Journal of Clinical Oncology

Our medical research library holds 40 studies published in Journal of Clinical Oncology (1983–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 35 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it. For 3 studies PubMed has no abstract for, we give the abstract printed in the article or, where there is none, a summary we wrote from it, each labeled as such.

About the journal

• Publisher: American Society of Clinical Oncology
• Published: 1983 to the present, United States
• Language: English
• ISSN: 0732-183X (print), 1527-7755 (electronic)
• Its record in the NLM Catalog

2020s

• Five-Year Clinical Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Unresectable Pleural Mesothelioma in CheckMate 743. A. Scherpereel, P. Baas, A.K. Nowak, et al. 2026;44(9):742-749. Randomized trial PubMed · Publisher · Free full text

  Abstract

  In this 5-year follow-up from the CheckMate 743 study in patients with unresectable pleural mesothelioma (PM), we evaluated updated efficacy and safety outcomes and biomarkers and performed treatment-switching analyses with first-line nivolumab plus ipilimumab versus chemotherapy. With a median follow-up of 66.8 months, nivolumab plus ipilimumab demonstrated continued overall survival (OS) benefit versus chemotherapy in all randomly assigned patients (5-year OS rates, 14% v 6%; hazard ratio [HR], 0.74 [95% CI, 0.62 to 0.88]); similar benefit was observed regardless of tumor histology. Of biomarker-evaluable patients treated with nivolumab plus ipilimumab (n = 242), high baseline monocytic myeloid-derived suppressor cell (M-MDSC) levels correlated with worse OS versus low M-MDSC levels (HR, 1.25 [95% CI, 1.09 to 1.43]). After adjusting for 24% of patients in the chemotherapy arm who received subsequent immunotherapy, nivolumab plus ipilimumab demonstrated continued OS benefit versus chemotherapy (HR, 0.64 [95% CI, 0.53 to 0.78]). No new safety signals were observed. These results demonstrate long-term, durable clinical benefit with nivolumab plus ipilimumab versus chemotherapy, which continued to be preserved even after treatment-switching adjustment in the chemotherapy arm. Exploratory analyses suggested greater benefit with nivolumab plus ipilimumab in the low M-MDSC subgroup. These results further support first-line nivolumab plus ipilimumab as standard of care for unresectable PM.

• Dendritic Cell-Based Immunotherapy in Patients With Resected Pancreatic Cancer. F.R. van 't Land, M. Willemsen, K. Bezemer, et al. 2024;42(26):3083-3093. PubMed · Publisher · Free full text

  Abstract

  Purpose: Immunotherapies have shown limited responses in patients with advanced pancreatic cancer. Recently, we reported that dendritic cell (DC)-based immunotherapy induced T-cell responses against pancreatic cancer antigens. The primary objective of this study was to determine the efficacy of DC-based immunotherapy to prevent recurrence of disease.

  Methods: This was a single-center, open-label, single-arm, combined phase I/II trial. The primary end point was the 2-year recurrence-free survival (RFS) rate. A 2-year RFS rate of ≥60% was defined as a clinically meaningful improvement. We included patients with pancreatic cancer after resection and completion of standard-of-care (SOC) treatment without recurrent disease on cross-sectional imaging. Patients were treated with autologous DCs pulsed with an allogeneic mesothelioma tumor cell lysate, comprising antigens also expressed in pancreatic ductal adenocarcinoma.

  Results: Thirty-eight patients were included in the analysis of the primary end point (47% male, 53% female). The median age was 62 years (IQR, 55-68). Twenty-eight patients (74%) received five DC vaccinations and completed the study protocol. Three patients (8%) received four vaccinations, and seven patients (16%) received three vaccinations. After a median follow-up of 25.5 months, 26 patients (68%) had not developed recurrence of disease. The estimated 2-year RFS was 64%. Vaccination led to the enrichment of circulating activated CD4+ T cells and the detection of treatment-induced immune responses in vitro. T-cell receptor-sequencing analyses of a resected solitary lung metastasis showed influx of vaccine-specific T cells.

  Conclusion: This study reached its primary end point of a 2-year RFS rate of ≥60% following pancreatectomy after SOC treatment and adjuvant DC-based immunotherapy in patients with pancreatic cancer. These results warrant a future randomized trial.

• First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors. R. Hassan, G.R. Blumenschein, K.N. Moore, et al. 2020;38(16):1824-1835. PubMed · Publisher · Free full text

  Abstract

  Purpose: This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.

  Patients And Methods: This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.

  Results: Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.

  Conclusion: Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

2010s

• A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations. S. Pastorino, Y. Yoshikawa, H.I. Pass, et al. 2018;36(35):JCO2018790352. PubMed · Publisher · Free full text

  Abstract

  Purpose: We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years.

  Patients And Methods: Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing.

  Results: Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001).

  Conclusion: We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

• Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma. V. Panou, M. Gadiraju, A. Wolin, et al. 2018;36(28):2863-2871. PubMed · Publisher · Free full text

  Abstract

  Purpose: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM).

  Methods: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.

  Results: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).

  Conclusion: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

• Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. H.L. Kindler, N. Ismaila, S.G. Armato, et al. 2018;36(13):1343-1373. Guideline PubMed · Publisher · Free full text

  Abstract

  Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .

• Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1-Deficient Thoracic Cancers. E. Beddowes, J. Spicer, P.Y. Chan, et al. 2017;35(16):1778-1785. PubMed · Publisher · Free full text

  Abstract

  Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) -negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non-small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.

• Mesothelin Immunotherapy for Cancer: Ready for Prime Time?. R. Hassan, A. Thomas, C. Alewine, et al. 2016;34(34):4171-4179. Review PubMed · Publisher · Free full text

  Abstract

  Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.

• Clinicopathologic characteristics of malignant mesotheliomas arising in patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. L.R. Chirieac, J.A. Barletta, B.Y. Yeap, et al. 2013;31(36):4544-9. PubMed · Publisher

  Abstract

  Purpose: Studies have reported an association between pleural diffuse malignant mesothelioma (PDMM) and chest radiation for lymphoma. The clinicopathologic characteristics of malignant mesotheliomas arising in these patients have not been established.

