2) qd and 1.0 to 2.2 g/m(2) tid were explored. A total of 49 patients were studied. PATIENT CHARACTERISTICS median age, 57 years (range, 27 to 77 years); 23 patients were women (47%); 98% had a Zubrod PS of 1%; 98% had PS of 1; and 21 had non-small-cell lung, 19 had head & neck cancer, three had mesothelioma, and six had other. Mild to moderate toxicities were seen at most dose levels and promptly reversed on discontinuation of GTE. Dose-limiting toxicities were caffeine related and included neurologic and gastrointestinal effects. The maximum-tolerated dose was 4.2 g/m(2) once daily or 1.0 g/m(2) three times daily. No major responses occurred; 10 patients with stable disease completed 6 months of GTE. Pharmacokinetic analyses found accumulation of caffeine levels that were dose dependent, whereas epigallocatechin gallate levels did not accumulate nor appear dose related. CONCLUSION A dose of 1.0 g/m(2) tid (equivalent to 7 to 8 Japanese cups [120 mL] of green tea three times daily) is recommended for future studies. The side effects of this preparation of GTE were caffeine related. Oral GTE at the doses studied can be taken safely for at least 6 months.

Phase II trial of docetaxel in patients with stage III and IV non-small-cell lung cancer.

PURPOSE This phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Docetaxel was administered to 29 patients with unresectable stage III and IV NSCLC at a dose of 100 mg/m2 intravenously (IV) over 1 hour every 21 days. No premedication was given to the first 16 patients. Premedication with diphenhydramine was instituted for the remainder. No patient had previously received chemotherapy. Seven patients had undergone prior radiation therapy. RESULTS All patients were assessable for response and toxicity. Eleven of 29 patients (38%) had a major objective response (95% confidence interval, 21% to 58%). The median duration of response was 5.3 months. Febrile neutropenia occurred in 41% of patients and in 11% of 134 courses of docetaxel. Nonhematologic toxicities included infusion-related hypersensitivity reactions, fluid retention, rash, alopecia, and sensory neuropathy. Premedication with diphenhydramine did not decrease the incidence of infusion-related hypersensitivity reactions. CONCLUSION At this dose and schedule, docetaxel demonstrates significant antitumor activity in patients with advanced NSCLC. Further investigations of this agent in NSCLC are indicated.

Gefitinib Versus Placebo in Completely Resected Non–Small-Cell Lung Cancer: Results of the NCIC CTG BR19 Study

PURPOSE Survival of patients with completely resected non-small-cell lung cancer (NSCLC) is unsatisfactory, and in 2002, the benefit of adjuvant chemotherapy was not established. This phase III study assessed the impact of postoperative adjuvant gefitinib on overall survival (OS). PATIENTS AND METHODS Patients with completely resected (stage IB, II, or IIIA) NSCLC stratified by stage, histology, sex, postoperative radiotherapy, and chemotherapy were randomly assigned (1:1) to receive gefitinib 250 mg per day or placebo for 2 years. Study end points were OS, disease-free survival (DFS), and toxicity. RESULTS As a result of early closure, 503 of 1,242 planned patients were randomly assigned (251 to gefitinib and 252 to placebo). Baseline factors were balanced between the arms. With a median of 4.7 years of follow-up (range, 0.1 to 6.3 years), there was no difference in OS (hazard ratio [HR], 1.24; 95% CI, 0.94 to 1.64; P = .14) or DFS (HR, 1.22; 95% CI, 0.93 to 1.61; P = .15) between the arms. Exploratory analyses demonstrated no DFS (HR, 1.28; 95% CI, 0.92 to 1.76; P = .14) or OS benefit (HR, 1.24; 95% CI, 0.90 to 1.71; P = .18) from gefitinib for 344 patients with epidermal growth factor receptor (EGFR) wild-type tumors. Similarly, there was no DFS (HR, 1.84; 95% CI, 0.44 to 7.73; P = .395) or OS benefit (HR, 3.16; 95% CI, 0.61 to 16.45; P = .15) from gefitinib for the 15 patients with EGFR mutation-positive tumors. Adverse events were those expected with an EGFR inhibitor. Serious adverse events occurred in ≤ 5% of patients, except infection, fatigue, and pain. One patient in each arm had fatal pneumonitis. CONCLUSION Although the trial closed prematurely and definitive statements regarding the efficacy of adjuvant gefitinib cannot be made, these results indicate that it is unlikely to be of benefit.

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