An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

This corrects the article DOI: 10.1038/bjc.2017.85.

Factors associated with survival in a large series of patients with malignant pleural mesothelioma in New South Wales.

BACKGROUND: Although the prognosis of most patients presenting with malignant pleural mesothelioma (MPM) is poor, a small proportion survives long term. We investigated factors associated with survival in a large patient series. METHODS: All patients registered with the NSW Dust Diseases Board (2002-2009) were included in an analysis of prognostic factors using Kaplan-Meier and Cox regression analysis. On the basis of these analyses, we developed a risk score (Prognostic Index (PI)). RESULTS: We identified 910 patients: 90% male; histology (epithelioid 60%; biphasic 13%; sarcomatoid 17%); stage (Tx-I-II 48%; III-IV 52%); and calretinin expression (91%). TREATMENT: chemotherapy(CT) 44%, and extrapleural-pneumonectomy (EPP) 6%. Median overall survival (OS) was 10.0 months. Longer OS was associated with: age <70 (13.5 vs 8.5 months; P<0.001); female gender (12.0 vs 9.9 months; P<0.001); epithelioid subtype (13.3 vs 6.2 months; P<0.001); ECOG status 0 (27.4 vs 9.7 months; P=0.015), calretinin expression (10.9 vs 5.5 months; P<0.001); neutrophil-lymphocyte ratio (NLR) <5 (11.9 vs 7.5 months; P<0.001); platelet count <400 (11.5 vs 7.2 months; P<0.001); and normal haemoglobin (16.4 vs 8.8 months; P<0.001). On time-dependent analysis, patients receiving pemetrexed-based chemotherapy (HR=0.83; P=0.048) or EPP (HR=0.41; P<0.001) had improved survival. Age, gender, histology, calretinin and haematological factors remained significant on multivariate analysis. In all, 24% of patients survived >20 months: 16% of these receiving EPP, and 66% CT. The PI offered improved prognostic discrimination over one of the existing prognostic models (EORTC). CONCLUSIONS: We identified calretinin expression, age, gender, histological subtype, platelet count and haemoglobin level as independent prognostic factors. Patients undergoing EPP or pemetrexed-based chemotherapy demonstrated better survival, but 84% and 34% of long survivors, respectively, did not receive radical surgery or chemotherapy.

An RNAi-based screen reveals PLK1, CDK1 and NDC80 as potential therapeutic targets in malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is an aggressive tumour originating in the thoracic mesothelium. Prognosis remains poor with 9- to 12-month median survival, and new targets for treatments are desperately needed. METHODS: Utilising an RNA interference (RNAi)-based screen of 40 genes overexpressed in tumours, including genes involved in the control of cell cycle, DNA replication and repair, we investigated potential therapeutic targets for MPM. Following in vitro characterisation of the effects of target silencing on MPM cells, candidates were assessed in tumour samples from 154 patients. RESULTS: Gene knockdown in MPM cell lines identified growth inhibition following knockdown of NDC80, CDK1 and PLK1. Target knockdown induced cell-cycle arrest and increased apoptosis. Using small-molecule inhibitors specific for these three proteins also led to growth inhibition of MPM cell lines, and Roscovitine (inhibitor of CDK1) sensitised cells to cisplatin. Protein expression was also measured in tumour samples, with markedly variable levels of CDK1 and PLK1 noted. PLK1 expression in over 10% of cells correlated significantly with a poor prognosis. CONCLUSION: These results suggest that RNAi-based screening has utility in identifying new targets for MPM, and that inhibition of NDC80, CDK1 and PLK1 may hold promise for treatment of this disease.

Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma.