  Patients And Methods: We studied 1,618 consecutive patients diagnosed with pleural PDMM from July 1993 to February 2008 and identified patients with a history of radiation for Hodgkin and non-Hodgkin lymphoma. We evaluated the histology in the surgical resection specimens and compared clinicopathologic features with overall survival.

  Results: We identified 22 patients who developed PDMM after chest radiation as part of their treatment for lymphoma (mean latency time, 21.4 years; 95% CI, 17.0 to 25.8 years). Asbestos bodies in lymphoma-associated PDMM were lower than in asbestos-associated PDMM (median count, 15 v 325 bodies, respectively; P < .001) and similar to an unexposed control group (median count, 15 v 10 bodies, respectively; P = .6). Seventeen lymphoma-associated PDMMs (77%) were epithelioid and five (23%) were biphasic. Seven PDMMs (32%) had unusual histologies (pleomorphic, myxoid, clear cell, and signet ring cell). Patients with lymphoma-associated PDMM were younger than patients with asbestos-associated PDMM (median age, 45 v 64 years, respectively; P < .001) and had a significantly longer overall survival time (median, 32.5 v 12.7 months, respectively; P = .018). In multivariate analysis, independent favorable predictors for overall survival were history of prior radiation (P = .022), female sex (P < .001), age ≤ 65 years (P = .005), cytoreductive surgery (P < .001), and epithelioid histology (P < .001).

  Conclusion: Patients with lymphoma-associated PDMM are likely to have unusual histologic features, are significantly younger, and seem to have a longer overall survival compared with patients with asbestos-associated PDMM.

• Metabolic response to pegylated arginine deiminase in mesothelioma with promoter methylation of argininosuccinate synthetase. P.W. Szlosarek, P. Luong, M.M. Phillips, et al. 2013;31(7):e111-3. Case report PubMed · Publisher

  Summary

  This case report described a patient with malignant pleural mesothelioma treated with the arginine-depleting enzyme pegylated arginine deiminase (ADI-PEG20). A 57-year-old man with previous asbestos exposure in the power-plant industry was diagnosed with epithelioid malignant mesothelioma in June 2010 after breathlessness and a left-sided pleural effusion. His disease progressed after three cycles of cisplatin and pemetrexed, and again after 2 months in a phase III trial of vorinostat versus placebo. In March 2011 he entered the ADAM trial, a randomized phase II study of ADI-PEG20 plus best supportive care versus best supportive care alone in mesothelioma lacking the enzyme argininosuccinate synthetase 1 (ASS1). Immunohistochemistry showed his tumor was ASS1-deficient, and methylation-specific polymerase chain reaction confirmed ASS1 promoter methylation. He was randomly assigned to 320 IU/m2/wk of ADI-PEG20 by intramuscular injection. After 3 doses, FDG-PET showed a partial metabolic response, with a 40% reduction in maximum standardized uptake value (5.5 to 3.5), while CT showed stable disease. Plasma arginine fell from 63 µmol/L at baseline to 2 µmol/L by the second week and returned to pretreatment levels by the fourth week, as anti-ADI-PEG20 antibody titers rose to a plateau. Symptoms remained stable for an additional 3 weeks, then breathlessness, chest-wall pain and subdiaphragmatic extension of disease developed. He died in August 2011, 14 months after diagnosis. The authors concluded that resistance was likely due to neutralizing antibodies, and that FDG-PET may provide a sensitive method for early evaluation of response to arginine deprivation in tumors with ASS1 methylation.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

2000s

• Malignant pleural mesothelioma after household exposure to asbestos. A.V. Patel, P.N. Bogner, D. Klippenstein, et al. 2008;26(33):5480-3. Case report PubMed · Publisher

  Summary

  The authors described two women who developed malignant mesothelioma without direct asbestos exposure, apparently after household (second-hand) exposure. The first patient, a 70-year-old former smoker (20 pack-years, quit 25 years earlier), presented with cough, pleuritic chest pain, dyspnea on exertion and a 10-pound weight loss. She denied occupational exposure. Her husband of 35 years had sprayed asbestos (crocidolite) as a fire repellant in construction and had died of mesothelioma 12 years earlier. She had shaken out and washed his clothes. CT showed a large right pleural effusion and nodular pleural masses, and pleural biopsy showed sarcomatoid mesothelioma. Her disease progressed on cisplatin-pemetrexed and on gemcitabine. Vinorelbine-cisplatin caused grade 4 neutropenia, and she was receiving single-agent vinorelbine. The second patient, a 77-year-old former grocery store clerk with a 70 pack-year smoking history, had a right upper lobectomy for stage IA adenocarcinoma. A left pleural nodule grew from 1.5 cm × 1 cm to 2.7 cm × 2.3 cm over 4 years, and needle biopsy showed epithelioid mesothelioma. Her husband of 53 years, a pipe fitter, had died of mesothelioma, and she had shaken out and washed his clothes daily. The authors reviewed published reports of household asbestos exposure and mesothelioma. They concluded that physicians should consider mesothelioma in patients with secondary as well as direct asbestos exposure.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Lung cancer in never smokers: a review. J. Subramanian, R. Govindan. 2007;25(5):561-70. Review PubMed · Publisher

  Abstract

  Lung cancer is the leading cause of cancer-related death in the United States. Although tobacco smoking accounts for the majority of lung cancer, approximately 10% of patients with lung cancer in the United States are lifelong never smokers. Lung cancer in the never smokers (LCINS) affects women disproportionately more often than men. Only limited data are available on the etiopathogenesis, molecular abnormalities, and prognosis of LCINS. Several etiologic factors have been proposed for the development of LCINS, including exposure to radon, cooking fumes, asbestos, heavy metals, and environmental tobacco smoke, human papillomavirus infection, and inherited genetic susceptibility. However, the relative significance of these individual factors among different ethnic populations in the development of LCINS has not been well-characterized. Adenocarcinoma is the predominant histologic subtype reported with LCINS. Striking differences in response rates and outcomes are seen when patients with advanced non-small-cell lung cancer (NSCLC) who are lifelong never smokers are treated with epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors such as gefitinib or erlotinib compared with the outcomes with these agents in patients with tobacco-associated lung cancer. Interestingly, the activating mutations in the EGFR-TK inhibitors have been reported significantly more frequently in LCINS than in patients with tobacco-related NSCLC. This review will summarize available data on the epidemiology, risk factors, molecular genetics, management options, and outcomes of LCINS.

