Search

Four patients with massive pleural effusions due to pancreatic pseudocysts who were initially treated conservatively with percutaneous pleural drainage are described. In two patients the pleural effusions and the pancreatic pseudocysts disappeared, but two required surgery, in one case because conservative treatment failed and in the other at a later date for a recurrent pancreatic pseudocyst.

Carboplatin, a cisplatinum analogue, has no reported nephrotoxicity in phase I/II studies, assessed by creatinine clearance. We prospectively determined renal function in 10 untreated lung cancer patients with normal baseline renal function, treated with carboplatin 400 mg m-2 day 1 and vincristine 2 mg day 1 and 8 every 4 weeks (max. five cycles) by means of clearance studies with 125I-sodium thalamate and 131I-hippurate to determine GFR and ERPF respectively. Tubular damage was monitored by excretion of tubular enzymes and relative beta 2-microglobulin clearance. During the first course no changes in renal function were seen. After the second course a significant fall in GFR and ERPF started, ultimately leading to a median decrease in GFR of 19.0% (range 6.8-38.7%) and in ERPF of 14% (range 0-38.9%). No increases in the excretion of tubular enzymes or changes in the relative beta 2-microglobulin clearances were seen. We conclude from our data that carboplatin causes considerable loss of renal function. Monitoring renal function in patients treated with multiple courses of carboplatin is warranted.

Firstly, the effect of Vindesine was studied on four different human lung carcinoma cell lines (two small cell, one adeno and one squamous cell) with the Fast Green dye exclusion assay (FGA) and the clonogenic assay. Both methods demonstrate a clear dose response relationship and the estimated drug efficacy is similar for both assays. In the cell lines with the longest doubling time a plateau was reached in the FGA, most probably due to the short culture time in this assay. Secondly, the effect of Vindesine on human lung carcinoma specimens (N = 64), mainly bronchoscopy biopsies (n = 48), was evaluated with the FGA. The FGA has merits as predictive test in the clinic in the situation that only a small number of cells can be obtained. In this study, due to the high number of bronchoscopy biopsies only in a minority of cases a conclusion could be obtained (37.5%).

A phase I study with continuous administration of epirubicin for 21 days using a venous access port and a portable pump was performed. The first dose step was 2 mg/m2/d for 21 days. Interval between courses was 3 weeks. Dose increment per step was 1 mg/m2/d. Twenty-two patients entered the study and received a total of 58 courses with a median of two (range, one to nine). Up to 5 mg/m2/d no toxicity (according to World Health Organization [WHO] criteria) occurred. At 6 mg/m2/d (six pts), one patient had leukopenia grade 3. Two others had some hair loss. At 7 mg/m2/d (four patients), all patients developed mucositis (two grade 3). Three patients had bone marrow depression (one grade 3 anemia, one grade 4 leukocytopenia), and one patient developed the hand-foot syndrome. No other toxicity occurred in the patients. One patient obtained a partial response (18 weeks), ten had stable disease (12 to 54 weeks), seven had progressive disease, and four were not evaluable for response. One patient developed cellulitis around the port, responding to antibiotic treatment; one patient developed a vena cava superior syndrome that resolved with urokinase and removal of the access port. No septicemia occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with fluorometric detection. Plasma steady state was reached after 57 hours. During steady state there was a linear relationship between epirubicin dose administered and epirubicin level in plasma (r = .58, P less than .05), whole blood (r = .75, P less than .005), and in leukocytes (r = .68, P less than .05). The area under the curve in leukocytes was higher with continuous infusion of 6 mg/m2 for 21 days compared with bolus injection of 80 mg/m2. This method of continuous infusion with epirubicin may be a way to increase intracellular drug-uptake as expressed by intracellular area under curve (AUC). We recommend 6 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.

