Chemotherapy of thymomas and thymic carcinomas.

Thymomas are chemosensitive tumors with overall response rates of about 70% to various chemotherapy regimens. A fraction of patients (up to 25%-30%) will obtain a CR after chemotherapy. These results justify the use of chemotherapy in a multimodality fashion for the treatment of patients with advanced tumors. With radiotherapy added to chemotherapy, if necessary and if technically feasible, inoperable tumors may become resectable, leading to excellent long-term survival. On the other hand, thymic carcinomas are more refractory to chemotherapy, and their prognoses remain poor.

Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase II clinical trial and pharmacokinetic profile.

BACKGROUND: The purpose of this study was to assess the efficacy and toxicity of a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients with malignant pleural mesothelioma and to characterize the pharmacokinetic profiles of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). METHODS: Fifteen previously untreated patients with malignant pleural mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2 on Days 1, 8, and 15) administered intravenously and followed by a 1-week rest period. The course of treatment was repeated every 28 days. After intravenous administration, the levels of CPT-11 and SN-38 in the plasma and pleural fluid were determined for each histologic subtype of mesothelioma. RESULTS: All patients were evaluable for response and toxicity. Four partial responses (response rate of 26.7%) with a median response duration of 25.9 weeks and 2 regressions of evaluable disease (overall response rate of 40%) were observed. The median survival time after chemotherapy was 28.3 weeks, and the median time to treatment failure was 22.1 weeks. The 1-year survival rate for all patients was 38.5%. Toxicity was well tolerated, and there were no treatment-related deaths. World Health Organization Grade 3 leukopenia occurred in 3 patients (20%), and Grade 1 or 2 diarrhea occurred in 3 patients (20%). There was no excess toxicity in patients with large pleural effusions compared with those with no pleural effusions. CPT-11 and SN-38 were detected in the pleural fluid 1 hour after intravenous administration. The maximum concentrations of CPT-11 and SN-38 in the pleural fluid were 36.5% and 75.8%, respectively, of the corresponding plasma values. CONCLUSIONS: The combination of cisplatin and CPT-11 had definite activity against malignant pleural mesothelioma and was well tolerated. The intravenous administration of CPT-11 produced adequate distribution of CPT-11 and its active metabolite SN-38 into the pleural fluid and allowed a higher concentration of the more active SN-38 to make contact with mesothelioma cells in the thoracic cavity. These results warrant further clinical evaluation of this combination chemotherapy for the treatment of malignant pleural mesothelioma in a confirmatory Phase II trial.

Interleukin 6 and its relationship to clinical parameters in patients with malignant pleural mesothelioma.

The relationship between interleukin 6 (IL-6) levels and clinical parameters was studied in 25 patients with malignant pleural mesothelioma. The serum levels of IL-6, C-reactive protein, alpha1-acid glycoprotein and fibrinogen were significantly higher in mesothelioma than in lung adenocarcinoma with cytology-positive pleural effusion. Serum IL-6 levels correlated with the levels of the acute-phase proteins. We demonstrated a high incidence of thrombocytosis (48%) and a significant correlation between platelet count and the serum IL-6 level. The level of IL-6 in the pleural fluid of patients with mesothelioma was significantly higher than in the pleural fluid of patients with adenocarcinoma, and was about 60-1400 times higher than in the serum. However, even higher levels of IL-6 in the pleural fluid and of thrombocytosis were found in patients with tuberculous pleurisy. These results indicate that large amounts of IL-6 from the pleural fluid of patients with mesothelioma leak into the systemic circulation and induce clinical inflammatory reactions. These profiles are not specific to mesothelioma as similar profiles are found in patients with tuberculous pleurisy. However, the detection of a markedly increased level of IL-6 in pleural fluid argues against a diagnosis of adenocarcinoma.

Effectiveness of cisplatin, paclitaxel, and suramin against human malignant mesothelioma xenografts in athymic nude mice.