BACKGROUND: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches to therapy are needed. Reduced expression of miR-15/16 in a range of cancer types has suggested a tumour suppressor function for these microRNAs, and re-expression has been shown to inhibit tumour cell proliferation. The miR-15/16 status in MPM is largely unknown. MATERIALS AND METHODS: MicroRNA expression was analysed by TaqMan-based RT-qPCR in MPM tumour specimens and cell lines. MicroRNA expression was restored in vitro using microRNA mimics, and effects on proliferation, drug sensitivity and target gene expression were assessed. Xenograft-bearing mice were treated with miR-16 mimic packaged in minicells targeted with epidermal growth factor receptor (EGFR)-specific antibodies. RESULTS: Expression of the miR-15 family was consistently downregulated in MPM tumour specimens and cell lines. A decrease of 4- to 22-fold was found when tumour specimens were compared with normal pleura. When MPM cell lines were compared with the normal mesothelial cell line MeT-5A, the downregulation of miR-15/16 was 2- to 10-fold. Using synthetic mimics to restore miR-15/16 expression led to growth inhibition in MPM cell lines but not in MeT-5A cells. Growth inhibition caused by miR-16 correlated with downregulation of target genes including Bcl-2 and CCND1, and miR-16 re-expression sensitised MPM cells to pemetrexed and gemcitabine. In xenograft-bearing nude mice, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of MPM tumour growth. CONCLUSIONS: The miR-15/16 family is downregulated and has tumour suppressor function in MPM. Restoring miR-16 expression represents a novel therapeutic approach for MPM.

Patterns of care for malignant pleural mesothelioma patients compensated by the Dust Diseases Board in New South Wales, Australia.

BACKGROUND: The silent epidemic of mesothelioma in Australia is steadily increasing, and 30% of cases occur in New South Wales (NSW). AIM: To describe the patterns of care and outcomes of patients with malignant pleural mesothelioma (MPM) in NSW. METHODS: MPM patients in NSW applying for compensation at the NSW Dust Diseases Board from 2007 to 2009 were included. Survival from time of diagnosis was determined by the Kaplan-Meier method. The Chi-squared test was used to determine if there was an association between utilisation of treatment and geographical location. RESULTS: A total of 138 patients was included: median age was 72.5; 91.3% male; 60.1% epithelial subtype; and 65.2% lived in major cities. All patients had at least one chest X-ray and computed tomography scan, and 21% had a positron emission tomography scan; 93.5% and 4.3% had histological or cytological confirmation respectively. Thoracoscopy (59.4%) was the most commonly used diagnostic procedure. Treatment utilisation: 53.6% chemotherapy; 35.5% radiotherapy; 9.4% extrapleural pneumonectomy (EPP); and 72.5% had palliative care involvement. There were no major differences in treatment utilisation between patients living in major cities and those in regional NSW (chemotherapy P = 0.42; radiotherapy P = 0.13 and palliative care P = 0.60), except for a higher rate of EPP in regional patients (16.7% vs 5.6%; P = 0.03). Median survival was 9.7 versus 12.3 months for city and regional patients respectively (P = 0.22). CONCLUSION: Survival and treatment utilisation was not significantly different between MPM patients living in major cities and regional NSW, except for a higher rate of EPP in patients in regional NSW.

A phase III randomized study of gemcitabine and cisplatin with or without PF-3512676 (TLR9 agonist) as first-line treatment of advanced non-small-cell lung cancer.

BACKGROUND: This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS). RESULTS: A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P=0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade≥3 AEs (experimental arm). CONCLUSIONS: Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Differential diagnosis of pulmonary carcinoma following head and neck cancer by genetic analysis.

PURPOSE: Patients with head and neck cancer often develop a lung tumor that can be diagnosed as distant metastasis (DM) or second primary tumor (SPT). In this study, we use TP53 mutation analysis for validation of an allelic loss marker panel and a decision algorithm for distinguishing between DM and SPT. EXPERIMENTAL DESIGN: Tumor pairs of 39 patients were analyzed for TP53 mutations, for patterns of allelic loss and immunohistochemical analysis of p53 expression. Results of these three analyses were compared, using mutation analysis as gold standard. RESULTS: Loss of heterozygosity (LOH) analysis indicated DM in 15 and SPT in 23 cases (one inconclusive). TP53 mutation analysis was informative in 15 cases. Based on the p53 mutation status alone, nine tumors were diagnosed as SPT and six as DM. In all 15 cases the LOH analysis was in concordance with the TP53 mutation analysis. Immunostaining for p53 showed promise as a first scan to diagnose lung tumors as SPT but cannot be used to diagnose DM. CONCLUSION: The TP53 mutation data validate the suitability of the LOH marker panel and decision algorithm for differential diagnosis of DM and SPT in the lung. LOH analysis can theoretically be exploited in almost all cases and is less laborious than TP53 mutation analysis.