Two new, good growing cell lines (GLC- 8 , GLC- 11 ) have been established from biopsies of small cell lung cancer (SCLC). Tumor biopsies were procured by rigid bronchoscopy from tumor recurrences at the site of the primary lesions. Both tumors were clinically resistant to chemotherapy. Cytogenetic analysis revealed deletions in the short arm of chromosome 3 . GLC- 8 shows amplification of N-myc. Both cell lines show SCLC differentiations; neurosecrotory granules were present and the SCLC related hormones dopa-decarboxylase and creatine kinase were elevated. Both cell lines behave as so-called ‘classic’ SCLC cell lines.

In 13 patients with therapy-resistant solid tumors the feasibility of high-dose cyclophosphamide (7 g/m2) in combination with increasing doses of VP 16-213 with autologous bone marrow transplantation was studied. Dose-limiting extramedullary toxicity appeared to be mucositis and occurred after 2.5 g/m2. Two toxic deaths were observed in patients older than 55 yr. Responses were seen in eight out of nine evaluable patients. Two patients with ovarian cancer still have no signs of disease progression after 12+ months. High-dose cyclophosphamide (7 g/m2) can be combined with VP 16-213 1.5 g/m2 without important extramedullary toxicity. Age is probably a limiting factor for this kind of therapy.

In this review we will discuss some aspects of chemotherapy in elderly patients with cancer, with special emphasis on SCLC

A prospective study with mild general analgesia and sedation together with local anesthesia during bone marrow harvest was performed. Thirty-one patients underwent 33 bone marrow collections. Pretreatment consisted of 100 mg meperidine i.m. and 20 mg diazepam i.m. 1 h before start of procedure. Eight patients got additional meperidine and diazepam during the procedure, all patients got lidocaine 1% locally. A mean volume of 1.321 was obtained with 42.5 punctures. Twenty-two patients had no complications, 4 vomited, 4 had easily correctable hypotension of short duration, one got oxygen for cyanosis of short duration. Acceptance was good in 23 patients, in 6 reasonably well, in two bad. Only one patient experienced pain problems, due to suction. Anxiety was no major problem due to good information before the procedure and mild sedation. This form of anesthesia for bone marrow collection is a safe procedure, it is generally well accepted by the patient and it can be performed on an out-patient basis.

Symptomatic brain metastases are found in about 40% of patients with small cell lung cancer.Cranial irradiation is the first line treatment for this form of metastatic disease. Frequently brain metastases recur after this treatment or develop after prophylactic cranial irradiation. For these patients no effective antitumour therapy is available. In this study the efficacy of high dose etoposide 1.5 gm-2 was evaluated. In 10 (43%) out of 23 evaluable patients a response was seen. Toxicity was severe with five aplasia-related deaths. For palliative purposes this regimen is too toxic in heavily pretreated patients.

Thirty five previously untreated patients with small cell lung cancer older than 70 years were treated with oral etoposide (800 mg/m2 over five consecutive days) every four weeks. Twenty two patients had extensive disease and 13 limited disease. The overall response rate was 71%. The median survival for patients with limited diseases was 16 (range 6-32) months and for patients with extensive disease nine (range 4-17) months. There was mild haematological toxicity and alopecia but no major toxicity. It is concluded that etoposide in this dose regimen is an effective and well tolerated treatment for elderly patients with small cell lung cancer.

In 13 patients an open window thoracostomy (OWT) was performed for post pneumonectomy pleural empyema. The operation, and life with an OWT cavity, were tolerated well. Early closure of an OWT is not advisable because of a high chance of recurrence of the infection and, in lung cancer patients also the risk of tumour relapse within two years after tumour surgery.

In 37 patients with small cell lung cancer treatment with five cycles of cyclophosphamide, doxorubicin and etoposide (CDE), resulted in 23 complete (CR) and 14 partial responses (PR). Median response duration was 34 weeks. At relapse all patients were retreated with CDE. In 23 (62%) patients this gave a second response (6 CR, 17 PR). Factors influencing the occurrence of a second response were: 1. a CR after the first five cycles of CDE; 18 out of 23 CR patients responded again whereas only five of the 14 PR patients responded (P less than 0.01). 2. 15 out of 19 patients with a first response duration greater than 34 weeks reached a second response and in eight of the other 18 patients retreatment was successful (P less than 0.05). Reinduction at relapse, after short term chemotherapy and a treatment-free interval, with the induction regimen is an effective second line treatment in patients with an initial CR and a first response duration of greater than 34 weeks.