BACKGROUND AND OBJECTIVES: Malignant mesothelioma has a poor prognosis and is refractory to many agents. The antitumor effectiveness of cisplatin, paclitaxel, and suramin as single agents and in combination was evaluated in vivo against four lines of human pleural malignant mesothelioma xenografts in athymic nude mice, including one epithelial type and three fibrosarcomatous. METHODS: After growth of tumors occurred by day 54 or 55, mice were randomized in groups of four each to receive either cisplatin 4 mg/kg intraperitoneally weekly x5, or paclitaxel (Taxol) 12.5 mg/kg subcutaneously daily 5 days/week for 3 consecutive weeks, or suramin 60 mg/kg intraperitoneally daily x4,versus controls treated with normal saline. RESULTS: Cisplatin was very effective against one line and also to a lesser degree against another line. Paclitaxel showed antitumor effects similar to cisplatin, being very effective in one line, and also showed good activity in another line. Suramin was basically inactive in all four lines. Following the results obtained with these single agents, it was decided to evaluate the combination of cisplatin and paclitaxel, which resulted in more pronounced antitumor effect in all four cell lines. CONCLUSIONS: These results indicate that the combination of cisplatin and paclitaxel is superior to each agent alone in this model, and that it deserves to be evaluated in patients with malignant mesothelioma.

Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B.

PURPOSE: To examine the individual and joint effect of various pretreatment clinical characteristics on the survival of patients with mesothelioma treated by the Cancer and Leukemia Group B (CALGB). PATIENTS AND METHODS: Between June 1984 and September 1994, 337 patients with malignant mesothelioma and no prior chemotherapy were accrued to seven phase II studies conducted by the CALGB which screened the efficacy of 10 treatment regimens or dose levels. The eligibility criteria for all studies were virtually identical. Patient characteristics include the following: age older than 60 years (63%); male (83%); performance status (PS) of 0 or 1 (81%); chest pain (60%); definite asbestos exposure (62%); >5% weight loss (41%); and pleural involvement (94%). Median survival time (MST) for the 10 treatment regimens ranged from 3.9 to 9.8 months (overall=7.2; 95% confidence interval [CI], 6.5 to 8.3), with 1-year survival between 14% and 50% (overall=27%; 95% CI, 23 to 33%). RESULTS: Cox survival models and exponential regression trees were used to examine the prognostic importance of pretreatment patient characteristics. Univariate analyses show that patients with poor Eastern Cooperative Oncology Group PS, chest pain, dyspnea, platelet count (PLT) >400,000/microL, weight loss, serum lactate dehydrogenase (LDH) level >500 IU/L, pleural involvement, low hemoglobin (HGB) level, high WBC count, and increasing age over 75 years have a worse prognosis. With decreasing risk ratio, multivariate Cox analyses showed that pleural involvement, LDH >500 IU/L, poor PS, chest pain, PLT >400,000/microL, nonepithelial histology, and increasing age older than 75 years jointly predict poor survival. PS was the most important prognostic split in the regression tree. Terminal nodes were amalgamated to form six distinct prognostic subgroups with MST (2-year survival) of 13.9 (38%) in 36 patients, 9.5 (21%) in 36 patients, 9.2 (10%) in 146 patients, 6.5 (3%) in 33 patients, 4.4 (0%) in 73 patients, and 1.4 (0%) in 13 patients (p<0.0001). CONCLUSIONS: The subgroup with the best survival (MST=13.9 months) included patients with PS=0 and age younger than 49 years, and patients with PS=0, age of 49 years or older, and HGB > or =14.6. The worst survival (MST= 1.4 months) occurred for patients with PS= 1/2 and WBC > or =15.6/microL.

Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B.