Malignant mesothelioma.

Malignant mesothelioma (MM) is an aggressive tumour that commonly affects the mesothelial surfaces of the pleural and peritoneal cavities, and occasionally, the tunica vaginalis and the pericardium. Formerly a rare tumour, MM is increasing in incidence in Australia due to the heavy nationwide use of asbestos from 1940 until the 1980s. The incidence is expected to peak in Australia in the next decade, mirroring the long latency period between asbestos exposure and development of MM. Diagnosis of MM can be difficult. Definitive pathological diagnosis is required and it often requires an experienced pathologist to differentiate MM from other benign or malignant processes. Treatment of MM requires a multidisciplinary approach, regardless of palliative or curative intent. Treatment options, such as surgery, chemotherapy, radiotherapy and active symptom control or a combination of these, may be used. Further research is needed to advance the therapeutic options for MM, and strategies to realize personalisation of therapy through discovery of predictive markers. In the Australian society where asbestos contamination of the built environment is very high, education and stringent public health measures are required to prevent a second wave of increased MM incidence.

Non-small cell lung carcinoma of the superior sulcus: favourable outcomes of combined modality treatment in carefully selected patients.

The combination of radiotherapy and concurrent chemotherapy followed by surgery (trimodality treatment) is currently regarded as optimal treatment for non-small cell lung cancer of the superior sulcus (SST) or Pancoast tumour. The possibility to administer intensive combined modality treatment is influenced by tumour stage, comorbidity and performance status of these patients, and therefore a strict patient selection is necessary. This study focuses on patient selection and its results. We retrospectively evaluated choices of treatment and outcome of all patients with SST treated in the Netherlands Cancer Institute from 1994 to 2004. After identification of patients with SST in registration databases, the following characteristics were analyzed: symptoms, comorbidity, tumour stage, treatment characteristics, toxicity, local control, disease-free and overall survival. Fifty-two patients, 37 men and 15 women, were identified. They were diagnosed with stage IIB (27%), stage IIIA (8%), stage IIIB (42%) and stage IV (23%). Twelve patients after induction (chemo)radiotherapy underwent surgical resection. In eight patients a pathologic complete response was found. The 2- and 5-year survival after induction treatment and surgery was 75 and 39%, respectively. Other patients did not receive surgical treatment because of stage IV disease (n=12), comorbidity (n=8), irresectability (extensive tumour growth and/or persisting N2-3 status; n=14) or insufficient response to induction treatment (n=6). Eleven patients were treated with concurrent chemoradiotherapy (5-year survival 20%) and 17 patients with (sequential) radiotherapy and/or chemotherapy (5-year survival 6%). Local recurrence rates were 0% after induction treatment and surgical resection, 32% after concurrent chemoradiotherapy and 72% after (sequential) radiotherapy and/or chemotherapy. In conclusion, only 30% of M0 patients with SST were eligible for combined modality treatment followed by surgery. In this subgroup, concurrent chemoradiotherapy followed by surgery was associated with excellent local control and acceptable survival.

[Perspectives in the treatment of non-small cell lung cancer stage III with radiotherapy and concomitant low-dosage chemotherapy]. / Perspectieven in de behandeling van het niet-kleincellige longcarcinoom stadium III met radiotherapie en gelijktijdig gegeven laaggedoseerde chemotherapie.

Patients with a non-small cell lung cancer stage III should preferably be treated with a combination of concomitant radiotherapy and platinum-containing chemotherapy. Concomitant chemoradiation results in improved survival compared to sequential chemoradiation, although this type oftreatment is associated with higher oesophagus toxicity. With concomitant chemoradiation the chemotherapy can be added in several ways to high-dosage radiotherapy, for example in the form of 2 courses of high dose, platinum-containing polychemotherapy once every 3 weeks. Concomitant chemoradiation with just a daily low dose of cisplatin is a good alternative. In view of its low risk of haematological and renal toxicity and ototoxicity and smaller cardiac load this is the therapy of choice and is also highly suitable for elderly patients with comorbidity.

EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups.

BACKGROUND: Preclinical evidence suggests that retinoids and antioxidants may prevent or delay the occurrence of cancer in the upper or lower airways, but such effects have not been reliably established in clinical studies. To assess the chemopreventive effects of vitamin A (retinyl palmitate) and N-acetylcysteine, we conducted a large randomized intervention study in patients with head and neck cancer or with lung cancer, most of whom had a history of smoking. METHODS: From June 1988 through July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with lung cancer) were randomly assigned to receive 1) retinyl palmitate (300000 IU daily for 1 year followed by 150000 IU for a 2(nd) year), 2) N-acetylcysteine (600 mg daily for 2 years), 3) both compounds, or 4) no intervention. All statistical tests were two-sided. RESULTS: Of the patients, 93.5% had smoked tobacco at sometime in their lives (and 25% continued to smoke after cancer diagnosis). After a median follow-up of 49 months, 916 patients were reported with an event (recurrence, second primary tumor, or death). No statistically significant difference was observed in overall survival or event-free survival between patients who received retinyl palmitate and patients who did not. Similarly, no difference was seen in overall survival or event-free survival between patients who received N-acetylcysteine and patients who did not. There was a lower incidence of second primary tumors in the no intervention arm, but the difference was not statistically significant. CONCLUSION: A 2-year supplementation of retinyl palmitate and/or N-acetylcysteine resulted in no benefit-in terms of survival, event-free survival, or second primary tumors-for patients with head and neck cancer or with lung cancer, most of whom were previous or current smokers.

The psychological impact of annual chest X-ray follow-up in head and neck cancer.

CONCLUSION: Annual post-treatment screening of head and neck squamous cell carcinoma (HNSCC) patients for second primary lung cancer and metastatic recurrence appeared to form no major burden for head and neck cancer patients. A majority of patients regard the annual chest X-ray as a reassurance. Given these results a more intensive screening program seems psychologically justifiable for this group. OBJECTIVE: To assess the psychological impact of annual post-treatment screening for second primary lung cancer and metastases in HNSCC patients. PATIENTS AND METHODS: In a cohort of 106 patients, 68 men and 38 women, with a mean age of 56, the impact of the yearly chest radiograph was evaluated by means of a nine-item questionnaire. RESULTS: In all, 90% of the patients were in favor of annual post-treatment screening, 2% would not like to receive this screening, and 8% had no preference. A majority (98%) considered the screening as an extra medical check and 76% felt reassured. Although 21% of the patients were very nervous about the outcome of the screening, only 3% wanted to avoid the yearly chest X-ray for this reason.

Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

BACKGROUND: Thymomas are rare neoplasms of the mediastinum. The role of chemotherapy in advanced thymomas is not fully established. PATIENTS AND METHODS: In the European Organization for Research and Treatment of Cancer (EORTC) Lung Cancer Cooperative Group, 16 patients with recurrent or metastatic malignant thymoma were entered over 6 years onto a study of combination chemotherapy that consisted of cisplatin 60 mg/m2 on day 1 and etoposide 120 mg/m2 on days 1, 2, and 3, every 3 weeks. RESULTS: A median of six courses per patient was administered. Main side effects of treatment were leukopenia, nausea and vomiting, and alopecia. Five complete responses and four partial responses were obtained, with a median response duration of 3.4 years. The median progression-free survival and survival times were 2.2 years and 4.3 years, respectively, with a median follow-up duration of 7 years. CONCLUSION: The combination of cisplatin and etoposide is highly effective and well tolerated in advanced thymoma. The investigation of this combination in a neoadjuvant setting in unresectable invasive thymoma is warranted.

Epirubicin in malignant mesothelioma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

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.

Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study.