• Epidemiology of lung cancer: looking to the future. A.J. Alberg, M.V. Brock, J.M. Samet. 2005;23(14):3175-85. Review PubMed · Publisher

  Abstract

  In the United States, the 20th century witnessed the emergence of a lung cancer epidemic that peaked and began to decline by the century's end, a decline that continues today. However, lung cancer continues to be an unabating pandemic. In research carried out over the last half of the 20th century, many factors were causally associated with lung cancer and studies were implemented to identify determinants of susceptibility to these factors. Cigarette smoking was identified as the single most predominant cause of the lung cancer epidemic, but other causes were found, including workplace agents (eg, asbestos, arsenic, chromium, nickel, and radon) and other environmental factors (passive smoking, indoor radon, and air pollution). Contemporary epidemiologic research on lung cancer now focuses on a new set of issues, primarily related to susceptibility to the well-identified causal factors, particularly smoking, and on the consequences of changes in tobacco products for risks to smokers. Diet and the possibility of reducing risk through chemoprevention remain a focus of research emphasis through experimental and observational approaches. Questions have also been raised about possible differences in susceptibility to lung cancer by sex and race. Population patterns in smoking prevalence will continue to be the most powerful predictor of the future occurrence of lung cancer. Evaluation of recent US patterns in smoking prevalence indicates that for the next approximately 10 to 15 years, lung cancer rates will decrease, but will then level off starting in approximately 2030. Unless further reductions in the prevalence of cigarette smoking are achieved over the next decade, lung cancer will remain as an all too common, but avoidable, disease.

• Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors. A.A. Adjei, C. Erlichman, J.A. Sloan, et al. 2000;18(8):1748-57. PubMed · Publisher

  Abstract

  Purpose: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy.

  Patients And Methods: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses).

  Results: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m(2) for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA.

  Conclusion: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).

• Phase I, dose-finding, and pharmacokinetic study of raltitrexed combined with oxaliplatin in patients with advanced cancer. K. Fizazi, M. Ducreux, P. Ruffié, et al. 2000;18(11):2293-300. PubMed · Publisher

  Abstract

  Purpose: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the raltitrexed plus oxaliplatin combination regimen, to explore its safety and pharmacokinetics, and to assess its antitumor activity in patients with advanced solid tumors.

  Patients And Methods: Forty-eight patients received the combination of raltitrexed plus oxaliplatin. Raltitrexed was administered as a 15-minute infusion followed by oxaliplatin as a 2-hour infusion 1 hour later, repeated every 3 weeks. Seven dose levels were explored, ranging from 2 to 3.75 mg/m(2) and from 85 to 130 mg/m(2) for raltitrexed and oxaliplatin, respectively. The pharmacokinetics of both raltitrexed and oxaliplatin was assessed at the last three dose levels.

  Results: Forty-six patients were assessable for toxicity. Severe toxicities usually occurred from dose level V (raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2)). This combination was not myelosuppressive, eliciting only sporadic grades 3 and 4 neutropenia and/or thrombocytopenia without complications. There was no alopecia. DLTs were asthenia and nausea/vomiting, despite systematic antiemetic prophylaxis. Dose level VI (raltitrexed 3.5 mg/m(2) and oxaliplatin 130 mg/m(2)) was deemed to be the MTD. Eight confirmed partial responses were observed: six patients with malignant mesothelioma (both pretreated and nonpretreated), one with fluorouracil-refractory pancreatic carcinoma, and one with renal carcinoma. Evaluation of the pharmacokinetics of both drugs did not suggest any drug interaction.

  Conclusion: The combination of raltitrexed and oxaliplatin given as consecutive short infusions every 3 weeks seems to be an acceptable regimen that allows a dose-intensity as high as the sum of the recommended doses of each agent given alone. The dose recommended for further phase II studies is raltitrexed 3 mg/m(2) and oxaliplatin 130 mg/m(2) every 3 weeks. Promising antitumor activity has been observed in patients with malignant mesothelioma.

1990s

• Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin. R. Thödtmann, H. Depenbrock, H. Dumez, et al. 1999;17(10):3009-16. PubMed · Publisher

  Abstract

  Purpose: Multitargeted antifolate (MTA; LY231514) has broad preclinical antitumor activity and inhibits a variety of intracellular enzymes involved in the folate pathways. This study was designed to (1) determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of MTA combined with cisplatin; (2) determine a recommended dose for phase II studies; and (3) collect anecdotal information on the antitumor activity of MTA combined with cisplatin.

  Patients And Methods: Patients with solid tumors received MTA intravenously over 10 minutes and cisplatin over 2 hours once every 21 days. In cohort 1, both agents were administered on day 1 starting with MTA 300 mg/m(2) and cisplatin 60 mg/m(2). In cohort 2, MTA (500 or 600 mg/m(2)) was administered on day 1, followed by cisplatin (75 mg/m(2)) on day 2.

  Results: In cohort 1, 40 assessable patients received 159 courses of treatment. The MTD was MTA 600 mg/m(2)/cisplatin 100 mg/m(2). DLTs were reversible leukopenia/neutropenia and delayed fatigue. Hydration before cisplatin therapy did not influence MTA pharmacokinetics. Eleven objective remissions included one complete response in a patient with relapsed squamous cell head and neck carcinoma, and partial responses in four of ten patients with epithelial pleural mesothelioma. In cohort 2, 11 assessable patients received 23 courses of treatment. The MTD was MTA 600 mg/m(2) and cisplatin 75 mg/m(2). DLTs were neutropenic sepsis, diarrhea, and skin toxicity. Two patients died of treatment-related complications during the study. Two patients had objective remissions (one mesothelioma patient, one colon cancer patient).

  Conclusion: The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted.

• Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer. L.L. Herscher, S.M. Hahn, G. Kroog, et al. 1998;16(2):635-41. PubMed · Publisher

  Abstract

  Purpose: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel with concurrent thoracic irradiation in patients with malignant pleural mesothelioma and locally advanced non-small-cell lung cancer (NSCLC) using a 120-hour continuous infusion regimen. A secondary objective was to assess the effect of paclitaxel on the cell cycle through serial tumor biopsies.

  Patients And Methods: Paclitaxel was administered as a 120-hour (5-day) continuous infusion repeated every 3 weeks during the course of radiation therapy. The starting dose of paclitaxel was 90 mg/m2. Doses were escalated at 15-mg/m2 increments in successive cohorts of three patients. In NSCLC patients, radiation was delivered to the primary tumor and regional lymph nodes for a total tumor dose of 6,120 cGy. In mesothelioma patients, hemithoracic irradiation was delivered as the initial treatment field with a conedown to the tumor volume for a total dose of 5,760 to 6,300 cGy. Tumor biopsies were obtained, if possible, before and during paclitaxel treatment.

  Results: Thirty patients were entered onto this study through three dose levels (from 90 mg/m2 to 120 mg/m2). The MTD was determined to be 105 mg/m2. The dose-limiting toxicity was grade 4 neutropenia (two patients). Grade 2 gastrointestinal (GI) toxicity (nausea and vomiting) was also observed at 120 mg/m2. Three of 30 patients developed a hypersensitivity reaction. Six patients had grade 2 lung injury manifested by a persistent cough that required antitussives. Five patients underwent tumor biopsies. None of the patients showed a significant block of cells in mitosis (G2/M) after paclitaxel infusion.

  Conclusion: The MTD of paclitaxel, when administered as a 120-hour continuous infusion with concurrent radiotherapy, was determined to be 105 mg/m2. The dose-limiting toxicity was neutropenia. Continuous infusion paclitaxel administered with large field irradiation of the lung is well tolerated and deserves continued evaluation.

• Phase I trial of tirapazamine in combination with cisplatin in a single dose every 3 weeks in patients with solid tumors. C.A. Johnson, D. Kilpatrick, R. von Roemeling, et al. 1997;15(2):773-80. PubMed · Publisher

  Abstract

  Purpose And Methods: Tirapazamine (SR4233, WIN 59075) is a benzotriazine-di-N-oxide bioreductive agent that is selectively activated to a reactive DNA-damaging species in hypoxic tumors. Preclinical studies show that synergistic antitumor activity results from a schedule-dependent interaction between tirapazamine and several cytotoxic drug classes, including cisplatin. In a phase I combination study, tirapazamine (130 to 260 mg/m2) was administered as a 1-hour intravenous (IV) infusion beginning 3 hours before cisplatin (75 to 100 mg/m2). Thirteen patients received 41 courses of therapy. These patients had an excellent performance status and were not heavily pretreated. The predominant diagnosis was lung cancer.

  Results: The major acute side effects were nausea and vomiting, which were controlled with an intensive antiemetic regimen. Other acute effects included diarrhea and muscle cramping, while with repeated dosing, anorexia and fatigue predominated. Full doses of each agent were well tolerated in combination, although in this previously treated population, fatigue increased markedly after three cycles of therapy. Partial responses were observed in two patients (one with non-small-cell lung cancer and one with breast cancer), and a minor response occurred in a patient with mesothelioma. Tirapazamine pharmacokinetics were linear with respect to increasing dose with a mean maximum plasma concentration (Cmax) of 5.97 +/- 2.25 microg/mL and an area under the concentration-time curve (AUC) of 811.4 +/- 311.9 microg/mL.min at 260 mg/m2. These results are consistent with other ongoing single-agent and combination studies and indicate that therapeutically relevant levels of tirapazamine are achievable in patients based on animal models. The mean cisplatin AUC was 285.6 +/- 46.4 microg/mL.min with mean Cmax values of 3.38 +/- 0.43 microg/mL at 75 mg/m2. The clearance of cisplatin was unaffected by coadministration with tirapazamine.

  Conclusion: This trial shows that in previously treated patients, full doses of cisplatin are well tolerated with increasing doses of tirapazamine up to 260 mg/m2. The observation of clinical responses in this trial supports the phase II investigation of this regimen.

• Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a. P. Soulié, P. Ruffié, L. Trandafir, et al. 1996;14(3):878-85. PubMed · Publisher

  Abstract

  Purpose: To assess the tolerance, toxicity, and antitumoral activity of the weekly combination of cisplatin (CDDP) and interferon alfa-2a (IFNalpha2a) in advanced diffuse malignant mesothelioma (DMM).

  Patients And Methods: Twenty-six patients with DMM (23 pleural and three peritoneal), previously untreated, were enrolled onto this study between August 1991 and December 1992. All patients had measurable disease defined by computed tomographic (CT) scan and diagnostic confirmation by histopathology review panel. IFNalpha2a (3 x 10(6) IU subcutaneously on days 1 to 4) and CDDP (60 mg/m2/wk on day 2) were given weekly. Initially planned as a 5-weeks-on/3-weeks-off treatment cycle, poor patient tolerance observed in the first 12 patients treated (group A) led to schedule adaptation with a shorter treatment sequence and prolongation of the rest period (4 weeks on/4 weeks off) in the following 14 patients (group B). At least two cycles were administered to each patient in the absence of tumor progression.

  Results: Twenty-six patients were assessable for toxicity and 25 for efficacy (World Health Organization [WHO] criteria). Sixty-eight cycles of IFN/CDDP were given, with a median of three cycles per patient (range, one to five). Toxicity was mainly clinical, with progressive anorexia, asthenia, and prolonged nausea/emesis; these side effects have limited treatment acceptance in many patients. Thrombocytopenia and leukopenia were rarely noted as treatment-limiting toxicities. Objective responses (all partial) were obtained in 10 patients (95% confidence interval [CI], 20% to 60%). The median response duration was 11 months (range, 6 to 18). The median time to progression (TTP) for the whole cohort was 6 months and the median survival time was 12 months (range, 5 to 32). Objective responders had a significantly longer median TTP (21 months) and survival time (25 months) than nonresponders (3 and 8 months, respectively).