PURPOSE: The Cancer and Leukemia Group B (CALGB) conducted a randomized phase II multicenter trial to evaluate the activity of two cisplatin-containing regimens (cisplatin and mitomycin [CM], or cisplatin and doxorubicin [CD]) in patients with malignant pleural or peritoneal mesothelioma (protocol CALGB 8435). PATIENTS AND METHODS: Seventy-nine patients were entered between June 1984 and October 1986. Eligibility included a performance status of 0 to 2 by CALGB criteria, and no prior chemotherapy. Central pathology review was performed. Randomization was stratified according to the cell type (epithelial v mixed or sarcomatous) and the presence of measurable versus assessable disease. Of the 79 patients entered, 70 were included in this analysis (35 on CM and 35 on CD), including 48 with epithelial cell type and 22 with mixed or sarcomatous cell types. Sixty-six patients had pleural mesothelioma and four had peritoneal mesothelioma. There were 34 cases with measurable disease and 36 with assessable disease. RESULTS: The overall response rate was 26% for CM (two complete responses [CRs], three partial responses [PRs], and four regressions) and 14% for CD (four PRs and one regression). Median time to treatment failure was 3.6 months for CM and 4.8 months for CD, and median survival duration from study entry was 7.7 and 8.8 months, respectively, with no significant differences between treatments. Good performance status (0 or 1) was associated with significantly longer survival duration (P = .013). Both regimens were well tolerated and there were no treatment-related deaths due to toxicity. CONCLUSION: Moderate antitumor activity has been observed with both regimens. In this randomized phase II trial, the overall response rates, time to treatment failure, and overall survival appear to be similar for the two regimens tested.

Usefulness of the nude mouse model in mesothelioma based on a direct patient-xenograft comparison.

A patient with malignant mesothelioma experienced tumor recurrence 3 months after pleuropneumonectomy. Samples of the tumor were transplanted into nude mice to assess chemosensitivity. There was close concordance between the results in xenografts and the clinical outcome in this patient. Both mitomycin and to a lesser extent cisplatin were effective as single agents against the nude mouse xenografts, and the combination of these two drugs produced a complete response both in the patient and in the xenografts. The patient survived 18 months from onset of chemotherapy and 24 months from diagnosis. The duration of clinical complete response to chemotherapy was 14 months, despite the fact that mitomycin, the most effective agent against the xenografts, was discontinued after only two cycles because the patient developed pulmonary toxicity. This direct patient-xenograft correlation further validates the usefulness of the nude mouse model in the search for effective therapies for malignant mesothelioma, a tumor characterized by frequent refractoriness to most available agents.

Enzymic composition and growth rate of human pleural mesothelioma transplants in nude mice.

The enzymic composition of 7 human mesothelioma lines propagated in nude mice was compared with 4 of the original and 15 additional mesotheliomas sampled during the patients' surgery. The xenografts exhibited several-fold higher thymidine kinase (TK), uridine kinase (UK), phosphoserine phosphatase (PSP) and peptidyl proline hydroxylase (PPH) concentrations than the fresh human samples, while their DNA, gamma-glutamyl transpeptidase (GGT) and beta-galactosidase (Bgal) contents remained similar. The volume growth rate of the xenografts (doubling time, DT = 9.23 +/- 1.25 days) was much faster than that of tumors in the human host, and the decline of this rate with increasing nodule size was accompanied by decreases in TK and PSP concentrations. This first quantitative biochemical study of xenografted human neoplasms indicates that 1) pleural mesotheliomas, though preserving their histological characteristics after heterotransplantation, show considerable increases of enzymes in nucleic acid, collagen, and nonessential amino acid synthesis, and that 2) the concentration of TK is a good indicator of the different growth properties of tumors in a mouse rather than in the human host.

Chemotherapy with 5-fluorouracil (5-FU) and cisplatin or 5-FU, cisplatin, and vinblastine for advanced non-small cell lung cancer. A randomized phase II study of the cancer and leukemia group B.

Two hundred forty-seven patients with previously untreated nonresectable non-small cell lung cancer (NSCLC) were entered in a prospective, randomized Phase II trial. Response assessment was possible in 232 patients, and 237 patients were evaluable for survival. Thirteen partial responses (11%) and 5 regressions (4%) of evaluable disease were obtained for the 116 patients treated with 5-fluorouracil (5-FU) and cisplatin (C) (95% confidence interval [CI], 8.5% to 21.5%). The median time to progression was 2.2 months and the median survival time was 4.6 months for 5-FU plus C. Twenty-three partial responses (20%) and 4 regressions (3%) of evaluable disease were obtained for the 116 patients treated with 5-FU, C, and vinblastine (V) (95% CI, 15.3% to 30.7%). The median time to progression was 2.8 months and the median survival time was 5.6 months for 5-FU, C, and V. The 5-FU and C doses were equivalent in the two treatment regimens. Sixteen of 85 patients (19%) with a performance status of 0 and 18 of 103 patients (17%) with a performance status of 1 responded, whereas only 2 of 44 patients (5%) with a performance status of 2 or greater responded (P = 0.009). Patients who had received locoregional radiation therapy had a lower overall response rate then those in the no prior radiation therapy group (P = 0.028). The median survival time for patients with a performance status of 0 or 1 was 6.3 months compared with 1.9 months for patients with a performance status of 2 or greater (P less than 0.001). Performance status also appeared to be a significant factor for time to progression. More frequent and severe leukopenia, fever, genitourinary (GU) toxicity, and pulmonary toxicity was reported with 5-FU, C, and V. There were three treatment-related deaths with 5-FU, C, and V and one treatment-related death with 5-FU plus C. Grade III/VI myelotoxicity was not influenced by prior radiation therapy or performance status. Neither regimen is active enough to be considered as standard therapy for advanced NSCLC.