PURPOSE: To determine whether the clinical course and the response to chemotherapy of patients with advanced adenocarcinoma of the lung depends on the presence or absence of a ras mutation in the tumor. Mutational activation of K-ras is a strong adverse prognostic factor in stage I or II lung cancer and laboratory studies have suggested that ras mutations lead to resistance against ionizing radiation and chemotherapy. PATIENTS AND METHODS: Patients with advanced adenocarcinoma of the lung with measurable or assessable disease received chemotherapy with mesna, ifosfamide, carboplatin, and etoposide (MICE). Archival biopsies, fresh biopsies, or fine-needle aspirations were tested for the presence of ras gene mutations. Associations of ras mutations with clinical characteristics, response to chemotherapy, and survival were studied. RESULTS: The presence or absence of ras gene mutations could be established in 69 of 83 patients (83%). A total of 261 courses of MICE were administered to 62 informative patients, 16 of whom were shown to have a K-ras mutation-positive tumor. The frequency of mutations (26%) and the type of mutations closely matched the pattern we have previously reported in operable disease. Patients with a ras mutation in their tumor were more likely to have a close relative with lung cancer, but other clinical characteristics, such as pattern of metastases, response, and survival, were similar between the ras mutation-positive and ras mutation-negative groups. CONCLUSION: Patients with advanced lung adenocarcinoma who harbor a ras mutation may have major responses to chemotherapy and have similar progression-free and overall survival as patients with ras mutation-negative tumors. K-ras mutations may represent one of several ways in which early tumors are enabled to metastasize to distant sites.

Teniposide for brain metastases of small-cell lung cancer: a phase II study. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: Here we report the results of a phase II study of teniposide, one of the most active drugs against small-cell lung cancer (SCLC), in patients with brain metastases. PATIENTS AND METHODS: Patients with SCLC who presented with brain metastases at diagnosis (n = 11) or during follow-up evaluation after treatment (n = 69) were treated with teniposide at a dose of 150 mg/m2 intravenously on days 1, 3, and 5 at 3-week intervals in an outpatient setting. Response in the brain was evaluated by brain computed tomography (CT) after two, six, and 12 courses. RESULTS: In 26 of 80 assessable patients, an intracranial response was seen, with a response rate of 33% (95% confidence interval, 22% to 44%). The median response duration was 5.4 months for patients with a complete response (CR) and 4.2 months for patients with a partial response (PR). Patients who required corticosteroids for peritumoral edema had a significantly lower response rate than patients who did not receive corticosteroids. Neurologic function at the start of treatment had a significant influence (neurologic function 1 better than 2, respectively, better than 3 and 4; P < .001), as did the number of cycles of previous chemotherapy (0 better than 1 to 5 cycles, respectively, better than > 5 cycles; P = .043). Grade 3/4 leukocytopenia and thrombocytopenia were seen in 3% and 39%, respectively, of 80 patients. Toxicity-related death was seen in eight patients, seven of whom were previously treated with chemotherapy. CONCLUSION: Teniposide is active against brain metastases of SCLC. It is a suitable drug for palliation, especially of patients without extensive pretreatment and with a good neurologic function and performance status. Patients previously treated with cranial radiotherapy are also candidates for this therapy. If systemic chemotherapy is considered for tumor progression outside the brain, radiotherapy of brain metastases might be omitted or delayed pending the effect of chemotherapy. The use of corticosteroids in patients with brain metastases treated with chemotherapy might influence the efficacy of the chemotherapy.

Gemcitabine and cisplatin as induction regimen for patients with biopsy-proven stage IIIA N2 non-small-cell lung cancer: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955).