  Conclusion: The results of this pilot phase I-II study show encouraging antitumor activity in this traditionally resistant tumor, even if the specific contribution of IFN remains speculative and needs further clinical research. Our ongoing program is exploring the dose-intensity impact of IFN dose within the same combination.

• Malignant mesothelioma following treatment for Hodgkin's disease. L.B. Weissmann, J.M. Corson, A.I. Neugut, et al. 1996;14(7):2098-100. Case report PubMed · Publisher

  Abstract

  Purpose: Asbestos exposure is the major known risk factor for mesothelioma, but several case reports have suggested a link between radiation therapy and subsequent development of malignant mesothelioma. This report explores a possible association between radiation therapy for Hodgkin's disease and mesothelioma.

  Patients And Methods: Four cases of malignant mesothelioma were observed following Hodgkin's disease at the Mesothelioma Clinic of the Dana-Farber Cancer Institute. A fifth such patient was found after a review of the literature.

  Results: In all five cases, the mesothelioma arose in the field of prior radiotherapy. No history of asbestos exposure was elicited by careful questioning or by review of chest radiographs. Examination of lung tissue in one patient showed 250 ferruginous bodies per gram of lung tissue, consistent with no significant prior exposure. The mean interval between radiation treatment for Hodgkin's disease and development of mesothelioma was 15 years, which emphasizes the need for continued follow-up and evaluation of these patients and supports a causal relationship.

  Conclusion: Mesothelioma may need to be added to the list of second malignancies that arise following radiation therapy for Hodgkin's disease. Further support is given to a causal link between radiation exposure and mesothelioma.

• A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. V. Rusch, L. Saltz, E. Venkatraman, et al. 1994;12(6):1156-63. PubMed · Publisher

  Abstract

  Purpose: This study investigated the feasibility of a novel approach to the treatment of malignant pleural mesothelioma by combining surgical resection with immediate postoperative intrapleural chemotherapy and subsequent systemic chemotherapy.

  Patients And Methods: Patients with biopsy-proven, resectable malignant pleural mesothelioma underwent pleurectomy/decortication immediately followed by intrapleural chemotherapy with cisplatin 100 mg/m2 and mitomycin 8 mg/m2. Systemic chemotherapy was started 3 to 5 weeks postoperatively and included cisplatin 50 mg/m2 on days 1, 8, 15, 22, 36, 43, 50, and 57, and mitomycin 8 mg/m2 on days 1 and 36. Patients were then monitored by serial chest and abdominal computed tomographic (CT) scans every 3 months until death or for a minimum of 18 months, whichever occurred first.

  Results: Of 36 patients entered onto the study, 28 had pleurectomy/decortication and intrapleural chemotherapy. There was one postoperative death, and two episodes of grade 4 renal toxicity after intrapleural chemotherapy. The 23 patients who also had systemic chemotherapy received a median of 80% and 87% of the planned total cisplatin and mitomycin doses, respectively. No grade 3 or 4 toxicities were observed. The overall survival rate of the 27 patients who were originally candidates for systemic chemotherapy was 68% at 1 year and 40% at 2 years, with a median survival duration of 17 months. Locoregional disease was the most common form of relapse (16 of 20 patients).

  Conclusion: This short but aggressive combined modality regimen was generally well tolerated, but should not be used outside of a protocol setting because of the potential for serious toxicity. Overall survival was as good or better than with previously reported multimodality approaches, but other strategies are needed to improve local control.

• Trimetrexate in malignant mesothelioma: A Cancer and Leukemia Group B Phase II study. N.J. Vogelzang, L.B. Weissman, J.E. Herndon, et al. 1994;12(7):1436-42. PubMed · Publisher

  Abstract

  Purpose: Folic acid antagonists are reported to have activity against mesothelioma. The Cancer and Leukemia Group B (CALGB) undertook this phase II study of the new antifolate, trimetrexate (TMTX), to evaluate its response rate and toxicity in chemotherapy-naive patients with malignant mesothelioma.

  Patients And Methods: Fifty-two patients were accrued to this protocol. Because of concerns about TMTX toxicity in patients with malignant effusions and/or hypoalbuminemia, the first 17 patients were treated at a dose of 6 mg/m2 daily for 5 days every 21 days. Because minimal toxicity was observed, the subsequent 35 patients were treated at a dose of 10 mg/m2.

  Results: Two of 17 patients (12%) in the 6-mg/m2 treatment group had a partial response (PR) and four of 34 eligible patients (12%) in the 10-mg/m2 treatment group had a PR or regression (R) of assessable disease. No patient achieved a complete response (CR). Median survival durations were 5.0 and 8.9 months in the 6- and 10-mg/m2 treatment groups, respectively, while the 2-year survival rates were identical at 18%. At the 10-mg/m2 dose, toxicity was tolerable, with one toxic death from sepsis and a 12% rate of grade 4 thrombocytopenia and granulocytopenia.

  Conclusion: In this large trial, TMTX showed minor activity in the treatment of malignant mesothelioma. Myelosuppression was mild and dose-related. Future studies of higher doses of TMTX should be considered.

• Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. D.J. Sugarbaker, G.M. Strauss, T.J. Lynch, et al. 1993;11(6):1172-8. PubMed · Publisher

  Abstract

  Purpose: We studied a multimodality approach using extrapleural pneumonectomy, chemotherapy, and radiotherapy in patients with malignant pleural mesothelioma.

  Patients And Methods: From 1980 to 1992, 52 selected patients, underwent treatment. Median age was 53 years (range, 33 to 69). Initial patient evaluation was performed by a multimodality team. Pathologic diagnosis was reviewed and confirmed before therapy. Patients with no medical contraindication and potentially resectable mesothelioma on computed tomography (CT) (magnetic resonance imaging [MRI] when it became available) received extrapleural pneumonectomy, cyclophosphamide, doxorubicin, and cisplatin (CAP) chemotherapy, and radiotherapy.