Predictors of 5-year survival and curability in small cell lung cancer.

A retrospective analysis of various characteristics in 81 small cell lung cancer patients treated at the Mount Sinai Medical Center, New York, from 1974 to 1982 was carried out to identify factors which had prognostic significance for long-term survival, defined as actual disease-free survival for at least 5 years from initiation of therapy. Six patients, five female patients (16.7%) and one male patient (2%), including four limited disease (9.7%) and two extensive disease patients (5%) were long-term survivors (73 to 96+ months from onset of therapy), and among them three remain alive and disease-free at 84, 84, and 96 months from first treatment, respectively. Although several factors, including sex, stage of disease (limited versus extensive), and occurrence of herpes zoster predicted overall survival duration, female sex and an occurrence of herpes zoster were the only variables which were statistically significantly related to 5-year survival. Herpes zoster was a relatively late occurrence whereas female sex was an independent positive prognostic factor.

Malignant mesothelioma in young adults.

Ten cases of malignant mesothelioma presenting in patients 40 years old or younger at diagnosis were reviewed. Seven cases had a documented history of asbestos exposure of which five were household exposures. The median age at first exposure to asbestos was 10 years and the median duration of exposure was 120 months. The median latency period (time between initial asbestos exposure and diagnosis of malignant mesothelioma) was 19 years. The median interval from initial symptoms to definitive diagnosis was 5.5 months. The case history of each patient is presented. A significant delay in diagnosis in this age group compared with an age-unrestricted series is noted. The significance of nonoccupational exposure to asbestos is emphasized as a probable causative factor in the development of malignant mesothelioma. In addition, a possible genetic predisposition is briefly discussed.

A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B.

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.

Early diagnosis and monitoring of transplanted human malignant mesothelioma by serum hyaluronic acid.

Serum concentrations of unhydrolyzed hyaluronic acid (HA) in nude mice bearing human malignant mesothelioma xenografts were determined by size-exclusion chromatography. HA rose to 8-16 micrograms/mL (controls: less than 1 micrograms/mL) by the fourth to fifth day after tumor (epithelial) transplantation, 3 to 5 days before palpability. Decreases in HA during late tumor growth are probably attributed to tumor necrosis, based on the observation that HA was 2.5 times less in necrotic than in viable tumor tissues. This serum biomarker, recognizable before physical detectability of xenografted tumors, should have applicability to monitoring experimental chemotherapy in mice and to early diagnosis and monitoring of human malignant mesothelioma.

Prognostic factors in small-cell carcinoma of the lung: an analysis of 1,521 patients.

Cancer and Leukemia Group B (CALGB) accrued 1,745 patients with limited (LD) or extensive (ED) small-cell lung cancer (SCCL) to five separate trials between 1972 and 1986. We reviewed these data to evaluate the impact of pretreatment prognostic factors on outcome. In multivariate analysis, female gender was predictive of improved response (LD, P = .01; ED, P = .04) and survival (LD, P = .01; ED, P = .02). A performance status of 0 or 1 was associated with improved response rates in both subsets, but was statistically significant (P = .04) only for overall objective response in LD patients. Performance status was a highly significant predictor of survival in both LD and ED groups (P less than .001). Supraclavicular lymph node involvement, while still LD, had a borderline unfavorable impact on survival (P = .06) compared with a lesser extent of LD involvement. In ED patients, a decrease in survival rates was associated with an increased number of metastatic sites (P = .01). Changes in the patient population were noted with time: the percentage of women increased from 21% to greater than 35%; an increased number of metastatic sites was identified among ED patients; mean performance status improved for both LD and ED subsets. These trends reflect the changing demographics of lung cancer, improved lung cancer staging, and probably lead-time bias. Response rates, overall survival, and long-term (greater than 2-year) survival varied significantly among the five protocols, both before and after multivariate correction for identified prognostic variables. However, the changing character of the study population limits the ability to determine retrospectively how much improvements in therapy contributed to the positive changes in failure-free survival, overall survival, and long-term survival observed in our sequentially studied population.