VP 16-213 in standard doses is active against a number of solid tumors. Its penetration into the cerebrospinal fluid (CSF) is very limited at these dose levels. In 10 patients treated with high-dose VP 16-213 (0.9-2.5 g/m2), CSF levels of up to 0.54 microgram/mL were detected. In two patients with central nervous system (CNS) metastases of small cell lung cancer (SCLC) a response was seen after 1.0 and 1.5 g/m2 intravenously. High-dose VP 16-213 can possibly play a role in the treatment of CNS metastases of SCLC. Its application in late intensification regimens as a form of prophylaxis of CNS metastases should be investigated.

We present two patients with benign endobronchial tumours: polypi and a chondroma. Both were treated by Neodymium-YAG laser photoresection. There have been no signs of recurrence in the four years since treatment. Endobronchial resection by Neodymium-YAG laser is an effective treatment for benign endobronchial tumours.

Autologous platelets were harvested and cryopreserved in eight consecutive patients elected for ablative chemotherapy and autologous bone marrow transplantation (ABMT) for solid malignancy. There was a 19% loss in platelet count after the freeze thaw and wash procedure; with an in vitro functional loss of 40–60%. No correlation could be found for individual platelet transfusions between in vitro functional tests and in vivo recovery. Six consecutive patients received a total of 16 autologous platelet transfusions in the aplastic phase of ABMT. No bleeding was observed during the study period and there was no CMV infection in the recipients. While improvement in freezing and subsequent handling is desirable, autologous cryopreserved platelets can safely be used for the prophylaxis of bleeding during aplasia in patients treated with ABMT.

A total of 28 previously treated patients with small-cell lung cancer were treated at relapse with 400 mg/m2 carboplatin and 2 mg vincristine on days 1 and 8, every 4 weeks. Ten partial responses (PRs) (37%) but no complete responses (CRs) were seen. Median survival after the start of second-line treatment was 120 days (range, 39-503 days). Toxicity of this regimen was moderate, including WHO grade 3/4 myelosuppression in 26% of courses (n = 66). Eight PRs were seen in a subgroup of 22 patients who relapsed less than 3 months after first-line treatment. The responses seen in this group of patients may be due to the absence of cross-resistance between the regimens used.

The natural resistance of a fraction of cells in a tumor to a conventional dose of chemotherapy can partly be overcome by high dose (HD) chemotherapy [1]. HD chemotherapy may kill more tumor cells but could also cause long lasting or irreversible bone marrow aplasia.

Two patients with persistent minimal ovarian cancer after conventional polychemotherapy were treated with high doses of cyclophosphamide and VP 16-213 followed by autologous bone marrow infusion. Ten months afterward no clinical signs of tumor were apparent. In one patient the complete response was surgically documented. Toxicity included cardiac and pulmonary arrest during marrow infusion in one patient, but was otherwise manageable. This method of late intensification of chemotherapy in patients with persisting ovarian cancer merits further investigation.

Radiolabeled MOC-31 retains its immunoreactivity and shows good in vivo immunolocalization to human SCLC xenografted in nude rats.We evaluated the immunotargeting properties and safety of 111In-labeled monoclonal antibody (MAb) MOC-31 (125 MBq, 5 mg) in six patients with histologically proven small-cell lung cancer (SCLC). Scintigraphy and pharmacokinetics were performed up to 3 days after injection.No adverse reactions were found after injection of MAb MOC-31. Pharmacokinetics obtained from plasma radioactivity showed plasma disappearance described most properly by a monoexponential model with a mean half-life value of 17.0 +/- 1.4 hr. HPLC analysis documented the monomeric MOC-31 without evidence of immune complexes or radioactive lower molecular weight fractions. Mean 24-hr urinary excretion of radioactivity was 4.3% of the injected dose. Scintigraphy detected primary tumor or metastases in five of six patients. Localization of radioactivity in normal tissue was restricted, but additional experiments need to be performed to elucidate possible cross-reactivity of MOC-31 with normal tissue in vivo.Preliminary results justify further studies to reveal the possible usefullness of radiolabeled MOC-31 in the therapeutic and diagnostic management of SCLC.