  Results: Perioperative morbidity and mortality rates were 17% and 5.8%, respectively. The overall median survival duration is 16 months (range, 1 month to 8 years). The 32 patients with epithelial histologic variant had 1-, 2-, and 3-year survival rates of 77%, 50%, and 42%, respectively. Patients with mixed and sarcomatous cell disease had 1- and 2-year survival rates of 45% and 7.5%; no patient lived longer than 25 months (P < .01). At resection, positive regional mediastinal lymph nodes were found in 13. Positive lymph nodes were associated with poorer survival than were negative nodes (P < .01). Patients with epithelial variant and negative mediastinal lymph nodes had a survival rate of 45% at 5 years.

  Conclusion: Multimodality therapy including extrapleural pneumonectomy has acceptable morbidity and mortality for selected patients. Prolonged survival occurred in patients with epithelial histologic variant and negative mediastinal lymph nodes. These data provide a rationale for a revised staging system for malignant pleural mesothelioma; furthermore, they permit stratification of patients into groups likely to benefit from aggressive multimodality treatment.

• Epirubicin in malignant mesothelioma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. K. Mattson, G. Giaccone, A. Kirkpatrick, et al. 1992;10(5):824-8. PubMed · Publisher

  Abstract

  Purpose: The doxorubicin analog, epirubicin (EPI), was tested in patients with malignant mesothelioma.

  Patients And Methods: Sixty-three patients with malignant mesothelioma were given EPI 110 mg/m2 every 3 weeks. Histology was reviewed and confirmed by a pathology panel. On the basis of unconvincing or wrong histology, insufficient material or cytology only, nine cases were considered ineligible for the study. None of the patients had received prior chemotherapy.

  Results: The main side effects were myelosuppression, alopecia, and gastrointestinal toxicity. Tumor response, assessed by computed tomographic (CT) scans, was assessable in 48 patients. Seven patients (15%) achieved a partial response that lasted a median of 37 weeks; 19 patients had stable disease, and 22 patients progressed on treatment. Median survival time was 40 weeks from the start of chemotherapy, and the median survival of responding patients was 87 weeks. One responding patient is still alive and free of relapse 4 years from the start of chemotherapy.

  Conclusion: We conclude that further testing of EPI in malignant mesothelioma is warranted.

• Intrapleural cisplatin and mitomycin for malignant mesothelioma following pleurectomy: pharmacokinetic studies. V.W. Rusch, D. Niedzwiecki, Y. Tao, et al. 1992;10(6):1001-6. PubMed · Publisher

  Abstract

  Purpose: Intrapleural cisplatin-based chemotherapy has been used in the treatment of patients with malignant pleural mesothelioma and malignant pleural effusions, but the pharmacokinetics of this form of chemotherapy have not been previously evaluated. We performed pharmacokinetic studies on 12 patients who received both intrapleural cisplatin and mitomycin immediately following pleurectomy/decortication for malignant pleural mesothelioma.

  Patients And Methods: Simultaneous pleural fluid and plasma samples were collected at 15 and 30 minutes, and at 1, 2, 3, 4, and 24 hours after administration of the intrapleural chemotherapy (cisplatin 100 mg/m2 and mitomycin 8 mg/m2), and after cisplatin (total and free) and mitomycin levels were measured. The mean peak levels, the areas under the concentration-time curve (AUC) and the drug half-lives (t1/2s) in plasma and pleural fluid were compared using the paired t test. Differences were considered significant if P less than or equal to .05.

  Results: Systemic absorption was rapid, with peak plasma levels being reached within 1 hour of administration of the intrapleural chemotherapy. Peak plasma levels measured after intrapleural chemotherapy approximated those reportedly attained during systemic administration of these drugs at similar doses. However, the mean peak cisplatin and mitomycin levels, and their mean AUCs, were significantly higher in the pleural fluid than in the plasma. There was a three- to fivefold advantage (on a logarithmic scale) for pleural to plasma AUCs for both cisplatin and mitomycin. The mean t1/2s for cisplatin and mitomycin were significantly longer in the plasma than in the pleural fluid.

  Conclusions: The pharmacokinetics of intrapleural cisplatin-based chemotherapy are analogous to those of intraperitoneal chemotherapy. Our findings show that intrapleural cisplatin-based chemotherapy has a distinct local pharmacologic advantage, but also produces significant and sustained drug plasma levels.

• Ifosfamide, Fanconi's syndrome, and rickets. C.B. Pratt, W.H. Meyer, J.J. Jenkins, et al. 1991;9(8):1495-9. Case report PubMed · Publisher

  Abstract

  Three of 218 children treated with ifosfamide plus the uroprotectant mesna, in single- or combination-agent protocols, have developed Fanconi's renal syndrome, all of whom were in a subgroup of 86 children who had also received cisplatin or carboplatin therapy. Patients receiving ifosfamide who have received prior cisplatin (or carboplatin) are at significantly higher risk of developing Fanconi's syndrome than are those who have received no prior nephrotoxic therapy (P = .04). The role of prior nephrotoxic therapy, including cisplatin and its derivatives, and the total dose of ifosfamide should be considered in the assessment of this rare but serious and apparently irreversible side effect.

• Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial. V.W. Rusch, R. Figlin, D. Godwin, et al. 1991;9(2):313-9. PubMed · Publisher

  Abstract

  Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy, which is cytotoxic rather than sclerosing, has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience, however, with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma, the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987, 46 patients with cytologically proven, symptomatic, and previously untreated malignant pleural effusions were entered on study. A single dose of cisplatin 100 mg/m2 plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma.