Neurophysins as tumor markers for small cell carcinoma of the lung. A cancer and Leukemia Group B evaluation.

Plasma human neurophysins (HNPs) were evaluated as tumor markers for patients with small cell carcinoma of the lung (SCCL) who were entered on limited disease and extensive disease treatment trials conducted by Cancer and Acute Leukemia Group B (CALGB). HNP values obtained before treatment showed 44% of tumors secreting vasopressin-associated HNP (VP-HNP), 14% secreting oxytocin-associated HNP (OT-HNP), and 11% producing both HNPs. There was a significantly higher incidence of HNP-secreting tumors for patients with extensive disease and two or more metastatic lesions than for patients with limited disease. There were no clear differences in response to treatment or in survival between patients with HNP-secreting tumors and those with nonsecreting tumors. Response to treatment evaluated by the change in plasma HNP, gave a 91% agreement with independently derived clinical impressions. Our data indicates that HNP evaluations provide sufficient sensitivity to forecast clinical response when it cannot be clearly assessed by conventional methods.

Nonrandom chromosome alterations in human malignant mesothelioma.

Malignant mesothelioma (MM) is a neoplasm closely associated with asbestos exposure, which has been implicated in 70-80% of the cases. In this study, nine MM (two fresh surgical specimens, two permanent cell lines, and five xenografts in nude mice) were examined cytogenetically. Six patients had a known history of asbestos exposure. Seven MM were chromosomally abnormal, the majority having complex structural alterations affecting different chromosomes, whereas two fresh surgical specimens had a normal chromosome constitution. Alterations of chromosome 3 were detected in seven cases and changes involving chromosomes 1 and 7 were observed in six cases. The breakpoints of translocations and deletions on chromosome 1 involved several bands; however, 50% of the breakpoints were near the locations of Blym, L-myc, and ski protooncogenes. Forty % of the breaks on chromosome 7 involved bands q11.1-11.2 and 20% were at q22, the location of the met protooncogene. Nonrandom changes on chromosome 3 were interstitial or terminal deletions, and translocations involving the region p14-21. The deleted 3p segment was identifiable as part of a chromosome translocation in one MM and was apparently lost in the other six. The deletions involving 3p are either spontaneous or asbestos-induced lesions at vulnerable genomic sites and are the most common and nonrandom chromosome alterations observed. Possibly 3p abnormalities are causally related to the development of this malignancy.

Augmentation of activity of cis-diamminedichloroplatinum(II) and mitomycin C by interferon in human malignant mesothelioma xenografts in nude mice.

Two human mesothelioma xenograft lines, BG and ES, serially passaged in athymic mice, were studied to determine the efficacy of alpha-interferon in this type of tumor. Treatment began after progressive tumor growth was established. Recombinant human alpha-interferon-2a (Roferon- A) was given by s.c. injection, at a site distant from the tumor, at a dose of 2 x 10(5) IU 5 days per wk for 5 wk. Mild inhibitory activity was noted in both lines with interferon alone. cis-Diamminedichloroplatinum(II) (CDDP) (4 mg/kg) weekly x 5 was effective in line BG, while mitomycin C (1.5 mg/kg) weekly x 3 was effective in line ES. CDDP was not as effective in line ES. The moderate activity of CDDP in line BG and of mitomycin C in line ES was markedly increased by the addition of alpha-interferon. The combination of mitomycin C and alpha-interferon was as effective as mitomycin C and CDDP. No additional toxicity was noted by the addition of alpha-interferon. The combination of recombinant human alpha-interferon-2a and active chemotherapeutic agents is effective in mesothelioma xenografts.