BACKGROUND: We have modified a polymerase chain reaction (PCR)-aided transcript titration assay (1) in order to allow quantitation of low amounts of DNA topoisomerase II alpha mRNA in small RNA samples. EXPERIMENTAL DESIGN: The titration assay was used to quantitate the amount of DNA topoisomerase II alpha mRNA in a human small cell lung carcinoma cell line, GLC(4) and its drug-resistant sublines, GLC(4)/ADR and GLC(4)/CDDP. These cell lines show differences in DNA topoisomerase II alpha protein level and DNA topoisomerase II enzyme activity. To validate the titration assay, the results were compared with the results of a DNA topoisomerase II enzyme activity assay and DNA topoisomerase II alpha northern and western blotting assays. RESULTS: Using the titration assay, we were able to quantitate DNA topoisomerase II alpha mRNA on a picogram level starting with less than 1 mu g of total RNA/cell line. GLC(4)/ADR showed a markedly decreased DNA topoisomerase II alpha mRNA level that seemed to be unchanged in GLC(4)/CDDP when compared with the parental cell line. The results obtained with this assay are confirmed by the western blot data and are not in contradiction with the northern blot results obtained for the three cell lines. CONCLUSIONS: The DNA topoisomerase II alpha titration assay is a highly sensitive new technique to study the role of DNA topoisomerase II alpha in drug resistance and may help to identify cancer types and patients most likely to respond to DNA topoisomerase II targeted drugs. The decrease in DNA topoisomerase II alpha protein level and DNA topoisomerase II activity in GLC(4)/ADR may result from transcriptional down regulation of DNA topoisomerase II alpha.

The evaluation of the activity of new drugs against small cell lung cancer (SCLC) is discussed and the results with gemcitabine are presented. Gemcitabine has activity against untreated SCLC. Preliminary results from an ongoing study also indicate activity in so-called resistant SCLC.

We have modified a polymerase chain reaction (PCR)-aided transcript titration assay (1) in order to allow quantitation of low amounts of DNA topoisomerase II alpha mRNA in small RNA samples.The titration assay was used to quantitate the amount of DNA topoisomerase II alpha mRNA in a human small cell lung carcinoma cell line, GLC4 and its drug-resistant sublines, GLC4/ADR and GLC4/CDDP. These cell lines show differences in DNA topoisomerase II alpha protein level and DNA topoisomerase II enzyme activity. To validate the titration assay, the results were compared with the results of a DNA topoisomerase II enzyme activity assay and DNA topoisomerase II alpha northern and western blotting assays.Using the titration assay, we were able to quantitate DNA topoisomerase II alpha mRNA on a picogram level starting with less than 1 micrograms of total RNA/cell line. GLC4/ADR showed a markedly decreased DNA topoisomerase II alpha mRNA level that seemed to be unchanged in GLC4/CDDP when compared with the parental cell line. The results obtained with this assay are confirmed by the western blot data and are not in contradiction with the northern blot results obtained for the three cell lines.The DNA topoisomerase II alpha titration assay is a highly sensitive new technique to study the role of DNA topoisomerase II alpha in drug resistance and may help to identify cancer types and patients most likely to respond to DNA topoisomerase II targeted drugs. The decrease in DNA topoisomerase II alpha protein level and DNA topoisomerase II activity in GLC4/ADR may result from transcriptional down regulation of DNA topoisomerase II alpha.