• Etoposide and mesothelioma. E.F. Smit, H.H. Berendsen, P.E. Postmus. 1990;8(7):1281. Case report · Letter PubMed · Publisher

• Phase II trial of carboplatin in the management of malignant mesothelioma. D. Raghavan, P. Gianoutsos, J. Bishop, et al. 1990;8(1):151-4. PubMed · Publisher

  Abstract

  Thirty-one patients with advanced malignant mesothelioma, previously untreated or having received only one prior cytotoxic regimen, were treated in a prospective, single-arm phase II trial with carboplatin (NSC 241240) at a dose of 150 mg/m2 per day intravenously (IV) for 3 days (450 mg/m2/course). One complete remission and four partial remissions were achieved, yielding an overall objective response rate of 16% (95% confidence interval [CI], 5.4% to 34%). The median duration of remission was 8 months (range, 5 to 17). Nonhematological toxicity was mild (only 12% with World Health Organization [WHO] grade 3 vomiting); 16% suffered WHO grade 3 to 4 hematological toxicity, but there were no life-threatening episodes and no treatment-related deaths. Carboplatin has modest activity against malignant mesothelioma and, because of its low toxicity, has a role in the management of this disease.

1980s

• Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. P. Ruffie, R. Feld, S. Minkin, et al. 1989;7(8):1157-68. PubMed · Publisher

  Abstract

  Three-hundred thirty-two cases of pleural diffuse malignant mesothelioma (DMM) seen at large centers in Ontario and Quebec from 1965 to 1984 were reviewed retrospectively. Previous asbestos exposure was found in 44% of patients. Diagnosis was most often made by exploratory thoracotomy; pleural biopsy or cytology were rarely contributory. The delay in diagnosis was often long (median time, 3.5 months) and thrombocytosis (platelets greater than or equal to 400,000/microL) was common (41% of cases). The median survival (MS) was only 9 months. Eleven clinical variables were analyzed for prognostic significance. The three most important prognostic factors using a univariate analysis were stage, weight loss, and histologic type. For 118 patients with complete data, multivariate analysis showed that the stage of disease, high platelet count, and asbestos exposure were the most important prognostic factors. There was no cure of DMM, and we did not find any drastic differences in survival among groups of patients subjected to the different therapeutic measures. Radical surgery and radiotherapy were ineffective and we confirmed the low response rate to chemotherapeutic agents. This large retrospective trial can serve as a baseline for future studies in this field. In particular, it provides the basis for appropriate stratification variables to be used in future therapeutic trials.

• Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985. K. Antman, R. Shemin, L. Ryan, et al. 1988;6(1):147-53. PubMed · Publisher

  Abstract

  All mesothelioma patients identified by a computer search of pathologic diagnoses at the Dana-Farber Cancer Institute (DFCI) between 1965 and 1985 were the subjects of this analysis. A total of 180 patients were identified, 136 with pleural and 37 with peritoneal mesothelioma. There were five pericardial and two testicular primaries. Of the two decades included in the study, later patients were significantly older, with a more advanced disease stage, and a lower performance status than those accrued early in the study. Factors at diagnosis associated with a significantly prolonged survival for all patients with mesothelioma included a 0 to 1 performance status, absence of chest pain, age less than 50 years, and epithelial histology. Factors at diagnosis associated with prolonged survival for the subset of patients with pleural mesothelioma included epithelial histology, 0 to 1 performance status, the absence of chest pain, an interval of greater than 6 months from onset of symptoms, and treatment with chemotherapy and pleuropneumonectomy. This last result must be interpreted with caution, since this was not a randomized study.

• Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. A.S. Alberts, G. Falkson, L. Goedhals, et al. 1988;6(3):527-35. PubMed · Publisher

  Abstract

  From 1965 to 1985, 262 patients with malignant pleural mesothelioma were treated with cytostatics only; radiotherapy (RT); RT and cytostatics; or decortication plus RT plus cytostatics. The median survival (MS) from diagnosis was 9.6 months. This was similar for all comparable treatment groups. In a univariate analysis, significant favorable prognostic factors were good performance status (PS), duration of symptoms greater than 6 months at the time of diagnosis, early stage of disease, white race, and female sex. In a multivariate analysis, PS, race, duration of symptoms, and stage were of significance for a favorable prognosis. Age, pain as first symptom, histologic subtype, and RT dose were not of prognosis significance in this study. The stepwise addition of treatment modalities did not increase survival, which remained the same as that reported for untreated patients. Therefore, phase II trials of new agents offer the only hope for advance in the treatment of this disease.

• Randomized comparison of cyclophosphamide, imidazole carboxamide, and adriamycin versus cyclophosphamide and adriamycin in patients with advanced stage malignant mesothelioma: a Sarcoma Intergroup Study. M.K. Samson, L.P. Wasser, E.C. Borden, et al. 1987;5(1):86-91. Randomized trial PubMed · Publisher

  Abstract

  In 1980, a consensus chemotherapy intergroup study for advanced malignant mesothelioma was initiated based on a collaborative agreement among the Eastern Cooperative Oncology Group (ECOG), the Southwest Oncology Group (SWOG), and the Southeastern Cancer Study Group (SECSG). The purpose of the study was to evaluate cyclophosphamide (500 mg/m2 day 1), imidazole carboxamide (250 mg/m2 days 1 through 5), and doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) (50 mg/m2 day 1) v cyclophosphamide (500 mg/m2) and doxorubicin (50 mg/m2) in a randomized prospective clinical trial involving 76 fully evaluable patients with advanced stages II to IV malignant mesothelioma. A total of nine responses (12%) were documented, including three complete and six partial responses. There was no significant difference in response duration or survival between treatment arms. Leukopenia (greater than 2,000/microL) was observed in 46% of patients treated with the three-drug combination and 38% of patients receiving the two-drug combination. The variables of performance status 0-1 and the absence of prior chemotherapy/radiotherapy were significant with respect to favorable impact on survival. We conclude, based on the minimal benefit observed, that the combination of cyclophosphamide and doxorubicin with or without imidazole carboxamide does not warrant further investigation in patients with advanced-stage malignant mesothelioma.

