Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer.

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Phase II trial of ZD0473 as second-line therapy in mesothelioma.

A phase II, open-label, non-comparative, multicentre trial of the platinum analogue ZD0473 as second-line therapy for pleural mesothelioma has been completed. The objectives were to evaluate the activity and tolerability of ZD0473 in patients with relapsed or progressive disease who had received one prior chemotherapy regimen. Forty-seven patients were recruited onto the trial, all aged > 18 years with a life-expectancy > 12 weeks, and World Health Organization (WHO) performance status < or = 2. A starting dose of 120 mg/m2 was administered to 14 patients, six of whom subsequently had their dose escalated to 150 mg/m2. Thirty-three patients received a starting dose of 150 mg/m2. In total, 147 treatment cycles were administered (median number of cycles 3 [range 1-6]). The main toxicity of ZD0473 was haematological (thrombocytopenia) and the most common non-haematological adverse event was nausea. There was no clinically significant nephro-, neuro-, or oto-toxicity. Of the 43 patients evaluable for response, 12% had a minor response (defined by a reduction in lesion size > or = 10% but < 50%), 44% had stable disease, 40% had disease progression, and two patients died before an objective response could be assigned. Median time to progression and death in evaluable patients was 77 days (95% confidence interval [CI]: 44, 105 days) and 203 days (95% CI: 165, 277 days), respectively. In conclusion, although ZD0473 demonstrated a manageable tolerability profile, no complete or partial responses were seen in second-line treatment of mesothelioma. This trial also demonstrates that clinical trials in second-line mesothelioma patients are feasible.

Paclitaxel, carboplatin, and oral etoposide: a phase II trial in limited-stage small cell lung cancer.

Carboplatin/etoposide is an active regimen in the treatment of small cell lung cancer. This phase II trial evaluated whether adding paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this two-drug combination might increase its efficacy. Since April 1996, 55 patients were entered into the ongoing protocol. To date, 35 patients are evaluable for efficacy and toxicity. Most of the evaluable patients are male (28). The patients' median age is 60 years (range, 36 to 74 years); 32 patients have Eastern Cooperative Oncology Group performance status ratings of 1, and the balance are Eastern Cooperative Oncology Group performance status 0. All patients had limited-stage disease. Patients received paclitaxel 175 mg/m2 via 1-hour intravenous infusion on day 1, carboplatin dosed to an area under the concentration-time curve of 5, also on day 1, and oral etoposide 100 mg on days 2 through 8. Overall, 31 patients responded to paclitaxel/carboplatin/etoposide therapy, including complete response in 13 patients (37.1%) and partial response in 18 patients (51.4%). Disease was stable in three patients (8.6%) and disease progressed in one (2.0%). Hematologic toxicity included neutropenia (World Health Organization grade 3 in 24.1% of patients, grade 4 in 31.3%), anemia (4% grade 3, no grade 4), and thrombocytopenia (3.2% grade 3, 2.1% grade 4). Nonhematologic adverse events included minor nausea/vomiting (1.5% grade 3, 9.2% grade 2), polyneuropathy (2.3% grade 2, 17.5% grade 1), and myalgia/arthralgia (8.2% grade 2, 16.4% grade 1). Paclitaxel/carboplatin/etoposide is active in small cell lung cancer with moderate toxicity and good subjective tolerance. There were no life-threatening hematologic or nonhematologic complications in this phase II trial.

Phase III trial with and without lonidamine in non-small cell lung cancer.

One hundred eighty four patients with advanced inoperable non-small cell lung cancer were treated with either lonidamine (A), mitomycin-C/vindesine (B), or mitomycin-C/vindesine plus lonidamine (C) in a prospective randomized trial. The response rates for each treatment arm were 3.4% (A), 22.4% (B) and 25.9% (C), respectively. This difference is statistically significant (P less than 0.01). The median survival time for patients treated with mitomycin-C/vindesine and mitomycin-C/vindesine plus lonidamine was 194 days and 221 days, respectively. In comparison with 145 days for lonidamine alone there is a statistically significant difference in survival between the chemotherapy groups (P less than 0.01). When combined with mitomycin-C/vindesine, lonidamine induces an increase in the response rate and there is a higher proportion of patients living after 12 months of treatment (32% v 20%) in comparison to mitomycin-C/vindesine alone. The subjective tolerance of all treatment groups was very good, toxicity was only mild without major differences between the treatment arms. Combination chemotherapy with mitomycin-C/vindesine plus or minus lonidamine could prolong survival in advanced inoperable nonsmall cell lung cancer significantly without severe toxicity.

Ifosfamide, carboplatin and etoposide combined with 41.8 degrees C whole body hyperthermia for malignant pleural mesothelioma.