Background - A retrospective review was undertaken of the survival of 21 patients with histologically proven small cell carcinoma of the lung resected between 1977 and 1991. Methods - Twenty one patients (20 men) of median age 60 (range 44-73) years underwent surgical resection. Patients were subjected to standard clinical staging procedures. Preoperative diagnosis was small cell carcinoma of the lung in 13, non-small cell lung cancer in one, and uncertain in seven patients. Clinical staging was stage I disease in 11 and stage II in 10 patients. Results - Resection included pneumonectomy in 12 cases, lobectomy in eight, and one wedge resection. Resection was complete in 16 patients. Postoperative histopathological examination confirmed small cell carcinoma of the lung in 19 specimens and mixed small cell and nonsmall cell carcinoma of the lung in two. Pathological staging was stage I in 11, stage II in three, and stage III in seven patients. The final pathological diagnosis of the resected specimens (n=18) was atypical carcinoid in one, pure small cell carcinoma of the lung in 15, and mixed small cell and non-small cell carcinoma of the lung in two patients. Fourteen patients also received chemotherapy and 10 received prophylactic cranial irradiation postoperatively. Excluding the patient with a final diagnosis of atypical carcinoid, the median survival (n=20) was 29 months (range two to 133+). Median survival for patients with pathological stage I and II disease (n=13) was 40 months (range nine to 133+) and for patients with pathological stage III disease (n=7) 20 months (range two to 116+). The median disease free survival was 23 months. Eleven patients relapsed between two and 101 months. There was no advantage for those patients who received postoperative chemotherapy. Conclusion - Curative resection offers the best chance for long term survival in patients with small cell carcinoma of the lung with very limited stage disease.

Radiolabeled MOC-31 retains its immunoreactivity and shows good in vivo immunolocalization to human SCLC xenografted in nude rats. Methods: We evaluated the immunotargeting properties and safety of In-111-labeled monoclonal antibody (MAb) MOC-31 (125 MBq, 5 mg) in six patients with histologically proven small-cell lung cancer (SCLC). Scintigraphy and pharmacokinetics were performed up to 3 days after injection. Results: No adverse reactions were found after injection of MAb MOC-31. Pharmacokinetics obtained from plasma radioactivity showed plasma disappearance described most properly by a monoexponential model with a mean half-life value of 17.0 +/- 1.4 hr. HPLC analysis documented the monomeric MOC-31 without evidence of immune complexes or radioactive lower molecular weight fractions. Mean 24-hr urinary excretion of radioactivity was 4.3% of the injected dose. Scintigraphy detected primary tumor or metastases in five of six patients. Localization of radioactivity in normal tissue was restricted, but additional experiments need to be performed to elucidate possible cross-reactivity of MOC-31 with normal tissue in vivo. Conclusion: Preliminary results justify further studies to reveal the possible usefullness of radiolabeled MOC-31 in the therapeutic and diagnostic management of SCLC.

A phase I study of teniposide administered orally for 5 consecutive days was performed. The first dose was 60 mg/m2/d, with increments of 25 mg/m2/d. Nineteen patients entered the study and received a total of 77 courses with a median of two (range, 1 to 12). Dose-limiting toxicity occurred at 160 mg/m2/d and consisted of myelosuppression, mainly leukocytopenia, and gastrointestinal toxicity. Sufficient recovery of blood counts was seen by day 21 to allow for a repeat course. Two patients, treated with teniposide doses of 110 and 160 mg/m2/d, respectively, were considered toxic deaths. Partial alopecia was frequent at doses above 85 mg/m2/d. Retching and vomiting during administration of the drug were encountered in virtually all patients. Oral teniposide 135 mg/m2/d for 5 consecutive days on a 3-week schedule is recommended for evaluation of antitumor efficacy in phase II studies.