Comparative studies of human malignant mesothelioma in vivo, in xenografts in nude mice, and in vitro. Cell origin of malignant mesothelioma.

Several decades ago, it was reported that normal and malignant mesothelial cells were transformed into distinct cell types (epithelial to fibrous and fibrous to epithelial) when transferred to in vitro conditions. Those tissue culture data are still cited as evidence supporting that the mesothelial cell has multipotentiality of differentiation and the mesothelial cell is a sole precursor of malignant mesothelioma cells. Six cell lines of heterotransplanted human malignant mesothelioma in nude mice and one cell line of subcultured human malignant mesothelioma in vitro have been established. To establish the validity of the classic concept of multipotentiality of malignant mesothelioma, we studied malignant mesothelioma cells of the seven cases using in vivo cultures, xenografts in nude mice and an in vitro tissue culture, utilizing histology, histochemistry, immunocytochemistry and electron microscopy. The nature of the original malignant mesothelioma cells was clearly shown to be well preserved in both the heterotransplanted and subcultured cells. Data did not support earlier hypotheses that mesothelial cells are capable of differentiating into distinct cell lines. The mesothelial cell and the submesothelial connective tissue cells are the precursors of the neoplastic cells in malignant mesothelioma.

Enzyme pathology of human mesotheliomas.

In samples of 16 surgically resected mesotheliomas arising from the pleura of the human lung, 6 enzymes from different metabolic pathways, DNA, and mitotic frequency were quantified. The mesotheliomas, irrespective of cell type or grade, showed lower gamma-glutamyl transpeptidase (GGT) concentration than 36 of the 38 pulmonary adenocarcinomas. The mean concentration of this enzyme in the 15 mesotheliomas was an eighth of that in the 56 carcinomas, whereas their DNA content was similar. The quantitative correlation of thymidine kinase (TK), uridine kinase (UK), and phosphoserine phosphatase to mitotic frequency was highly significant for mesotheliomas, as well as for carcinomas. As estimated from their TK [and its recently established quantitative correlation to volume doubling time (DT)], the DT of the 16 mesotheliomas ranged from 50 to over 700 days, with a somewhat longer median than the median for pulmonary carcinomas. Subject survival, though shortest for the 2 sarcomatous mesothelioma cases, varied over an overlapping range for mesotheliomas with epithelial or mixed cell type. The biopsy samples' TK and UK concentrations, however, showed a significant inverse correlation with months of survival after diagnosis. Survival time after the first appearance of symptoms decreased linearly (on log scales) with TK concentration (P less than .001) over the 14 cases. The results of this first quantitative study of a spectrum of biochemical constituents of mesotheliomas identify GGT as an enzyme whose measurement guards against mistaking mesotheliomas and adenocarcinomas for one another and show that the TK concentrations of these mesothelioma samples bear a highly significant, inverse correlation to the postdiagnosis survival time of the individual subjects.

Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung.

We conducted a prospective, randomized study to clarify the role of radiotherapy of the primary tumor in limited small-cell cancer of the lung. After stratification for sex and for performance score based on the ability to ambulate, patients were randomly assigned to receive initial radiotherapy plus chemotherapy, delayed radiotherapy plus chemotherapy, or chemotherapy alone. The chemotherapy consisted of cyclophosphamide, etoposide (VP-16-213), and vincristine, with doxorubicin subsequently replacing etoposide in alternate cycles 7 through 18. Chemotherapy was given every three weeks for 18 months. The radiotherapy comprised 4000 rad in four weeks, followed by a 1000-rad "boost" directed against residual disease. All patients received prophylactic whole-brain radiation. The patients enrolled totaled 426, and 399 were evaluable. There was a statistically significant difference in the frequency of complete responses in favor of the two radiotherapy regimens (P = 0.0013). Failure-free survival was also longer with these two regimens (P less than 0.001), as was the interval before treatment failure in the chest (P less than 0.001) and overall survival (P = 0.0099). As expected, toxic effects--chiefly neutropenia--were also increased. The addition of radiotherapy of the primary tumor to combination chemotherapy improved both complete-response rates and survival, with increased but acceptable toxicity.