We performed a phase II study combining 41.8 degrees C whole body hyperthermia with ICE chemotherapy, i.e. ifosfamide (5 g/m(2)), carboplatin (300 mg/m(2)) and etoposide (150 mg/m(2) on days 2 and 3), administered every 4 weeks, for patients with malignant pleural mesothelioma. Of 27 chemonäive, non-metastatic patients enrolled, 25 patients were evaluable for response. Overall response rate was 20% (five partial remissions; 95% CI 8.9-39.1%). Median survival time from the start of treatment for all patients was 76.6 weeks (95% CI 65.4-87.8 weeks). Progression free survival for all patients measured 29.6 weeks (95% CI 24.4-34.7 weeks). One year overall survival was 68% and 2 year overall survival was 20%. Major treatment toxicities included grade 3/4 neutropenia and thrombocytopenia in 74 and 33% of treatment cycles, respectively. One patient died due to sepsis. These promising results are consistent with continued clinical investigation; a phase III clinical trial with whole body hyperthermia as the independent variable has been initiated.

Phase I study with combination therapy of pirarubicin, etoposide, and vincristine in small-cell lung cancer.

The toxicity and efficacy of the combination of pirarubicin (THP), etoposide, and vincristine were investigated in a phase I trial. The dose of THP was modified in steps of 10 mg/m2 or 5 mg/m2 differences, starting with 40 mg/m2 i.v. on day 1. Doses of etoposide (100 mg/m2 i.v. days 1-3) and vincristin 2 mg i.v. day 1) remained constant. The schedule was repeated every 3 weeks. A minimum of four patients were recruited at each dose level. The maximum tolerated dose (MTD) was defined as follows: toxicity WHO grade 3 and 4 in five of eight patients of one dose step (exception: leukocytopenia at the time of nadir WHO grade 4 is relevant for the MTD). Currently, 20 patients have been treated. The administered dose levels of THP were (mg/m2); 40 (5 patients), 50 (4 patients), 55 (6 patients), and 60 (5 patients). Screening of cardiac function (ECG, ultrasound cardiography) was performed at the start of the treatment and before each course. There were no signs of cardiotoxicity up to a cumulative dose of 360 mg/m2. Leukocytopenia WHO grade 3 was observed in seven courses (12%), and grade 4 was observed in two courses (3%) as main side effects. The subjective tolerability (nausea, vomiting, and alopecia) was mild to moderate. We decided upon 55 mg/m2 MTD because WHO grade 4 leukocytopenia developed in one patient after the first course and two not conclusively clarified early deaths occurred at the 60 mg/m2 pirarubicin dose level. Eighteen patients were evaluable for response: one CR (6%), eight PR (44%), four NC (22%), one EP (6%), and four ED (22%). This means a response rate of 50% and a median survival time of 10 months. We have initiated a phase II study with the elaborated schedule.

A randomized trial with mitomycin-C/ifosfamide versus mitomycin-C/vindesine versus cisplatin/etoposide in advanced non-small-cell lung cancer.

192 evaluable patients with advanced inoperable non-small-cell lung cancer were treated with either mitomycin-C/ifosfamide (A), mitomycin-C/vindesine (B), or cisplatin/etoposide (C) in a prospective randomized trial. The response rates for each treatment arm were 30.0% (A), 22.7% (B), and 25% (C), respectively. There was no statistically significant difference (p = 0.4) between treatment arms. The median survival time was 27 weeks (A), 23 weeks (B), and 25 weeks (C), respectively. With regard to toxicity the combination mitomycin-C/vindesine was superior to treatment arms A and C. Nausea and vomiting (WHO 3 + 4) occurred only in 6.1% of the patients versus 43.3% of those treated with mitomycin-C/ifosfamide and 36.7% of those treated with cisplatin/etoposide. This difference is statistically highly significant (p = 0.0001). Because of its very low toxicity, especially for gastrointestinal symptoms, the combination mitomycin-C/vindesine was judged superior to the other combinations. None of these regimens, however, had a major impact on survival in advanced non-small-cell lung cancer.

Lenograstim as support for ACE chemotherapy of small-cell lung cancer: a phase III, multicenter, randomized study.

This phase III study was conducted to evaluate the usefulness of lenograstim as support for ACE (doxorubicin, cyclophosphamide, and etoposide) chemotherapy in previously untreated patients with small-cell lung cancer. Patients were randomized to receive up to six 3-week cycles of either ACE alone (n = 139) or ACE with lenograstim support (150 microg/m2/day subcutaneously, days 4-13, n = 141). Compared with the chemotherapy-alone group, the lenograstim support group was more likely to achieve neutrophil recovery (absolute neutrophil count, > or =1.5 x 10(9) cells/l) by day 14 (95.8-100% vs. 14.3-24.1% across the cycles) and less likely to experience at least one infectious episode (36.7 vs. 54.0%; p = 0.004), chemotherapy delay (51.8 vs. 56.2%; NS), or dose reduction (17.3 vs. 27.7%; p = 0.037). Objective response and event-free and overall survival rates were similar. Lenograstim was well tolerated. Lenograstim may allow the interval between cycles of ACE to be reduced to 2 weeks; such dose intensification may lead to more favorable objective response and survival rates.

[Therapy of malignant pleural mesothelioma]. / Die Therapie des malignen Pleuramesothelioms.