Patients with locally advanced non-small cell lung cancer (NSCLC) may be treated with induction chemotherapy (IC) followed by surgery with curative intent. The impact of staging inaccuracies on the failure rate of this intensive combined modality treatment approach, i.e. non-curative chemotherapy and thoracotomy, requires further investigation.The records of a cohort of 38 consecutive NSCLC IIIA-N2 patients treated with IC followed by surgery were reviewed.The clinical course strongly suggested that the standard diagnostic algorithm failed to demonstrate stage IV disease in 34% of the cases. Surgery instigated by CT-based response criteria at restaging after chemotherapy proved to be irradical in 70% of cases.Our data confirm the limitations of the current work-up of patients with apparently locally advanced NSCLC. This applies to the selection of patients to be assigned to combined modality treatment as well as to the post-chemotherapy assessment of resectability. Improved (re)staging of these patients will enhance the efficiency of intervention trials and prevent patients from being exposed to intensive and toxic therapy from which they derive no benefit.

This report describes the validation of a polymerase chain reaction aided transcript titration assay (PATTY) for tumor samples. The results obtained with the PATTY were compared to those of RNase protection in a set of 7 human lung cancer cell lines and in 23 non-small cell lung cancer samples derived from resected patients. Whereas between PATTY and RNase protection assay a good correlation was observed in the cell lines (r = 0.74, p = 0.057), no correlation was observed within the tumor samples (r = 0.06, p = 0.78). This was also the case when only tumors with a high percentage of tumor cells (90%) were selected. Although PATTY is a valuable tool to measure mRNA expression in cell lines, our results caution the use of PATTY in human tumor samples without proper validation. The possible causes of these results are discussed.

To determine the effect of prophylactic cranial irradiation (PCI) in patients with extensive-disease small-cell lung cancer (ED-SCLC) who responded to chemotherapy.Randomised, controlled clinical trial; phase III study (EORTC nr 08993-22993; www.clinicaltrials.gov, nr NCT00016211).Patients aged 18-75 years with a functional status according to WHOor = 2, and with ED-SCLC and any response to chemotherapy, were randomized to observation (standard care) or PCI. The primary endpoint was time to symptomatic brain metastases. If any pre-defined, key symptom suggesting brain metastases presented, a CT or MRI scan of the brain was performed. The size of the study (143 patients per arm) was determined to detect a hazard ratio (HR) of 0.44 at 80% power with 2-sided alpha = 0.05.The study accrued 286 patients. PCI decreased the risk of developing symptomatic brain metastases (HR = 0.27 (95% CI: 0.16-0.44; p0.001)). The cumulative incidence of developing brain metastases within 1 year was 40% in the control group (95% CI: 32-49) and 15% in the PCI group (95% CI: 8-21). PCI prolonged disease-free (HR = 0.76; 95% CI: 0.59-0.96, p = 0.02) and overall survival (HR = 0.68; 95% CI; 0.52-0.88, p = 0.003). The 1-year survival rate was 27% (95% CI: 19-36) for the PCI group versus 13% (95% CI: 8-20) for controls. Acute and late treatment toxicity was acceptable. These side effects did not significantly impact on quality of life.PCI significantly reduced the incidence of symptomatic brain metastases and prolonged both disease-free and overall survival and should be part of standard care in SCLC patients who respond to chemotherapy.

INTRODUCTION IN A high percentage of SCLC patients, central nervous system (CNS) metastases are found and this usually results in considerable morbidity and mortality [ 11. This is especially the case in patients with meningeal carcinomatosis (MC). The incidence of MC in SCLC has been reported to be between 5 and 18%. With prolongation of survival , the chance of MC becoming symptomatic is rapidly increasing [ 11. The results of therapy for this devastating form of metastatic disease have been rather poor. After high-dose cyclophosphamide and etoposide with autologous bone marrow transplantation [2] and in a phase I study of etoposide [3], favourable responses of brain metastases from SCLC were found. In this report we describe the effect of highdose etoposide (HDE) in five patients with MC from SCLC.

Lobus venae azygos was found in five out of 12 members of one family. There is vertical transmission of the abnormality through three generations. The mode of inheritance is probably autosomal dominant.