• Pulmonary complications of peritoneal access catheters. G.R. Weiss. 1985;3(12):1690-1. Case report · Letter PubMed · Publisher

• Tetracycline sclerosis in the management of malignant pericardial effusion. F.A. Shepherd, J.S. Ginsberg, W.K. Evans, et al. 1985;3(12):1678-82. PubMed · Publisher

  Abstract

  Twenty-two patients with malignant pericardial effusion were seen at the Toronto General Hospital between 1979 and 1984. Under ECG monitoring, an indwelling Kifa catheter was inserted into the pericardial sac and then connected to a Hemovac system and allowed to drain for 12 to 24 hours. Xylocaine hydrochloride, 100 mg, was first instilled intrapericardially, followed by tetracycline hydrochloride, 500 to 1,000 mg, dissolved in 20 mL normal saline. The catheter was clamped for one to two hours and then allowed to drain into the Hemovac. This procedure was repeated every 24 to 48 hours until the net drainage was less than 25 mL/24 hours. Nine men and 13 women were treated (median age, 55 years). The primary malignancy included lung in 15 patients, breast in two patients, and carcinoma of the stomach, ovary, pleural mesothelioma, chronic granulocytic leukemia, and adenocarcinoma of unknown primary in one patient each. Twenty patients received one to five instillations of tetracycline. In one patient the catheter could not be inserted into the pericardial sac, and in one patient the catheter clotted before tetracycline instillation. Minor complications included transient arrhythmia in two patients, postinjection pain in four patients, and self-limited temperature elevation greater than 38.5 degrees C in two patients. fifteen patients had good control of their malignant pericardial effusion for more than 30 days (median survival, 160 days; range, 38 to 275 days). Three patients died before 30 days without evidence of effusion, and no patient surviving longer than 30 days developed recurrent effusion or pericardial constriction. Intrapericardial tetracycline instillation is a safe and efficacious treatment for malignant pericardial effusion and should be considered the first treatment modality in this situation.

• Malignant mesothelioma of the tunica vaginalis testis. K. Antman, S. Cohen, N.V. Dimitrov, et al. 1984;2(5):447-51. Case report PubMed · Publisher

  Abstract

  Eighteen patients with malignant mesothelioma of the tunica vaginalis testis have been previously reported. These and the six patients reported here are reviewed for natural history and response to treatment. This tumor should be considered in men of any age with scrotal masses that include a hydrocele. Staging procedures should include computerized tomography scanning of the chest and abdomen. Inguinal orchiectomy appears to be the optimal primary surgical approach. Intraabdominal disease found at diagnostic laparotomy may be effectively treated by surgery and/or abdominal radiotherapy. Clinical features such as a long asymptomatic interval from initial presentation to clinical recurrence were observed and are also worthy of emphasis. Thus, serial follow-up is advised. Upon recurrence, treatment remains unsatisfactory but some responsiveness to chemotherapy has been noted. Doxorubicin-containing regimens were administered to five patients with measurable pulmonary nodules resulting in two partial regressions by standard criteria.

• Multiple primary malignancies. R.S. Hoffman, A.H. Rossof, R. Pazdur, et al. 1984;2(11):1305. Case report · Letter PubMed · Publisher

  Summary

  In this letter, the authors responded to a report by Antman et al of malignant mesothelioma after radiation exposure by describing one further case from their own practice in Chicago. In 1955, a 33-year-old man had surgery for a left testicular seminoma and received prophylactic radiation therapy to the para-aortic and mediastinal lymph node areas. The exact dose was unknown, but the local radiation therapist estimated it at 25 to 30 Gy. The man later developed a basal cell carcinoma of the cheek in 1972, treated with radiation, and a left shoulder tumor in 1974-1975, eventually diagnosed as malignant fibrous histiocytoma. In late 1979, a right-sided pleural effusion developed, and bilateral pleural malignant mesothelioma of epithelial type was diagnosed at thoracotomy, 24 years after the radiation for seminoma. He was treated with chemotherapy and further radiation and died about two months after starting cyclophosphamide. Autopsy found a previously unknown renal cell carcinoma with metastases. There was no history of asbestos exposure and no autopsy evidence of it. The authors noted that the latent period was similar to that reported for other radiation-associated tumors. They suggested that defects of DNA repair or immune factors were also possible, given his multiple primary cancers. They concluded that malignant mesothelioma without evidence of asbestos exposure should be considered among radiation-induced neoplasms.

  PubMed has no abstract for this study, and the article doesn't print one. We wrote this summary from the full article with the help of AI. It is not the authors' wording.

• Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system. J. Lokich, A. Bothe, T. Zipoli, et al. 1983;1(1):24-8. PubMed · Publisher

  Abstract

  Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.

• Malignant mesothelioma following radiation exposure. K.H. Antman, J.M. Corson, F.P. Li, et al. 1983;1(11):695-700. Case report PubMed · Publisher

  Abstract

  Mesothelioma developed in proximity to the field of therapeutic radiation administered 10-31 years previously in four patients. In three, mesothelioma arose within the site of prior therapeutic radiation for another cancer. Mesothelioma in the fourth patient developed adjacent to the site of cosmetic radiation to a thyroidectomy scar. None of these four patients recalled an asbestos exposure or had evidence of asbestosis on chest roentgenogram. Lung tissue in one patient was negative for ferruginous bodies, a finding considered to indicate no significant asbestos exposure. Five other patients with radiation-associated mesothelioma have been reported previously, suggesting that radiation is an uncommon cause of human mesothelioma. Problems in the diagnosis of radiation-associated mesotheliomas are considered.

• Peritoneal mesothelioma: natural history and response to chemotherapy. K.H. Antman, E.A. Pomfret, J. Aisner, et al. 1983;1(6):386-91. PubMed · Publisher

  Abstract

  Twenty-three patients with malignant peritoneal mesothelioma seen at the Dana Farber Cancer Institute and the University of Maryland Cancer Center from 1968 to 1982 were studied to assess the natural history of the disease and the efficacy of current treatment. Asbestos exposure was reported by 57%. Of 18 patients receiving a doxorubicin-containing regimen, 14 had measurable or evaluable disease. One complete response, four partial responses and one regression (in a patient with evaluable but not measurable disease) were observed, ranging in duration from 6 to 36 months. A single patient remains disease free for more than 36 months after subsequent radiotherapy. Significant clotting abnormalities (including disseminated intravascular coagulation, massive thrombosis, fatal pulmonary emboli, Coombs-positive hemolytic anemia, and phlebitis) occurred in 22% of the patients. Trends toward decreased survival were observed for smokers, patients presenting with ascites, and those with stage II-IV disease.

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