The different therapeutical procedures of malignant pleura-mesothelioma are reviewed. A comparison of studies published so far is difficult or impossible because of the heterogeneity of the clientele and of the protocols. The median survival of untreated patients is 6 months from the date of diagnosis. Radical surgical treatment results in 2-year survival in 10-37%. As these data are not different from those of untreated patients, and additionally this procedure is associated with a perioperative mortality of 6-31%, the indication for radical resection has to be applied very critically. As pleuramesotheliomas are often resistant to radiotherapy, tumour remissions under this treatment are extremely rare. However, this therapy has a palliative analgesic benefit. Chemotherapy with anthracycline containing combinations leads to partial remissions in 20% and a median survival of 11 months. Whether multimodal therapeutical concepts are advantageous or not, will have to be established.

[Interactions of theophylline and H2 receptor antagonists. Interaction modes--clinical relevance]. / Interaktionen von Theophyllin und H2-Rezeptor-Antagonisten. Interaktionsbereiche--klinische Relevanz.

UNLABELLED: Basic considerations: peptic ulcers and obstructive diseases occur jointly, since cigarette smoking is an important causal factor in both diseases. Major topics: The interaction possibilities of theophylline and H2-receptor antagonists on the various levels from absorption to elimination of the two drugs are discussed, with emphasis being attached to oxidative breakdown in the liver. The clinical relevance of such interactions arises from the limited therapeutic spectrum of theophylline. CONCLUSIONS: Treatment with both drugs should take account of the varying tendency of the individual H2-receptor antagonists to interact.

[The diuresis of cyclic adenosine-3'5'-monophosphate (cAMP) in primary and secondary disorders of the parathyroid glands]. / Die Diurese von zyklischem Adenosin-3'5'-monophosphat (cAMP) bei primären und Sekundären Funktionsstörungen der Nebenschilddrüsen.

The diuresis of cAMP in primary hyperparathyroidism was significantly higher at 7.3 +/- 2.5 mumol/g creatinine X 24 h (P less than 0.005) than that in healthy subjects (3.5 +/- 0.7 mumol/g creatinine X 24 h). After successful operation on the parathyroid gland, cAMP diuresis usually decreased within 24 hours to normal or subnormal values. In primary or secondary hypoparathyroidism subnormal amounts of cAMP (P less than 0.005) were excreted. The method gives false-negative results in functional disorders of the parathyroid glands accompanied or caused by renal failure.

[Hemoperfusion--a therapeutic alternative to early treatment of acute lindane poisoning]. / Hämoperfusion--eine therapeutische Alternative zur Frühbehandlung der akuten Lindan-Intoxikation.

Rapid lowering of serum concentrations to subtoxic values was seen in a 16-year-old girl with acute intoxication with the organochloroinsecticide gamma-hexachlorocyclohexane to subtoxic values using haemoperfusion over amberlite XAD-4. In vitro, an extraction coefficient of 0,99 for gamma-hexachlorocyclohexane using amberlite XAD-4 was determined. On the basis of this experience haemoperfusion is recommended as effective treatment in the early phase of acute gamma-hexachlorocyclohexane intoxication.

[Chemotherapy of non-small cell bronchial cancer with mitomycin C, vindesine and cisplatin. Results of a phase II study]. / Chemotherapie des nicht-kleinzelligen Bronchialkarzinoms mit Mitomycin C, Vindesin und Cisplatin. Ergebnisse einer Phase-II-Studie.

Forty-five patients (39 male, 6 female) with inoperable non-small-cell lung cancer were treated with combined mitomycin C, vindesine and cisplatin. All patients had measurable disease and had no previously received chemotherapy. The performance status of all patients was over 60%. Twenty-one patients had limited, 24 extensive disease. The overall remission rate was 53.3% (3 complete and 21 partial remissions) with a median remission duration of 9 months. Adeno- and squamous cell carcinoma responded to the chemotherapy with a remission rate of 63% (7 out of 11 patients) and 58% (14 out of 24 patients), but there were only 30% responders in large cell carcinoma (3 out of 10 patients). The median survival time for responders was 12 months, for those with no change and for patients with progressive disease 6 months. Myelosuppression and renal toxicity of the combination was generally not a treatment problem; subjective tolerance, however, (gastrointestinal upset) was poor.

[Conservative, palliative therapy of malignant pleural mesothelioma]. / Konservative, palliative Therapie des malignen Pleuramesothelioms.

No effective conventional therapy for malignant pleural mesothelioma has yet been described. Radiotherapy does not increase median survival, but there is a palliative analgesic benefit. Chemotherapy with a different regimen in 182 patients led to a median survival time of 12 months. In comparison to an untreated historical group of 142 patients, there is an advantage in survival of 5 months. Additional surgical treatment has not prolonged the life expectancy. The percentage of long-time survivors was 5.5%.

[Multiple pulmonary leiomyomatosis hamartoma (author's transl)]. / Multiples pulmonales leiomyomatöses Hamartom.

The multiple pulmonary leiomyomatosis hamartoma (MPLH) is rare. Typical is the difference between the marked pulmonary alterations on chest X-ray film and the poor symptomatology. The (MPLH) is observed nearly only in women. The diagnosis is linked to pathological-histological findings.