PURPOSE: Our objective was to better define the activity/feasibility of gemcitabine/cisplatin (GC) as induction chemotherapy in patients with stage IIIA N2 non-small-cell lung cancer (NSCLC) followed by surgery or radiotherapy within a large, ongoing comparative study (EORTC 08941). PATIENTS AND METHODS: Forty-seven chemotherapy-naive patients with NSCLC, median age of 58 years, stage IIIA N2 disease, World Health Organization performance status of 0 or 1, and the ability to tolerate a pneumonectomy received gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 and cisplatin 100 mg/m(2) on day 2, every 4 weeks. Patients received induction chemotherapy (three cycles) before re-evaluation and randomization to surgery or radiotherapy. RESULTS: Grade 3/4 thrombocytopenia, the main hematologic toxicity, occurred in 60% of patients but was not associated with bleeding. Full-dose gemcitabine was given in 48% of the courses. Severe nonhematologic toxicity was uncommon. Two patients with preexisting, autoimmune pulmonary fibrosis had deterioration of pulmonary function after radiotherapy. Thirty-three (70.2%; 95% confidence interval, 55.1% to 82.7%) of the 47 eligible patients had objective responses (three complete responses and 30 partial responses). Mediastinal nodes were tumor-free after induction therapy in 53% of cases. Resections were considered complete in 71% of the patients who underwent thoracotomy after induction therapy. Median survival for all recruited patients (N = 53) was 18.9 months, with an estimated 1-year survival rate of 69%. CONCLUSION: In patients with N2 stage IIIA NSCLC, GC is a highly active and well-tolerated induction regimen. GC should be explored in combination with surgery or radiotherapy in stage I and II patients.

Recovery of overall and local lung function loss 18 months after irradiation for malignant lymphoma.

PURPOSE: To determine the local and overall pulmonary injury 3 to 18 months after irradiation and to investigate whether the changes in overall lung function can be predicted using the three-dimensional (3-D) dose distribution in combination with dose-effect relations for local injury; and to study the influence of chemotherapy on the injury. PATIENTS AND METHODS: Local perfusion (Q), ventilation (V), and tissue density were measured in 25 patients treated for malignant lymphoma, before, 3 to 4 months after, and 18 months after irradiation. Dose-effect relations for local injury, calculated using correlated single-photon emission computed tomographic (SPECT) and computed tomographic (CT) data, were combined with the 3-D dose distribution, to calculate the estimated mean local changes over the complete lung for each patient. The result was correlated with the actual changes in pulmonary function. RESULTS: A dose-dependent increase with injury was observed at 3 to 4 months after irradiation, which at 18 months had recovered by approximately 50% to 60%. The estimated mean relative reduction of local Q predicted the change in overall lung function within 10% of the actually observed values in 63% to 73% of patients. Chemotherapy given before radiotherapy enhanced radiation-induced reduction of local Q significantly, with dose-modifying factors of 1.22 and 1.37 at 3 to 4 months and 18 months, respectively. CONCLUSION: Partial recovery of radiation-induced reduction of local and overall lung function was observed at 18 months after irradiation. The overall functional outcome of most patients could be well predicted, based on the estimated mean local injury over the complete lung. Chemotherapy given before radiotherapy enhanced the radiation-induced reduction of local Q.

Two schedules of teniposide with or without cisplatin in advanced non-small-cell lung cancer: a randomized study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: We conducted a randomized trial to investigate the value of the addition of cisplatin to teniposide (VM26) and to investigate the schedule dependence of the topoisomerase II inhibitor VM26, in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Two hundred twenty-five NSCLC patients were randomized to receive VM26 120 mg/m2 on days 1, 3, and 5 or 360 mg/m2 on day 1 only, either as a single drug or in combination with cisplatin 80 mg/m2 on day 1. Cycles were repeated every 3 weeks. Response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. RESULTS: The response rate of the two cisplatin-containing arms was superior to that of the two arms that contained VM26 only (22% v 6%, P < .001); progression-free survival and survival times were also longer in the cisplatin-containing arms (median, 4.3 v 2.2 months, P = .003; median 7.2 v 5.9 months, P = .008, respectively). Toxicity was significantly higher in the cisplatin-containing arms; the most frequent side effects were leukopenia, nausea and vomiting, and alopecia. The schedule of VM26 did not significantly influence the response rate, progression-free survival interval, or survival duration. However, the response rate of the 1-day administration was significantly lower than that of the 3-day administration when given as single drugs. CONCLUSION: The addition of cisplatin to VM26 improves the response rate, progression-free survival interval, and survival duration over VM26 alone, although at the cost of a significant increase in toxicity. Cisplatin should be considered as the basis for combination chemotherapies in advanced NSCLC.